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Articles 31 - 60 of 796

Full-Text Articles in Medical Specialties

The Lysine Demethylase Kdm4c Is An Oncogenic Driver And Regulates Erk Activity In Kras-Mutant Pancreatic Ductal Adenocarcinoma, Menna-T-Allah Shaheen, Sarah Dhebat, Kimal I Rajapakshe, Bidyut Ghosh, Benson Chellakkan Selvanesan, Shariq S Ansari, Cara L Haymaker, Dorsay Sadeghian, Huamin Wang, Ching-Fei Li, Haoqiang Ying, Anirban Maitra Jan 2026

The Lysine Demethylase Kdm4c Is An Oncogenic Driver And Regulates Erk Activity In Kras-Mutant Pancreatic Ductal Adenocarcinoma, Menna-T-Allah Shaheen, Sarah Dhebat, Kimal I Rajapakshe, Bidyut Ghosh, Benson Chellakkan Selvanesan, Shariq S Ansari, Cara L Haymaker, Dorsay Sadeghian, Huamin Wang, Ching-Fei Li, Haoqiang Ying, Anirban Maitra

Faculty, Staff and Student Publications

Deregulation of proteins involved in chromatin regulation is common in pancreatic ductal adenocarcinoma (PDAC). Lysine demethylase 4C (KDM4C) is one of the chromatin-modifying proteins frequently overexpressed across multiple solid cancers and is linked to chromatin instability, increased cell proliferation, and enhanced stem cell–like behavior. We observed upregulation of KDM4C protein in a panel of human PDAC cell lines and patient samples compared with nonneoplastic controls. CRISPR/Cas9-mediated deletion of KDM4C in human and murine PDAC cells reduced proliferation, clonogenicity, and increased survival of orthotopically implanted murine PDAC allografts. Transcriptomic and proteomic analyses revealed that loss of KDM4C in both human and …

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Engineering Mutation Clones In Mammalian Cells With Crispr/Cas9, Zijun Huo, Jian Tu, Rachel Shoemaker, Dung-Fang Lee, Ruiying Zhao Jan 2026

Engineering Mutation Clones In Mammalian Cells With Crispr/Cas9, Zijun Huo, Jian Tu, Rachel Shoemaker, Dung-Fang Lee, Ruiying Zhao

Faculty, Staff and Student Publications

CRISPR, Clustered Regularly Interspaced Short Palindromic Repeat, as a powerful genome engineering system, has been widely accepted and employed in gene editing of a vast range of cell types. Compared to zinc finger nucleases (ZFNs) or transcription activator-like effector nucleases (TALENs), CRISPR shows a less complicated process and higher efficiency. With the development of different CRISPR systems, it can be used not only to knock out a gene but also to make precise modifications, activate or repress target genes with epigenetic modifications, and even for genome wide screening. Here we will describe the procedure of generating a stable cell line …

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Nsd2 Inhibitors Rewire Chromatin To Treat Lung And Pancreatic Cancers, Jinho Jeong, Simone Hausmann, Hanyang Dong, Kacper Szczepski, Natasha M Flores, Andy Garcia Gonzalez, Liyang Shi, Xiaoyin Lu, Joanna Lempiäinen, Moritz Jakab, Liyong Zeng, Tourkian Chasan, Eric Bareke, Rui Dong, Emma Carlson, Reinnier Padilla, Dylan Husmann, Julia Thompson, Gerry A Shipman, Emily Zahn, Courtney A Barnes, Laiba F Khan, Liz Marie Albertorio-Sáez, Eva Brill, Vishnu Udayakumar Sunita Kumary, Matthew R Marunde, Danielle N Maryanski, Cheryl C Szany, Bryan J Venters, Carolina Lin Windham, Michal Eligiusz Nowakowski, Iwona Czaban, Mariusz Jaremko, Michael-Christopher Keogh, Kang Le, Michael J Soth, Benjamin A Garcia, Łukasz Jaremko, Jacek Majewski, Pawel K Mazur, Or Gozani Jan 2026

Nsd2 Inhibitors Rewire Chromatin To Treat Lung And Pancreatic Cancers, Jinho Jeong, Simone Hausmann, Hanyang Dong, Kacper Szczepski, Natasha M Flores, Andy Garcia Gonzalez, Liyang Shi, Xiaoyin Lu, Joanna Lempiäinen, Moritz Jakab, Liyong Zeng, Tourkian Chasan, Eric Bareke, Rui Dong, Emma Carlson, Reinnier Padilla, Dylan Husmann, Julia Thompson, Gerry A Shipman, Emily Zahn, Courtney A Barnes, Laiba F Khan, Liz Marie Albertorio-Sáez, Eva Brill, Vishnu Udayakumar Sunita Kumary, Matthew R Marunde, Danielle N Maryanski, Cheryl C Szany, Bryan J Venters, Carolina Lin Windham, Michal Eligiusz Nowakowski, Iwona Czaban, Mariusz Jaremko, Michael-Christopher Keogh, Kang Le, Michael J Soth, Benjamin A Garcia, Łukasz Jaremko, Jacek Majewski, Pawel K Mazur, Or Gozani

Faculty, Staff and Student Publications

NSD2 catalyses the epigenetic modification H3K36me2 (refs. 1,2) and is a candidate convergent downstream effector of oncogenic signalling in diverse malignancies3–5. However, it remains unclear whether the enzymatic activity of NSD2 is therapeutically targetable. Here we characterize a series of clinical-grade small-molecule catalytic NSD2 inhibitors (NSD2i) and show that the pharmacological targeting of NSD2 constitutes an epigenetic dependency with broad therapeutic efficacy in KRAS-driven preclinical cancer models. NSD2i inhibits NSD2 with single-digit nanomolar half-maximal inhibitory concentration potency and high selectivity over related methyltransferases. Structural analyses reveal that the specificity of NSD2i for NSD2 …

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Nampt Inhibition Uncovers Therapeutic Vulnerabilities To Venetoclax And Chemotherapy In Acute Myelogenous Leukemia, John R Sanchez, Chaomei Liu, Vishakha Pawar, Yanqing Huang, Daisy Diaz-Rohena, Jyotsana Singh, Priya Koppikar, Tzung-Huei Lai, Lisa St John, Vinay Puduvalli, Jeffrey Molldrem, Palaniraja Thandapani, Nitin Jain, Rosa Lapalombella, Deepa Sampath Jan 2026

Nampt Inhibition Uncovers Therapeutic Vulnerabilities To Venetoclax And Chemotherapy In Acute Myelogenous Leukemia, John R Sanchez, Chaomei Liu, Vishakha Pawar, Yanqing Huang, Daisy Diaz-Rohena, Jyotsana Singh, Priya Koppikar, Tzung-Huei Lai, Lisa St John, Vinay Puduvalli, Jeffrey Molldrem, Palaniraja Thandapani, Nitin Jain, Rosa Lapalombella, Deepa Sampath

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) cells depend on nicotinamide adenine dinucleotide (NAD

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Prickle4 Drives Microenvironmental Remodeling And Resistance To Parp Inhibition In Idh-Mutant Glioma, Ju Yang, Hua Yang, Yifan Yuan, Chenyang Zhang, Ziwei Fu, Yanyan Chen, Yinghong Xiong, Shuyu Chen, Kexin Ling, Ying Liu, Jason T Huse, Bo Chen, Timothy A Chan, Zengxin Qi, Zhao Zhang, Xiuping Liu, Yuxiang Wang Jan 2026

Prickle4 Drives Microenvironmental Remodeling And Resistance To Parp Inhibition In Idh-Mutant Glioma, Ju Yang, Hua Yang, Yifan Yuan, Chenyang Zhang, Ziwei Fu, Yanyan Chen, Yinghong Xiong, Shuyu Chen, Kexin Ling, Ying Liu, Jason T Huse, Bo Chen, Timothy A Chan, Zengxin Qi, Zhao Zhang, Xiuping Liu, Yuxiang Wang

Faculty, Staff and Student Publications

Mutations in isocitrate dehydrogenase (IDH) genes sensitize gliomas to PARP inhibition (PARPi) by inducing epigenetic reprogramming of DNA damage repair circuits. However, tumors treated with PARPi eventually relapse despite initial responsiveness. In this study, it is demonstrated that the anti-angiogenic agent lenvatinib synergizes effectively with PARPi, resulting in substantial tumor regression and significantly extended survival. Genomic analysis of tumors reveals that PARPi induces widespread transcriptomic changes that are predominantly pro-inflammatory, thereby promoting tumor angiogenesis. Prickle4, a planar cell polarity protein, is identified as a critical mediator of PARPi-induced neovascularization. Targeting Prickle4 effectively overcomes PARPi resistance in these tumors. Collectively, these …

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Batf2 Is A Glutamine-Responsive Tumour Suppressor Required For Type-I Interferon-Dependent Anti-Tumour Immunity, Wang Gong, Hülya F Taner, Yuesong Wu, Yumin He, Xingwu Zhou, Zaiye Li, Xin Hu, Charisse Ursin, Kala Chand Debnath, Kohei Okuyama, Qiang Hu, Christopher R Donnelly, Felipe Nör, Chamila D Perera, Emily Bellile, Arash Yunesi, Zhiqian Zhai, Mei Zhao, Wanqing Cheng, Zackary R Fitzsimonds, Luke Broses, Jiaqian Li, Shadmehr Demehri, Deepak Nagrath, Gregory T Wolf, Andrew G Sikora, Yanbao Yu, Haitao Wen, Lei Wei, Steven B Chinn, Jeffrey N Myers, Shizuo Akira, Yuying Xie, James J Moon, Yu Leo Lei Dec 2025

Batf2 Is A Glutamine-Responsive Tumour Suppressor Required For Type-I Interferon-Dependent Anti-Tumour Immunity, Wang Gong, Hülya F Taner, Yuesong Wu, Yumin He, Xingwu Zhou, Zaiye Li, Xin Hu, Charisse Ursin, Kala Chand Debnath, Kohei Okuyama, Qiang Hu, Christopher R Donnelly, Felipe Nör, Chamila D Perera, Emily Bellile, Arash Yunesi, Zhiqian Zhai, Mei Zhao, Wanqing Cheng, Zackary R Fitzsimonds, Luke Broses, Jiaqian Li, Shadmehr Demehri, Deepak Nagrath, Gregory T Wolf, Andrew G Sikora, Yanbao Yu, Haitao Wen, Lei Wei, Steven B Chinn, Jeffrey N Myers, Shizuo Akira, Yuying Xie, James J Moon, Yu Leo Lei

Faculty, Staff and Student Publications

Recent evidence highlights the significance of a new type of tumour suppressors, which are not frequently mutated but inhibited by metabolic cues in cancers. Here, we identify BATF2 as a tumour suppressor whose expression is epigenetically silenced by glutamine in Head and Neck Squamous Cell Carcinomas (HNSCC). BATF2 correlates with type-I interferon and Th1 signatures in human HNSCC, with correlation coefficients even stronger than those of the positive control, STING. The phosphorylation of BATF2 at serine 227 promotes the oligomerization of STING. BATF2 deficiency or high glutamine levels result in higher oxygen consumption rates and metabolic profiles unfavorable for …

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Eif3d And Eif3e Mediate Selective Translational Control Of Hypoxia That Can Be Inhibited By Small Molecules, Stephen C Purdy, Kate Matlin, Christopher Alderman, Amber Baldwin, Natasha Shrivastava, Goksu Sarioglu, Somnath Dutta, Kristofor J Webb, Arthur Wolin, Dillon P Boulton, Annika Gustafson, Jyoti Kapali, John D Landua, Michael T Lewis, M Cecilia Caino, James C Costello, William Old, Xiang Wang, Rui Zhao, Heide L Ford, Neelanjan Mukherjee Dec 2025

Eif3d And Eif3e Mediate Selective Translational Control Of Hypoxia That Can Be Inhibited By Small Molecules, Stephen C Purdy, Kate Matlin, Christopher Alderman, Amber Baldwin, Natasha Shrivastava, Goksu Sarioglu, Somnath Dutta, Kristofor J Webb, Arthur Wolin, Dillon P Boulton, Annika Gustafson, Jyoti Kapali, John D Landua, Michael T Lewis, M Cecilia Caino, James C Costello, William Old, Xiang Wang, Rui Zhao, Heide L Ford, Neelanjan Mukherjee

Faculty, Staff and Students Publications

Exposure to hypoxia is linked to increased cellular plasticity and enhanced metastasis, effects that are primarily attributed to the transcriptional activation of large gene programs downstream of hypoxia-inducible factors (HIFs). However, translational effects in hypoxia, which likely precede transcriptional effects, have remained largely unexplored. Using ribosome profiling, we uncovered a selective translational response in acute hypoxia that is eukaryotic initiation factor (eIF)3d/eIF3e dependent and controls downstream hypoxic responses, including HIF1α accumulation and cellular invasion. We further demonstrated that eIF3e copy number and eIF3e and eIF3d expression signatures are associated with worsened outcomes for patients with breast cancer. Finally, we identified …

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Sox11 Modulates Bcr Signaling Through The Pax5/Cd19 Axis For Therapeutic Targeting In Btk-Resistant Mantle Cell Lymphoma, Rudra Prasad Dutta, Heng-Huan Lee, Violetta V Leshchenko, Ravi Prakash Shukla, Fangfang Yan, Yang Liu, H Ümit Kaniskan, Xing Qiu, Jian Jin, Lapo Alinari, Michael Wang, Samir Parekh Dec 2025

Sox11 Modulates Bcr Signaling Through The Pax5/Cd19 Axis For Therapeutic Targeting In Btk-Resistant Mantle Cell Lymphoma, Rudra Prasad Dutta, Heng-Huan Lee, Violetta V Leshchenko, Ravi Prakash Shukla, Fangfang Yan, Yang Liu, H Ümit Kaniskan, Xing Qiu, Jian Jin, Lapo Alinari, Michael Wang, Samir Parekh

Faculty, Staff and Student Publications

Mantle cell lymphoma (MCL) is an incurable subtype of B-cell non-Hodgkin lymphoma. Despite multiple approved Bruton tyrosine kinase inhibitors (BTKis), resistance to BTKi continues to pose a major clinical challenge. The transcription factor sex determining region Y-box 11 (SOX11) is expressed in most patients with MCL and is associated with poor outcomes. We have previously demonstrated SOX11-dependent B-cell receptor (BCR) signaling in transgenic models of MCL. Here, we report that SOX11 drives BCR signaling via the transcriptional activation of the PAX5/CD19 axis. The translational potential of these results is significant as single-cell RNA sequencing data show that SOX11 is overexpressed …

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Vesicle-Mediated Mitochondrial Clearance Presents An Actionable Metabolic Vulnerability In Triple-Negative Breast Cancer, Jody Vykoukal, Yihui Chen, Mingxin Zuo, Riccardo Ballarò, Monica J Hong, Hansini Krishna, Daniela B Rodriquez-Perera, Hiroyuki Katayama, Ehsan Irajizad, Ranran Wu, Ricardo A León-Letelier, Jennifer B Dennison, Angelica M Gutierrez, Adriana Paulucci-Holthauzen, Timothy C Thompson, Leona Rusling, Yining Cai, Fu Chung Hsiao, Soyoung Park, Banu Arun, Samir Hanash, Johannes F Fahrmann Dec 2025

Vesicle-Mediated Mitochondrial Clearance Presents An Actionable Metabolic Vulnerability In Triple-Negative Breast Cancer, Jody Vykoukal, Yihui Chen, Mingxin Zuo, Riccardo Ballarò, Monica J Hong, Hansini Krishna, Daniela B Rodriquez-Perera, Hiroyuki Katayama, Ehsan Irajizad, Ranran Wu, Ricardo A León-Letelier, Jennifer B Dennison, Angelica M Gutierrez, Adriana Paulucci-Holthauzen, Timothy C Thompson, Leona Rusling, Yining Cai, Fu Chung Hsiao, Soyoung Park, Banu Arun, Samir Hanash, Johannes F Fahrmann

Faculty, Staff and Student Publications

Selective autophagy of mitochondria is known to promote cancer cell survival and progression, including in triple-negative breast cancer (TNBC). Here, we apply an integrated multi-omics approach together with functional experimental analyses to investigate metabolic adaptations that support mitochondrial quality control in TNBC. We detail a mitochondrial quality control mechanism, complementary to mitophagy, that is enabled by a program of heightened extracellular sphingomyelin salvaging in TNBC coupled with extracellular vesicle-mediated intracellular clearance of mitochondrial damage. Targeting of this onco-metabolic pathway via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase, results in ceramide-mediated compensatory mitophagy and cancer cell death …

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Lung Adenocarcinoma Surfaceome Remodeling With Egfr Inhibitors Uncovers Placental Alkaline Phosphatase As A Target For Combination Therapy, Yihui Chen, Rongzhang Dou, Monica J Hong, Hanwen Xu, Jody Vykoukal, Ricardo A León-Letelier, Yining Cai, Soyoung Park, Ehsan Irajizad, Fu Chung Hsiao, Jennifer B Dennison, Edwin J Ostrin, Johannes F Fahrmann, Hiroyuki Katayama, Samir M Hanash Dec 2025

Lung Adenocarcinoma Surfaceome Remodeling With Egfr Inhibitors Uncovers Placental Alkaline Phosphatase As A Target For Combination Therapy, Yihui Chen, Rongzhang Dou, Monica J Hong, Hanwen Xu, Jody Vykoukal, Ricardo A León-Letelier, Yining Cai, Soyoung Park, Ehsan Irajizad, Fu Chung Hsiao, Jennifer B Dennison, Edwin J Ostrin, Johannes F Fahrmann, Hiroyuki Katayama, Samir M Hanash

Faculty, Staff and Student Publications

Treatment of lung adenocarcinomas (LUADs) that exhibit activated epidermal growth factor receptor (EGFR) with EGFR tyrosine kinase inhibitors (TKIs) has limited efficacy. Assessment of the impact of EGFR TKI on the LUAD surfaceome remodeling reveals potential therapeutic targets. We identify placental type alkaline phosphatase (ALPP), which has restricted expression in normal tissues, among upregulated surface proteins following EGFR TKI treatment of both TKI sensitive as well as resistant cells. EGF treatment represses ALPP expression, whereas EGFR TKIs upregulate its expression through dephosphorylation and activation of FoxO3a, a transcriptional regulator that binds to the promoter region of ALPP. The combination of …

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Targeting Kinesin Family Member 20a Sensitizes Stem-Like Triple-Negative Breast Cancer Cells To Standard Chemotherapy, Yayoi Adachi, Weilong Chen, Cheng Zhang, Tao Wang, Nina Gildor, Rachel Shi, Haoyong Fu, Masashi Takeda, Qian Liang, Fangzhou Zhao, Hongyi Liu, Jun Fang, Jin Zhou, Hongwei Yao, Lianxin Hu, Shina Li, Lei Guo, Lin Xu, Ling Xie, Xian Chen, Chengheng Liao, Qing Zhang Dec 2025

Targeting Kinesin Family Member 20a Sensitizes Stem-Like Triple-Negative Breast Cancer Cells To Standard Chemotherapy, Yayoi Adachi, Weilong Chen, Cheng Zhang, Tao Wang, Nina Gildor, Rachel Shi, Haoyong Fu, Masashi Takeda, Qian Liang, Fangzhou Zhao, Hongyi Liu, Jun Fang, Jin Zhou, Hongwei Yao, Lianxin Hu, Shina Li, Lei Guo, Lin Xu, Ling Xie, Xian Chen, Chengheng Liao, Qing Zhang

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC), being both aggressive and highly lethal, poses a major clinical challenge in terms of treatment. Its heterogeneity and lack of hormone receptors or HER2 expression further restrict the availability of targeted therapy. Breast cancer stem cells (BCSCs), known to fuel TNBC malignancy, are now being exploited as a vulnerability for TNBC treatment. Here, we dissected the transcriptome of BCSCs and identified kinesin family member 20A (KIF20A) as a key regulator of BCSC survival and TNBC tumorigenesis. Genetic depletion or pharmacological inhibition of KIF20A impairs BCSC viability and tumor initiation and development in vitro and in vivo. …

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Actin Dysregulation Induces Neuroendocrine Plasticity And Immune Evasion: A Vulnerability Of Small Cell Lung Cancer, Yoojeong Seo, Shengzhe Zhang, Jinho Jang, Kyung-Pil Ko, Kee-Beom Kim, Yuanjian Huang, Dong-Wook Kim, Bongjun Kim, Gengyi Zou, Jie Zhang, Sohee Jun, Wonhong Chu, Nicole A Kirk, Ye Eun Hwang, Young Ho Ban, Shilpa S Dhar, Joseph M Chan, Min Gyu Lee, Charles M Rudin, Kwon-Sik Park, Jae-Il Park Dec 2025

Actin Dysregulation Induces Neuroendocrine Plasticity And Immune Evasion: A Vulnerability Of Small Cell Lung Cancer, Yoojeong Seo, Shengzhe Zhang, Jinho Jang, Kyung-Pil Ko, Kee-Beom Kim, Yuanjian Huang, Dong-Wook Kim, Bongjun Kim, Gengyi Zou, Jie Zhang, Sohee Jun, Wonhong Chu, Nicole A Kirk, Ye Eun Hwang, Young Ho Ban, Shilpa S Dhar, Joseph M Chan, Min Gyu Lee, Charles M Rudin, Kwon-Sik Park, Jae-Il Park

Faculty, Staff and Student Publications

Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. Capping protein inhibiting regulator of actin dynamics (CRACD) that promotes actin polymerization, is frequently inactivated in SCLC. However, the role of CRACD loss in SCLC is unknown. Here we show that CRACD depletion drives neuroendocrine (NE) cell plasticity and immune evasion in SCLC. Mechanistically, CRACD inactivation disrupts actin organization, leading to suppression of Yap1-NOTCH signaling and subsequent NE gene upregulation. Simultaneously, CRACD loss drives EZH2-mediated histone methylation via nuclear actin disruption, leading to repression of MHC-I genes and depletion of CD8⁺ T cells. Consequently, CRACD-downregulated tumors exhibit …

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Hsp90 Buffers Deleterious Genetic Variations In Brca1, Brant Gracia, Xing-Han Zhang, Patricia Montes, Tin Chanh Pham, Min Huang, Junjie Chen, Georgios Ioannis Karras Dec 2025

Hsp90 Buffers Deleterious Genetic Variations In Brca1, Brant Gracia, Xing-Han Zhang, Patricia Montes, Tin Chanh Pham, Min Huang, Junjie Chen, Georgios Ioannis Karras

Faculty, Staff and Student Publications

Protein-folding chaperone heat shock protein 90 (HSP90) buffers genetic variation in diverse organisms, but the clinical significance of HSP90 buffering in human disease remains unclear. Here, we show that HSP90 buffers mutations in the BRCT domain of BRCA1. HSP90-buffered BRCA1 mutations result in protein variants that retain interactions with partner proteins and strongly rely on HSP90 for protein stability and function in cell survival. Moreover, HSP90-buffered BRCA1 variants confer poly (ADP-ribose) polymerase (PARP) inhibitor resistance in cancer cells. Low-level HSP90 inhibition overcomes this resistance, revealing a cryptic and mutant-specific HSP90-contingent synthetic lethality. Furthermore, by stabilizing metastable variants across the entirety …

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Hif-2-Dependent Regulation Of Pthrp And Paraneoplastic Hypercalcemia In Aggressive Clear-Cell Renal Cell Carcinoma, Arijit Mal, Bingqing Xie, Zane Gray, Charlotte Small, Susmita G Ramanand, Yunpeng Gao, Vanina Toffessi Tcheuyap, Sashi Debnath, Alana Christie, Jeffrey Miyata, Brooklyn Jackson, Hua Zhong, Boning Gao, Jay Lohrey, Naim M Maalouf, Sangeetha M Reddy, John D Minna, Ivan Pedrosa, Xiankai Sun, Ram S Mani, Payal Kapur, James Brugarolas Dec 2025

Hif-2-Dependent Regulation Of Pthrp And Paraneoplastic Hypercalcemia In Aggressive Clear-Cell Renal Cell Carcinoma, Arijit Mal, Bingqing Xie, Zane Gray, Charlotte Small, Susmita G Ramanand, Yunpeng Gao, Vanina Toffessi Tcheuyap, Sashi Debnath, Alana Christie, Jeffrey Miyata, Brooklyn Jackson, Hua Zhong, Boning Gao, Jay Lohrey, Naim M Maalouf, Sangeetha M Reddy, John D Minna, Ivan Pedrosa, Xiankai Sun, Ram S Mani, Payal Kapur, James Brugarolas

Faculty, Staff and Student Publications

Renal cell carcinoma (RCC) patients with hypercalcemia (HC) have worse outcomes. HC often involves PTHrP, and the role of HIF-2 is incompletely understood. Leveraging RCC tumorgraft (TG) models of HC, which were characterized by tumor cell autonomous inflamatory/immune signatures, we show that HIF-2 inhibition with PT2399 frequently normalized calcium, downregulated circulating PTHrP and reduced HIF-2 binding to the PTHLH (PTHrP) promoter. Likely contributing to the selective induction of PTHrP in a subset of HIF-2-dependent tumors, the PTHLH locus was generally more accessible in TG(HC). However, PTHLH chromatin accessibility was grossly unaffected by PT2399, unlike elsewhere (including EPO locus in a …

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Derivation Of Pluripotent Stem Cell Lines (Rfsci005-A, Rfsci006-A) From Siblings Harboring Identical High-Risk Complement Variants With Discordant Age-Related Macular Degeneration, Naresh Rajendran, Ajeet Singh, Wendy Runyon, Sam Hu, Ritu Kumar, Rinki Ratnapriya, Karl Csaky, Srinivasa R Sripathi Dec 2025

Derivation Of Pluripotent Stem Cell Lines (Rfsci005-A, Rfsci006-A) From Siblings Harboring Identical High-Risk Complement Variants With Discordant Age-Related Macular Degeneration, Naresh Rajendran, Ajeet Singh, Wendy Runyon, Sam Hu, Ritu Kumar, Rinki Ratnapriya, Karl Csaky, Srinivasa R Sripathi

Faculty, Staff and Students Publications

Age-related macular degeneration (AMD) is a complex disease influenced by genetic and environmental factors. Variants in the complement pathway, especially in the CFH gene, increase AMD risk, yet disease severity can differ among individuals with identical high-risk genotypes. We generated induced pluripotent stem cell (iPSC) lines from siblings carrying identical high-risk complement variants but displaying discordant AMD phenotypes. These lines provide a unique platform to study epigenetic, transcriptomic, and environmental factors driving AMD heterogeneity. By comparing differentiated retinal cells, we aim to reveal mechanisms behind variable disease susceptibility and inform personalized therapies for AMD.

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The Microstructure Of Metastatic Bone Lesions Suggests Tumor Mediated Alterations In Bone Mineralization, Hanwen Fan, Zhan Xu, Carla Berrospe Rodriguez, Noah Dover, Andrei Demkov, Morgan Lilly, Guillermo Aguilar, Larry J Suva, Xiang H-F Zhang, Yuxiao Zhou Dec 2025

The Microstructure Of Metastatic Bone Lesions Suggests Tumor Mediated Alterations In Bone Mineralization, Hanwen Fan, Zhan Xu, Carla Berrospe Rodriguez, Noah Dover, Andrei Demkov, Morgan Lilly, Guillermo Aguilar, Larry J Suva, Xiang H-F Zhang, Yuxiao Zhou

Faculty, Staff and Students Publications

Breast, prostate and lung cancer cells frequently metastasize to bone, leading to disruption of the bone microstructure. This study utilized mechanical testing coupled with micro-CT imaging, digital volume correlation (DVC), and atomic force microscopy (AFM) nanomechanical testing to examine the mechanical property variations in mouse long bones (tibia) with metastatic lung cancer cell involvement, spanning from the whole-bone scale to the microstructural level. In addition, we also investigated how metastatic invasion alters the morphology of hydroxyapatite nanocrystals in bone at the nanometer scale. The biochemical composition within metastatic lesions was assessed using Raman spectroscopy and correlated with AFM mechanical testing …

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A Class Of Benzofuranoindoline-Bearing Heptacyclic Fungal Ripps With Anticancer Activities, Qiuyue Nie, Fanglong Zhao, Xuerong Yu, Mithun C Madhusudhanan, Caleb Chang, Siting Li, Sandipan Roy Chowdhury, Bryce Kille, Andy Xu, Rory Sharkey, Chunxiao Sun, Hongzhi Zeng, Shuai Liu, Dishu Zhou, Xin Yu, Kevin Yang, Sandra A C Figueiredo, Maria Zotova, Zichen Hu, Alan Y Du, Dongyin Guan, Rui Tang, Todd Treangen, Jin Wang, Pedro N Leão, Yang Gao, Junjie Chen, Peng Liu, Hans Renata, Xue Gao Dec 2025

A Class Of Benzofuranoindoline-Bearing Heptacyclic Fungal Ripps With Anticancer Activities, Qiuyue Nie, Fanglong Zhao, Xuerong Yu, Mithun C Madhusudhanan, Caleb Chang, Siting Li, Sandipan Roy Chowdhury, Bryce Kille, Andy Xu, Rory Sharkey, Chunxiao Sun, Hongzhi Zeng, Shuai Liu, Dishu Zhou, Xin Yu, Kevin Yang, Sandra A C Figueiredo, Maria Zotova, Zichen Hu, Alan Y Du, Dongyin Guan, Rui Tang, Todd Treangen, Jin Wang, Pedro N Leão, Yang Gao, Junjie Chen, Peng Liu, Hans Renata, Xue Gao

Children’s Nutrition Research Center Staff Publications

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a promising source of new pharmaceuticals, yet the therapeutic potential of fungal RiPPs remains largely underexplored. Here, we report asperigimycins as a distinct class of fungal RiPPs, featuring a unique heptacyclic scaffold consisting of a benzofuranoindoline core and three additional macrocycles, primarily assembled by six distinct fungi-specific DUF3328 oxidases. Inspired by the enhancement of anticancer activity through the N-terminal pyroglutamate in naturally occurring asperigimycins C and D, we chemically modify the inactive asperigimycin B with a series of lipid substitutions at its N-terminus. A derivative with a C-11 linear fatty …

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Tumor Intrinsic Mettl5 Modulates Atf4 Translation To Prevent T Cell-Induced Ferroptosis In Ovarian Cancer, Jiakai Hou, Cheng-Wei Ju, Nicholas A Egan, Yanjun Wei, Yunfei Wang, Minghao Dang, Tianyi Zhou, Leilei Shi, Ningbo Zheng, Si Chen, Ashley M Guerrero, Xiaofang Liang, Wanfu Wu, Areej Akhtar, Chitra Dhiman, Debanwita Roy Burman, Andro E Gerges, Mason D Flores, Han Li, Li-Sheng Zhang, Marleen Kok, Xiaobo Mao, Linghua Wang, Qin Feng, Yiwen Chen, Sanghoon Lee, Daniel J Mcgrail, Nidhi Sahni, Chuan He, Amir A Jazaeri, Weiyi Peng Dec 2025

Tumor Intrinsic Mettl5 Modulates Atf4 Translation To Prevent T Cell-Induced Ferroptosis In Ovarian Cancer, Jiakai Hou, Cheng-Wei Ju, Nicholas A Egan, Yanjun Wei, Yunfei Wang, Minghao Dang, Tianyi Zhou, Leilei Shi, Ningbo Zheng, Si Chen, Ashley M Guerrero, Xiaofang Liang, Wanfu Wu, Areej Akhtar, Chitra Dhiman, Debanwita Roy Burman, Andro E Gerges, Mason D Flores, Han Li, Li-Sheng Zhang, Marleen Kok, Xiaobo Mao, Linghua Wang, Qin Feng, Yiwen Chen, Sanghoon Lee, Daniel J Mcgrail, Nidhi Sahni, Chuan He, Amir A Jazaeri, Weiyi Peng

Faculty, Staff and Student Publications

Poor clinical responses to immune checkpoint blockade (ICB) observed in ovarian cancer (OC) highlight an unmet need to understand the mechanisms driving immune evasion in this disease. To address this, an integrative analysis is conducted by combining in vitro genome‐wide immune screens, in vivo ICB screens, and clinical data mining, and METTL5 is identified as a crucial OC‐intrinsic factor that promotes immune resistance. Immunologically “cold” OC tumors and poor responders to ICB exhibit elevated METTL5 expression. Mechanistically, knocking out (KO) METTL5 in OC disrupts ATF4 translation by altering 18S rRNA m6A levels, leading to the downregulation of SLC7A11 and SLC3A2 …

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Kras Inhibition Activates An Actionable Cd24 "Do Not Eat Me" Signal In Pancreatic Cancer, Yongkun Wei, Minghui Liu, Er-Yen Yen, Jun Yao, Zhenzhen Xun, Phuoc T Nguyen, Xiaofei Wang, Zecheng Yang, Abdelrahman Yousef, Dean Pan, Yanqing Jin, Ching-Fei Li, Madelaine S Theardy, Jangho Park, Yiming Cai, Mitsunobu Takeda, Matthew Vasquez, Elizabeth M Park, David H Peng, Yong Zhou, Hong Zhao, Timothy P Heffernan, Andrea Viale, Huamin Wang, Stephanie S Watowich, Han Liang, Dan Zhao, Ronald A Depinho, Wantong Yao, Haoqiang Ying Dec 2025

Kras Inhibition Activates An Actionable Cd24 "Do Not Eat Me" Signal In Pancreatic Cancer, Yongkun Wei, Minghui Liu, Er-Yen Yen, Jun Yao, Zhenzhen Xun, Phuoc T Nguyen, Xiaofei Wang, Zecheng Yang, Abdelrahman Yousef, Dean Pan, Yanqing Jin, Ching-Fei Li, Madelaine S Theardy, Jangho Park, Yiming Cai, Mitsunobu Takeda, Matthew Vasquez, Elizabeth M Park, David H Peng, Yong Zhou, Hong Zhao, Timothy P Heffernan, Andrea Viale, Huamin Wang, Stephanie S Watowich, Han Liang, Dan Zhao, Ronald A Depinho, Wantong Yao, Haoqiang Ying

Faculty, Staff and Student Publications

KRASG12C inhibitors (G12Ci) have produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment is therefore crucial. To better understand the function of KRASG12C and possible G12Ci bypass mechanisms, we developed an autochthonous KRASG12C-driven PDAC model. Compared to the classical KRASG12D PDAC model, the G12C model exhibits slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRASG12C tumors produced modest impact despite stimulating a ‘hot’ tumor immune microenvironment. Immunoprofiling revealed that CD24, a ‘don’t eat me’ signal, is significantly upregulated on cancer …

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Caspase 3-Specific Cleavage Of Ubiquitin-Specific Peptidase 48 Enhances Drug-Induced Apoptosis In Aml, Zhanglin Zhang, Xiang Lin, Yaling Yang, Xuemei Wang, Yi Wang, Xianbao Huang, Miao Hong, Wei Gao, Hua He, M James You, Yi Yang, Guangyao Kong Dec 2025

Caspase 3-Specific Cleavage Of Ubiquitin-Specific Peptidase 48 Enhances Drug-Induced Apoptosis In Aml, Zhanglin Zhang, Xiang Lin, Yaling Yang, Xuemei Wang, Yi Wang, Xianbao Huang, Miao Hong, Wei Gao, Hua He, M James You, Yi Yang, Guangyao Kong

Faculty, Staff and Student Publications

Dysfunction or dysregulation of deubiquitination is closely related to the initiation and development of multiple cancers. Targeted regulation of deubiquitination has been recognized as an important strategy in tumor therapy. However, the mechanism by which drugs regulate deubiquitinase is not clear. Here, we identified ubiquitin-specific peptidase 48 (USP48), a member of the ubiquitin-specific protease family highly expressed in various tumors, as a specific substrate for the activated caspase-3. During drug induced apoptosis of AML cells, activated caspase-3 cleaves USP48 through recognizing the conservative motif DEQD located at 611-614 sites of human USP48. Subsequent analysis showed that the cleavage USP48 N-terminal …

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Periostin Promotes Sarcoma Growth By Promoting Tumor-Associated Macrophage Migration And Differentiation, Jin-Fen Xiao, Kristin Ishaya, Emily Y Ko, Annaliese Fowler, Marina T Broz, Jlenia Guarnerio Dec 2025

Periostin Promotes Sarcoma Growth By Promoting Tumor-Associated Macrophage Migration And Differentiation, Jin-Fen Xiao, Kristin Ishaya, Emily Y Ko, Annaliese Fowler, Marina T Broz, Jlenia Guarnerio

Faculty, Staff and Student Publications

Soft-tissue sarcomas (STS) are characterized by abundant extracellular matrix (ECM) deposition, yet the functional contribution of specific ECM components remains poorly understood. In this study, we identify periostin (POSTN), a matricellular protein, as a regulator of sarcoma progression and the tumor immune microenvironment. Analysis of human sarcoma datasets revealed that high POSTN expression correlates with poor prognosis and elevated expression of ECM-related and myeloid cell–associated genes. In murine genetic models of sarcoma, tumors expressing high levels of Postn displayed enhanced expression of ECM genes and monocyte-recruiting cytokines. Functional silencing of Postnin vivo reduced tumor growth without altering tumor cell …

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The Deubiquitinating Enzyme Cezanne Stabilizes Brca1 By Counteracting Apc/C And Ube2s-Dependent Lys11-Linked Ubiquitination, Longqiang Wang, Xiao Wu, Atanu Paul, Jun Yao, Bin Wang Dec 2025

The Deubiquitinating Enzyme Cezanne Stabilizes Brca1 By Counteracting Apc/C And Ube2s-Dependent Lys11-Linked Ubiquitination, Longqiang Wang, Xiao Wu, Atanu Paul, Jun Yao, Bin Wang

Faculty, Staff and Student Publications

The breast and ovarian tumor suppressor BRCA1 is a cell cycle-regulated protein and tumors with reduced BRCA1 protein level may share molecular features of BRCA1-mutant tumor and respond to PARPi therapy. Here, we identify that BRCA1 protein stability is controlled through ubiquitin lysine 11 (K11)-linkage modification under the regulation of Cezanne deubiquitinating enzyme, APC/C E3 ligase, and Ube2S E2 conjugating enzyme in a cell cycle-dependent manner. Cezanne-deficiency leads to increased BRCA1 K11-ubiquitination, decreased BRCA1 protein level, and increased cellular sensitivity to PARPi. The BRCA1 K11-linked ubiquitination is carried out through a degron on BRCA1 that is recognized by APC/C cofactor …

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Targeting The Hepatic Circadian Clock Concomitant With Tyrosine Kinase Inhibition Reverses Late-Stage Hepatocellular Carcinoma, Baharan Fekry, Savera Aggarwal, Rachel Van Drunen, Rafael Bravo, Andy Escalante, Constance Atkins, Sheng Pan, Zheng Chen, Kai Sun, David R Hall, Mamoun Younes, Kristin Eckel-Mahan Nov 2025

Targeting The Hepatic Circadian Clock Concomitant With Tyrosine Kinase Inhibition Reverses Late-Stage Hepatocellular Carcinoma, Baharan Fekry, Savera Aggarwal, Rachel Van Drunen, Rafael Bravo, Andy Escalante, Constance Atkins, Sheng Pan, Zheng Chen, Kai Sun, David R Hall, Mamoun Younes, Kristin Eckel-Mahan

Faculty, Staff and Student Publications

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. Most patients present at advanced stages, and the effectiveness of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors is constrained by limited patient response. A subset of HCC shows elevated expression of the promoter 2 ("P2")-driven hepatocyte nuclear factor 4 alpha (HNF4α) isoform, which directly transcriptionally represses the circadian brain and muscle ARNT-like protein 1 (BMAL1) transcription factor. This subtype of HCC is robustly inhibited by the plant-based flavonoid nobiletin (NOB), a circadian-fortifying compound. Using patient-matched human HCC and serum, we show that BMAL1-deficient HCC shows exaggerated carnitine palmitoyl transferase …

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Naphthalimide-Based Type-I Nano-Photosensitizers For Enhanced Antitumor Photodynamic Therapy: H2s Synergistically Regulates Pet And Self-Assembly, Huiyu Niu, Songnan Wang, Yang Liu, Nana Ma, Shuaiwei Cheng, Beidou Feng, Hyunsun Jeong, Yonggang Yang, Ge Wang, Tony D James, Juyoung Yoon, Jonathan L Sessler, Hua Zhang Nov 2025

Naphthalimide-Based Type-I Nano-Photosensitizers For Enhanced Antitumor Photodynamic Therapy: H2s Synergistically Regulates Pet And Self-Assembly, Huiyu Niu, Songnan Wang, Yang Liu, Nana Ma, Shuaiwei Cheng, Beidou Feng, Hyunsun Jeong, Yonggang Yang, Ge Wang, Tony D James, Juyoung Yoon, Jonathan L Sessler, Hua Zhang

Faculty, Staff and Student Publications

Photodynamic therapy (PDT) relies on a combination of light and photosensitizers (PSs) to achieve local control over cancerous lesions. However, it is subject to limitations, including tumor hypoxia, low tumor targeting, off‐target phototoxicity, and always‐on fluorescence. Here, we propose a design strategy for activated nano‐PSs (N‐PSs) to simultaneously overcome the limitations of PDT, wherein photoinduced electron transfer (PeT) is coupled with an endogenous H2S‐regulated self‐association process to promote Type‐I photochemical reactions. Using theoretical calculations, spectral analysis, and microscopic imaging, we verified the generation of self‐assembly and occurrence of PeT. And it was also shown that H2S could synergistically inhibit the …

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Tca Cycle Mode Switch Determines The Fate Of Pirtobrutinib-Tolerant Persister Cells In Mantle Cell Lymphoma, Wei Wang, Qingsong Cai, Yang Liu, Lei Nie, Heng-Huan Lee, Fangfang Yan, Yue Fei, Yixin Yao, Yijing Li, Lin Tan, Philip L Lorenzi, Ying-Nai Wang, Jun Yao, Zhihong Chen, Joseph Mitchell Mcintosh, Cheng-Tai Yu, Preetesh Jain, Vivian C Jiang, Jovanny Vargas, Xiaolin Li, Tianci Zhang, Shaoying Li, David Santos, Selvi Thirumurthi, Erin Heather Seeley, Lukas Mikolaj Simon, Christopher Flowers, Chi Young Ok, Michael Wang Nov 2025

Tca Cycle Mode Switch Determines The Fate Of Pirtobrutinib-Tolerant Persister Cells In Mantle Cell Lymphoma, Wei Wang, Qingsong Cai, Yang Liu, Lei Nie, Heng-Huan Lee, Fangfang Yan, Yue Fei, Yixin Yao, Yijing Li, Lin Tan, Philip L Lorenzi, Ying-Nai Wang, Jun Yao, Zhihong Chen, Joseph Mitchell Mcintosh, Cheng-Tai Yu, Preetesh Jain, Vivian C Jiang, Jovanny Vargas, Xiaolin Li, Tianci Zhang, Shaoying Li, David Santos, Selvi Thirumurthi, Erin Heather Seeley, Lukas Mikolaj Simon, Christopher Flowers, Chi Young Ok, Michael Wang

Faculty, Staff and Student Publications

Bruton tyrosine kinase inhibitors (BTKis) and cell therapy have successfully been used to treat mantle cell lymphoma (MCL). However, therapy resistance inevitably emerges. Cancer cells can progressively develop stable resistance by traversing through a transient drug-tolerant persister (DTP) state. The mechanisms enabling DTP cells to reversibly adapt to therapies and evolve to acquire heterogeneity remain poorly understood, and characterizing DTP cells in MCL continues to pose a challenge for clinic translation. Here, using pirtobrutinib, a recently US Food and Drug Administration-approved noncovalent BTKi, we identified pirtobrutinib-tolerant persister cells exhibiting morphological variability by presenting a unique population of enlarged cells (giant …

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Genome-Wide Discovery Of Multiple Sclerosis Genetic Risk Variant Allelic Regulatory Activity, Marissa Granitto, Lois Parks, Molly S Shook, Carmy Forney, Xiaoting Chen, Lee E Edsall, Omer A Donmez, Sreeja Parameswaran, Kristen S Fisher, Aram Zabeti, Lucinda P Lawson, Matthew T Weirauch, Leah C Kottyan Nov 2025

Genome-Wide Discovery Of Multiple Sclerosis Genetic Risk Variant Allelic Regulatory Activity, Marissa Granitto, Lois Parks, Molly S Shook, Carmy Forney, Xiaoting Chen, Lee E Edsall, Omer A Donmez, Sreeja Parameswaran, Kristen S Fisher, Aram Zabeti, Lucinda P Lawson, Matthew T Weirauch, Leah C Kottyan

Faculty, Staff and Students Publications

Multiple sclerosis is an immune-mediated demyelinating disease of the central nervous system with a complex etiology involving environmental and genetic factors. Numerous genetic risk loci for multiple sclerosis have been nominated through genome-wide association studies, with most associated variants residing in noncoding regions. However, further work is needed to understand how genetic variation contributes to disease-related alterations to gene expression. Here, we use Massively Parallel Reporter Assays to identify genetic risk variants with genotype-dependent enhancing or silencing activity within a set of 14,275 variants distributed among multiple sclerosis risk loci that have reached genome-wide or suggestive significance. We applied our …

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Preclinical Efficacy Of Tasquinimod-Based Combinations In Advanced Myeloproliferative Neoplasms In Blastic Phase, Warren Fiskus, Lucia Masarova, Christopher P Mill, Christine E Birdwell, Kaberi Das, Hanxi Hou, John A Davis, Antrix Jain, Anna Malovannaya, Taghi Manshouri, Andrew Dunbar, Surbhi Sharma, Tapan M Kadia, Courtney D Dinardo, Prithviraj Bose, Naveen Pemmaraju, Sanam Loghavi, Xiaoping Su, Raajit K Rampal, Marie Törngren, Kapil N Bhalla Nov 2025

Preclinical Efficacy Of Tasquinimod-Based Combinations In Advanced Myeloproliferative Neoplasms In Blastic Phase, Warren Fiskus, Lucia Masarova, Christopher P Mill, Christine E Birdwell, Kaberi Das, Hanxi Hou, John A Davis, Antrix Jain, Anna Malovannaya, Taghi Manshouri, Andrew Dunbar, Surbhi Sharma, Tapan M Kadia, Courtney D Dinardo, Prithviraj Bose, Naveen Pemmaraju, Sanam Loghavi, Xiaoping Su, Raajit K Rampal, Marie Törngren, Kapil N Bhalla

Faculty, Staff and Students Publications

The alarmins, S100A8 (A8) and S100A9 (A9), are low molecular weight proteins belonging to the S100 protein family. A8 and A9 are secreted into the extracellular space and plasma, in which they interact with Toll-like receptor 4, receptor for advanced glycation end products, and CD33. In these studies, we determined the preclinical efficacy of tasquinimod (TQ) against advanced myeloproliferative neoplasm (MPN) cell lines and patient-derived (PD) CD34+ blastic phase (BP; >5% blasts in the peripheral blood) MPN cells. TQ induced loss of viability in cell lines and PD MPN-BP cells, but not in normal CD34+ progenitor cells. In TQ-treated PD …

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Reprogramming Tumor Microenvironment Via Systemic Delivery Of Tlr3 Agonist And Manganese Nanoparticle, Young Seok Cho, Xingwu Zhou, Xiaoqi Sun, Ziye Wan, Julia Crowther, Mariko Takahashi, Swetha Kodamasimham, Qi Wu, May Thazin Phoo, Youngseo Na, Kai Han, Zaiye Li, Anna Schwendeman, Steven P Schwendeman, Yu Leo Lei, James J Moon Nov 2025

Reprogramming Tumor Microenvironment Via Systemic Delivery Of Tlr3 Agonist And Manganese Nanoparticle, Young Seok Cho, Xingwu Zhou, Xiaoqi Sun, Ziye Wan, Julia Crowther, Mariko Takahashi, Swetha Kodamasimham, Qi Wu, May Thazin Phoo, Youngseo Na, Kai Han, Zaiye Li, Anna Schwendeman, Steven P Schwendeman, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Toll-like receptor (TLR) agonists, as potent immunostimulatory adjuvants, play a critical role in linking the innate and adaptive immune responses. However, their antitumor effects as cancer immunotherapeutic agents have been limited. Here, we report our finding that manganese ion (Mn2+) potentiates various TLR agonists, leading to robust activation of the TLR pathway and the stimulator of interferon genes (STING) pathway among innate immune cells. In particular, we have observed robust antitumor efficacy after intratumoral administration of a TLR3 agonist and Mn2+. To achieve systemic codelivery of TLR3 agonist and Mn2+, we have developed a low-molecular-weight poly(inosinic:cytidylic acid)-Mn2+ coordination lipid nanoparticle …

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Genome-Wide Crispr Screens Identify Critical Targets To Enhance Car-Nk Cell Antitumor Potency, Alexander Biederstädt, Rafet Basar, Jeong-Min Park, Nadima Uprety, Rejeena Shrestha, Francia Reyes Silva, Merve Dede, John Watts, Sunil Acharya, Donghai Xiong, Bin Liu, May Daher, Hind Rafei, Pinaki Banerjee, Ping Li, Sanjida Islam, Huihui Fan, Mayra Shanley, Jingling Jin, Bijender Kumar, Vernikka Woods, Paul Lin, Silvia Tiberti, Ana Karen Nunez Cortes, Xin Ru Jiang, Inci Biederstädt, Patrick Zhang, Ye Li, Seema Rawal, Enli Liu, Luis Muniz-Feliciano, Gary M Deyter, Elizabeth J Shpall, Natalie Wall Fowlkes, Ken Chen, Katayoun Rezvani Nov 2025

Genome-Wide Crispr Screens Identify Critical Targets To Enhance Car-Nk Cell Antitumor Potency, Alexander Biederstädt, Rafet Basar, Jeong-Min Park, Nadima Uprety, Rejeena Shrestha, Francia Reyes Silva, Merve Dede, John Watts, Sunil Acharya, Donghai Xiong, Bin Liu, May Daher, Hind Rafei, Pinaki Banerjee, Ping Li, Sanjida Islam, Huihui Fan, Mayra Shanley, Jingling Jin, Bijender Kumar, Vernikka Woods, Paul Lin, Silvia Tiberti, Ana Karen Nunez Cortes, Xin Ru Jiang, Inci Biederstädt, Patrick Zhang, Ye Li, Seema Rawal, Enli Liu, Luis Muniz-Feliciano, Gary M Deyter, Elizabeth J Shpall, Natalie Wall Fowlkes, Ken Chen, Katayoun Rezvani

Faculty, Staff and Student Publications

Adoptive cell therapy using engineered natural killer (NK) cells is a promising approach for cancer treatment, with targeted gene editing offering the potential to further enhance their therapeutic efficacy. However, the spectrum of actionable genetic targets to overcome tumor and microenvironment-mediated immunosuppression remains largely unexplored. We performed multiple genome-wide CRISPR screens in primary human NK cells and identified critical checkpoints regulating resistance to immunosuppressive pressures. Ablation of MED12, ARIH2, and CCNC significantly improved NK cell antitumor activity against multiple treatment-refractory human cancers in vitro and in vivo. CRISPR editing augmented both innate and CAR-mediated NK cell function, associated with enhanced …

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Mutant P53 Variants Differentially Impact Replication Initiation And Activate Cgas-Sting To Affect Immune Checkpoint Inhibition, Kang Liu, Lidija A Wilhelms Garan, Fang-Tsyr Lin, Weei-Chin Lin Nov 2025

Mutant P53 Variants Differentially Impact Replication Initiation And Activate Cgas-Sting To Affect Immune Checkpoint Inhibition, Kang Liu, Lidija A Wilhelms Garan, Fang-Tsyr Lin, Weei-Chin Lin

Faculty, Staff and Students Publications

Prior research shows that Akt-dependent phosphorylation of TopBP1 in S phase results in the switch of TopBP1/Treslin binding to TopBP1/E2F1 binding, which is important to prevent replication re-initiation in late S and G2 phases. Here, we demonstrate that contact, but not conformational, mutant p53 can override this switch by binding to both TopBP1 and Treslin, thereby facilitating persistent TopBP1/Treslin interaction in late S and G2 phases, which ultimately leads to over-firing of replication initiation. This increases micronuclei formation, which is further enhanced by genotoxic stressors such as doxorubicin, PARP inhibitors, or ATR inhibitors. Consequently, contact mutant p53 increases the sensitivity …

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