Genetic Phenomena Commons^™

Human And Mouse Alzheimer's Seeds Differentially Affect Amyloid Deposition And Microglia-Dependent Plaque Response In Aged Mice, Juana Andreo-Lopez, Cristina Nuñez-Diaz, Kelly Do Huynh, Marie Minh Thu Nguyen, Celia Da Cunha, Francisco J Cantero-Molina, Cynthia Campos-Moreno, Stefania Zimbone, Francesco Bellia, Maria Laura Giuffrida, Laura Trujillo-Estrada, Juan Antonio Garcia-Leon, Miriam Bettinetti-Luque, Nazaret Gamez, Catalina Valdes, Rodrigo Morales, Stefania Forner, Alessandra C Martini, Antonia Gutierrez, Frank M Laferla, David Baglietto-Vargas

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is a complex neurodegenerative proteinopathy in which Aβ and tau misfold and aggregate into entities that structurally unsettle native proteins, mimicking a prion-like or "seeding" process. These Aβ and tau "seeds" can arrange in different conformations or strains that might display distinct pathogenic properties. Furthermore, recent evidence suggests that microglia play a key role in the amyloidogenic event and can modulate the propagation and aggregation processes. Here, we employed histological and molecular approaches to determine whether seeds from human AD brains compared to those from transgenic mice (3xTg-AD) are more prone to induce Aβ and tau aggregates …

The Glycosyltransferase Poglut1 Regulates Muscle Stem Cell Development And Maintenance In Mice, Soomin Cho, Emilia Servián-Morilla, Victoria Navarro, Beatriz Rodriguez-Gonzalez, Youxi Yuan, Raquel Cano, Arjun A Rambhiya, Radbod Darabi, Robert S Haltiwanger, Carmen Paradas, Hamed Jafar-Nejad

Faculty, Staff and Students Publications

Mutations in protein O-glucosyltransferase 1 (POGLUT1) cause a recessive limb-girdle muscular dystrophy (LGMDR21) with reduced satellite cell number and NOTCH1 signaling in adult patient muscles and impaired myogenic capacity of patient-derived muscle progenitors. However, the in vivo roles of POGLUT1 in the development, function, and maintenance of satellite cells are not well understood. Here, we show that conditional deletion of mouse Poglut1 in myogenic progenitors leads to early lethality, postnatal muscle growth defects, reduced Pax7 expression, abnormality in muscle extracellular matrix, and impaired muscle repair. Poglut1-deficient muscle progenitors exhibit reduced proliferation, enhanced differentiation, and accelerated fusion into myofibers. Inducible loss …

Mx1-Labeled Pulp Progenitor Cells Are The Main Contributors Of Odontoblast And Dentin Regeneration In Murine Molars, Dongwook Yang, Youngjae Jeong, Laura Ortinau, Jea Giezl Solidum, Dongsu Park

Faculty, Staff and Students Publications

Regeneration of dentin and odontoblasts from dental pulp progenitor cells is essential for the maintenance of permanent tooth. However, the in vivo identity of endogenous pulp progenitor cells and how they contribute to reparative dentinogenesis remain elusive. Here we show that comparative single-cell analysis of pulp cells before and after molar eruption reveal that endogenous pulp progenitor cells are enriched in coronal papilla-like cells with Mx1-Cre and Cxcl12–GFP expression. Further, lineage tracing and fluorescence-activated cell sorting analysis indicated that Mx1-labeled (Mx1+) pulp cells include long-term repopulating progenitor cells with higher expression of stem cell markers. Notably, …

Inhibition Of Methylthioadenosine Phosphorylase Protects From Experimental Acute Kidney Injury, Afaf Saliba, Yidong Chen, Jonathan W Nelson, Abhinav Vetcha, Wei Wei Wang, Li Kang, Nagarjunachary Ragi, Soumya Maity, Hamid Rabb, W Brian Reeves, Kumar Sharma

Faculty, Staff and Student Publications

Methylthioadenosine phosphorylase (MTAP) is a key enzyme in purine metabolism that may influence cellular responses to injury. We evaluated the effects of prophylactic MTAP inhibition in mouse models of ischemia-reperfusion and cisplatin-induced acute kidney injury (AKI). MTAP inhibition was confirmed by accumulation of methylthioadenosine (MTA). Treated mice showed reduced renal injury and decreased tubular damage. Transcriptomic analysis revealed protection from inflammatory and stress pathways, while maintaining oxidative phosphorylation, fatty acid metabolism, and epithelial integrity-related genes. Analysis of human single-cell RNA-seq data from the Kidney Precision Medicine Project indicated that MTAP is highly expressed in kidney injury marker-positive adaptive proximal tubule …

Nanotechnology For Immuno-Oncology, Adam J Grippin, Daeyong Lee, Eileen E Parkes, Wen Jiang, Betty Y S Kim

Faculty, Staff and Student Publications

Although the first generation of cancer immunotherapeutics produced unprecedented improvements in clinical outcomes for individuals with cancer, novel strategies to increase treatment specificity, delivery efficiency and pharmacokinetics are still needed. In this Review, we describe the potential advantages and current limitations of nanomaterials for cancer immunotherapy and highlight rational uses of nanosystems to generate potent and durable antitumor immune responses. We close with a review of the current state of clinical development of nanomedicine for cancer immunotherapy.

Gd3 Synthase Drives Resistance To P53-Induced Apoptosis In Breast Cancer By Modulating Mitochondrial Function, Vivek Anand, Fouad El-Dana, Natalia Baran, Jenny Borgman, Zheng Yin, Hong Zhao, Stephen T Wong, Michael Andreeff, V Lokesh Battula

Faculty, Staff and Student Publications

TP53 mutations are common in breast cancer (BC) and are associated with poor prognosis. GD3 synthase (GD3S/ST8SIA1), a gene associated with breast cancer stem cells, is upregulated in tumors with p53 mutations. However, the functional relationship between GD3S and p53 is unknown. Here, we show that GD3S levels are highest in breast tumors with specific p53 mutations. Functional studies revealed that wild-type (WT) p53 inhibits GD3S expression, whereas mutation in p53 enhances GD3S expression by upregulating GD3S promoter activity. Moreover, we found that GD3S inhibits wild-type p53-induced apoptosis in BC cells, while BC cells harboring gain-of-function p53 mutations are dependent …

Orp2 Regulates Free Cholesterol Accumulation In Hepatocytes During Mash, Jin Wu, Yudi Zhao, Liwen Qiu, Qiaoli Chen, Xiaowei Wang, Jingwen Gu, Yan Liang, Yingjie Zhang, Hong-Yu Wang, Yang Liu, Xiaoqin Wu, Shuai Chen, Feng-Jung Chen, Mingming Gao, Hongyuan Yang

Faculty, Staff and Student Publications

Background: Cholesterol crystals in hepatocytes are known to strongly associate with human metabolic dysfunction-associated steatohepatitis. However, it remains unclear which molecular pathway(s) regulates free cholesterol accumulation and the formation of cholesterol crystals in hepatocytes. In cultured cell lines, oxysterol-binding protein-related protein 2 (ORP2) functions to deliver cholesterol to the plasma membrane from endosomal compartments.

Methods: Here, we generated liver-specific ORP2 knockout (ORP2-LKO) mice and characterized their metabolic phenotypes on chow and high-fat diet.

Results: The ORP2-LKO mice developed much more severe hepatic steatosis than floxed control mice after high-fat diet feeding. They also demonstrated more severe liver inflammation and damage. …

Acquired Resistance In Cancer: Towards Targeted Therapeutic Strategies, Alice Soragni, Erik S Knudsen, Thomas N O'Connor, Cristina E Tognon, Jeffrey W Tyner, Beatrice Gini, Donghwa Kim, Trever G Bivona, Xingxing Zang, Agnieszka K Witkiewicz, David W Goodrich, Dadi Jiang, Seth T Gammon, Christopher D Willey, Paul C Boutros, Vlad C Sandulache, Abdullah A Osman, Jeffrey N Myers, Kamiya Mehla, Pankaj K Singh, Keith S Chan, Hongbo Gao, Himangi Marathe

Faculty, Staff and Student Publications

Development of acquired therapeutic resistance limits the efficacy of cancer treatments and accounts for therapeutic failure in most patients. How resistance arises, varies across cancer types and differs depending on therapeutic modalities is incompletely understood. Novel strategies that address and overcome the various and complex resistance mechanisms necessitate a deep understanding of the underlying dynamics. We are at a crucial time when innovative technologies applied to patient-relevant tumour models have the potential to bridge the gap between fundamental research into mechanisms and timing of acquired resistance and clinical applications that translate these findings into actionable strategies to extend therapy efficacy. …

Mitophagy’S Impacts On Cancer And Neurodegenerative Diseases: Implications For Future Therapies, Jason Huang, Vincent Truong Pham, Shaozi Fu, Gang Huang, Ya-Guang Liu, Lei Zheng

Faculty, Staff and Student Publications

Substantial evidence supports an inverse relationship between cancer and neurodegenerative diseases (NDDs), but few studies investigate the biological mechanisms underlying this phenomenon. While previous explanations-such as inflammation, reactive oxygen species (ROS), genetic mutations, and cell death-remain significant, they ultimately converge on mitophagy. This review identifies mitophagy as a pivotal factor in the development of both cancer and NDDs, while also evaluating specific mechanisms and processes to clarify how mitophagy connects these opposing disease trajectories. By examining these factors, we aim to uncover the underlying mechanisms that explain the inverse relationship between cancer and NDDs, which will help develop therapeutic strategies …

Sleep Drive, Not Total Sleep Amount, Increases Seizure Risk, Vishnu Anand Cuddapah, Cynthia T Hsu, Fernanda Valle Sirias, Yongjun Li, Hrishit M Shah, Christopher Saul, Samantha Killiany, Camilo Guevara, Joy Shon, Zhifeng Yue, Gabrielle L Gionet, Mary E Putt, Amita Sehgal

Duncan NRI Faculty and Staff Publications

Sleep loss has been associated with increased seizure risk since antiquity. Using automated video detection of spontaneous seizures in Drosophila epilepsy models, we show that seizures worsen only when sleep restriction raises homeostatic "sleep drive," not simply when total sleep amount falls. This is supported by the paradoxical finding that acute activation of sleep-promoting circuits worsens seizures, because it increases sleep drive without changing sleep amount. Sleep-promoting circuits become hyperactive after sleep loss and are associated with increased whole-brain activity. During sleep restriction, optogenetic inhibition of sleep-promoting circuits to reduce sleep drive protects against seizures. Downregulation of the 5HT1A serotonin …

Melanoma Antigens In Pediatric Medulloblastoma Contribute To Tumor Heterogeneity And Species-Specificity Of Group 3 Tumors, Rebecca R J Collins, Rebecca R Florke Gee, Sima Tozandehjani, Tara Bayat, Maria Camila Hoyos Sanchez, Juan Sebastian Solano Gutierrez, Barbara Breznik, Anna K Lee, Samuel T Peters, Jon P Connelly, Shondra M Pruett-Miller, Martine F Roussel, Dinesh Rakheja, Heather S Tillman, Patrick Ryan Potts, Klementina Fon Tacer

Faculty, Staff and Student Publications

Medulloblastoma (MB) is the most malignant childhood brain cancer. Group 3 MB (G3 MB) subtype accounts for about 25% of MB and is associated with the worst outcomes. Herein, we report that more than half of G3 MB tumors express melanoma antigens (MAGEs), which are potential prognostic and therapeutic markers. MAGEs are cancer-testis antigens, aberrantly expressed in several adult cancers, and associated with poorer prognosis and therapy resistance; however, their role in pediatric cancers is mostly unknown. This study aimed to determine whether MAGEs are activated and important in pediatric MB. We obtained formalin-fixed paraffin-embedded tumor samples of 34 patients, …

Human Ipsc-Based Breast Cancer Model Identifies S100p-Dependent Cancer Stemness Induced By Brca1 Mutation, Jingxin Liu, Cai Zhao, Jiahao Chen, Pengguihang Zeng, Qingjian Li, Ranran Dai, Xingqiang Lai, Wenqian Song, Jianing Chen, Xixi Zhu, Xinyi Liu, Jun Sun, Jia Wang, Peihang Fang, Tengfei Wang, Wenjie Chen, Diana Guallar, Nan Cao, Jianli Zhao, Shicheng Su, Andy Peng Xiang, Yi Arial Zeng, Jie Li, Junchao Cai, Dung-Fang Lee, Jinxin Bei, Yongliang Huo, Hai Hu, Shengbao Suo, Dong-Feng Huang, Jin Bai, Junjun Ding

Faculty, Staff and Student Publications

Breast cancer is the most common malignancy in females and remains the leading cause of cancer-related deaths for women worldwide. The cellular and molecular basis of breast tumorigenesis is not completely understood partly due to the lack of human research models which simulate the development of breast cancer. Here, we developed a method for generating functional mammary-like cells (MCs) from human-induced pluripotent stem cells (iPSCs). The iPSC-MCs closely resemble human primary MCs at cellular, transcriptional, and functional levels. Using this method, a breast cancer model was generated using patient-derived iPSCs harboring germline

The Histone H3 Lysine 36 Demethylase Kdm2a/Fbxl11 Controls Polycomb-Mediated Gene Repression And Germ Cell Development In Male Mice, Michael T Bocker, Grigorios Fanourgakis, Kristie Wetzel, Pavel A Komarov, Hélène Royo, Alexia Rohmer, Sunwoo Chun, Ching-Yeu Liang, Hubertus Kohler, Taiping Chen, Xiaohong Mao, Mark A Labow, Reginald A Valdez, Michael B Stadler, Dirk G De Rooij, Paola Capodieci, John Tallarico, Antoine H F M Peters, Thomas B Nicholson

Faculty, Staff and Student Publications

KDM2A/FBXL11 is a Jumonji-domain containing lysine demethylase catalyzing the removal of mono- and di-methyl modifications of histone H3 lysine 36 (H3K36me1/2). While Kdm2a is required for mouse embryogenesis, its role in adult physiology has been largely unexplored. Using conditional deletion approaches, we demonstrate that Kdm2a deficiency leads to testicular atrophy and male infertility. Although spermatogonial stem cells remain unaffected, proliferating and differentiating spermatogonia exhibit delayed cell cycle progression and apoptosis. RNA-sequencing of purified spermatogonia and spermatocytes reveals Kdm2a-dependent repression of over 750 genes during spermatogonial differentiation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) demonstrates increased H3K36me2 levels at CpG-rich gene promoters …

An Alternative Neural Basis Underlying Leptin Resistance, Hongli Li, Cunjin Su, Yuanzhong Xu, Mette Q Ludwig, Jon Davis, Qingchun Tong

Faculty, Staff and Student Publications

Overconsumption of a palatable Western diet, a condition linked to central leptin resistance, contributes extensively to the current obesity epidemic. In this context, intensive efforts have focused on detailing the molecular mechanisms underlying leptin resistance. Here, we demonstrate that chronic inhibition of hypothalamic arcuate GABAergic neurons (ArcGABA) effectively reduced diet-induced obesity (DIO). Interestingly, palatable food exposure increased the activity level of ArcGABA neurons, which do not express the leptin receptor (non-LepR neurons; nonresponsive to leptin). Chronic activation of ArcGABA non-LepR neurons led to massive obesity, which was associated with normal leptin-induced pSTAT3 signaling but phenotypic leptin resistance; i.e., high leptin …

Efficacy Of A Novel Bcl-Xl Degrader, Dt2216, In Preclinical Models Of Jak2-Mutated Post-Mpn Aml, Zhe Wang, Anna Skwarska, Gowri Poigaialwar, Sovira Chaudhry, Alba Rodriguez-Meira, Pinpin Sui, Emmanuel Olivier, Yannan Jia, Varun Gupta, Warren Fiskus, Cassandra L Ramage, Guangrong Zheng, Alexandra Schurer, Kira Gritsman, Eirini P Papapetrou, Kapil Bhalla, Daohong Zhou, Adam J Mead, Raajit K Rampal, Jeffrey W Tyner, Hussein A Abbas, Naveen Pemmaraju, Qi Zhang Tatarata, Marina Konopleva

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) that evolves from myeloproliferative neoplasm (MPN) is known as post-MPN AML. Current treatments do not significantly extend survival beyond 12 months. B-cell lymphoma-extra large (BCL-xL) has been found to be overexpressed in leucocytes from patients with MPN, making it a potential therapeutic target. We investigated the role of BCL-xL in post-MPN AML and tested the efficacy of DT2216, a platelet-sparing BCL-xL proteolysis-targeting chimera, in preclinical models of post-MPN AML. We found that BCL2L1, the gene encoding BCL-xL, is expressed at higher levels in patients with post-MPN AML than in those with de novo AML. Single-cell multiomics …

Epha4 Signaling Dysregulation Links Abnormal Locomotion And The Development Of Idiopathic Scoliosis, Lianlei Wang, Xinyu Yang, Sen Zhao, Pengfei Zheng, Wen Wen, Kexin Xu, Xi Cheng, Qing Li, Anas M Khanshour, Yoshinao Koike, Junjun Liu, Xin Fan, Nao Otomo, Zefu Chen, Yaqi Li, Lulu Li, Haibo Xie, Panpan Zhu, Xiaoxin Li, Yuchen Niu, Shengru Wang, Sen Liu, Suomao Yuan, Chikashi Terao, Ziquan Li, Shaoke Chen, Xiuli Zhao, Pengfei Liu, Jennifer E Posey, Zhihong Wu, Guixing Qiu, Disco Study Group (Deciphering Disorders Involving Scoliosis & Comorbidities), Shiro Ikegawa, James R Lupski, Jonathan J Rios, Carol A Wise, Jianguo T Zhang, Chengtian Zhao, Nan Wu

Faculty, Staff and Students Publications

Idiopathic scoliosis (IS) is the most common form of spinal deformity with unclear pathogenesis. In this study, we first reanalyzed the loci associated with IS, drawing upon previous studies. Subsequently, we mapped these loci to candidate genes using either location-based or function-based strategies. To further substantiate our findings, we verified the enrichment of variants within these candidate genes across several large IS cohorts encompassing Chinese, East Asian, and European populations. Consequently, we identified variants in the EPHA4 gene as compelling candidates for IS. To confirm their pathogenicity, we generated zebrafish mutants of epha4a. Remarkably, the zebrafish epha4a mutants exhibited …

The Integrated Stress Response Pathway Coordinates Translational Control Of Multiple Immune Checkpoints In Lung Cancer, Shayna Thomas-Jardin, Shruthy Suresh, Ariana Arce, Nicole Novaresi, Qing Deng, Emily Stein, Lisa Thomas, Cheryl Lewis, Chul Ahn, Bret M Evers, Esra A Akbay, Maria E Salvatierra, Wei Lu, Khaja Khan, Luisa M Solis Soto, Ignacio I Wistuba, John D Minna, Kathryn A O'Donnell

Faculty, Staff and Student Publications

The integrated stress response (ISR) is an adaptive pathway hijacked by cancer cells to survive cellular stresses in the tumor microenvironment. ISR activation potently induces PD-L1, leading to suppression of antitumor immunity. In this study, we sought to uncover additional immune checkpoint proteins regulated by the ISR to elucidate mechanisms of tumor immune escape. The ISR coordinately induced cluster of differentiation 155 (CD155) and PD-L1, enhancing translation of both immune checkpoint proteins through bypass of inhibitory upstream open reading frames in their 5' untranslated regions. Analysis of primary human lung tumors identified a significant correlation between expression of PD-L1 and …

Met Pathway Inhibition Increases Chemo-Immunotherapy Efficacy In Small Cell Lung Cancer, Raúl Del Rey-Vergara, Miguel Alejandro Galindo-Campos, Pedro Rocha, Marina Carpes, Carlos Martínez, Laura Masfarré, Silvia Menéndez, Fabricio Quimis, Adrià Rossell, Albert Iñañez, Sandra Pérez-Buira, Federico Rojo, Ramon Gimeno, Dolores Isla, Jon Zugazagoitia, Cristina Martí Blanco, Rosario García-Campelo, Alberto Moreno-Vega, Luis León-Mateos, Ángel Callejo Mellén, Kwon-Sik Park, Simon Heeke, John V Heymach, Álvaro Taus, Luis Paz-Ares, Ana Rovira, Edurne Arriola

Faculty, Staff and Student Publications

The introduction of immunotherapy as a first-line treatment for advanced small cell lung cancer (SCLC) represents significant progress, yet there remains an opportunity to further improve patient outcomes. Hepatocyte growth factor (HGF) receptor (MET) pathway activation promotes epithelial-mesenchymal transition, driving chemoresistance and potentially impairing the efficacy of immunotherapy. In SCLC mouse models, adding MET inhibition to chemo-immunotherapy (anti-PD-L1) reduces tumor growth, extends survival, and reshapes the tumor microenvironment by decreasing suppressive myeloid cell infiltration and enhancing the immune response. Analysis of pretreatment human SCLC tumor samples reveals that myeloid-enriched immune infiltrates may contribute to chemo-immunotherapy resistance. Elevated serum HGF levels …

Synergistic Activity Of Combined Flt3-Itd And Mdm2 Inhibition With Quizartinib And Milademetan In Flt3-Itd Mutant/Tp53 Wild-Type Acute Myeloid Leukemias, Weiguo Zhang, Li Li, Muharrem Muftuoglu, Mahesh Basyal, Noriko Togashi, Koichi Iwanaga, Fumie Tanzawa, Masashi Numata, Dale L Bixby, Harry P Erba, Nikolai Podoltsev, Gary J Schiller, Prasanna Kumar, Arnaud Lesegretain, Takeshi Isoyama, Takahiko Seki, Naval Daver, Michael Andreeff

Faculty, Staff and Student Publications

Purpose: Acute myeloid leukemia (AML) is characterized by frequent mutations in FMS-like tyrosine kinase 3 (FLT3), overexpression of murine double minute 2 (MDM2), and TP53 wild-type (WT). Monotherapies targeting FLT3 frequently result in the development of resistant disease. In this study, we investigated the antileukemic efficacy of co-targeting FLT3 and MDM2 with quizartinib and milademetan (Q/M) in FLT3 internal tandem duplication (FLT3-ITD) AML cell lines, xenograft and patient-derived xenograft (PDX) models, and a phase I clinical trial.

Experimental design: Preclinical studies used human and murine cell lines carrying FLT3-ITD and/or tyrosine kinase domain mutations, TP53 WT/knockdown, leukemia cell xenograft models, …

Targeting The Cd40 Costimulatory Receptor To Improve Virotherapy Efficacy In Diffuse Midline Gliomas, Sara Labiano, Javier Marco-Sanz, Iker Ausejo-Mauleon, Virginia Laspidea, Reyes Hernández-Osuna, Marc Garcia-Moure, Daniel De La Nava, Sara Nuin, Marisol Gonzalez-Huarriz, Timothy N Phoenix, Ibon Tamayo, Marta Zalacain, Andrea Lacalle, Lucía Marrodan, Montserrat Puigdelloses, Irati Hervás-Corpión, Maria C Ochoa, Noelia Casares, Oren J Becher, Candelaria Gomez-Manzano, Juan Fueyo, Jaime Gallego Perez-Larraya, Ana Patiño-Garcia, Marta M Alonso

Faculty, Staff and Student Publications

Diffuse midline glioma (DMG) is a devastating pediatric brain tumor. The oncolytic adenovirus Delta-24-RGD has shown promising efficacy and safety in DMG patients but is not yet curative. Thus, we hypothesized that activating dendritic cells (DCs) through the CD40 costimulatory receptor could increase antigen presentation and enhance the anti-tumor effect of the virus, resulting in long-term responses. This study shows that the intratumoral co-administration of Delta-24-RGD and a CD40 agonistic antibody is well tolerated and induces long-term anti-tumor immunity, including complete responses (up to 40%) in DMG preclinical models. Mechanistic studies revealed that this therapy increased tumor-proliferating T lymphocytes and …

Antitumor Efficacy Of Intermittent Low-Dose Erlotinib Plus Sulindac Via Mhc Upregulation And Remodeling Of The Immune Cell Niche, Chakrapani Tripathi, Jorge E Tovar Perez, Sabeeta Kapoor, Ahmed Muhsin, Wan Mohaiza Dashwood, Yunus Demirhan, Melek Demirhan, Alessandro Shapiro, Altaf Mohammed, Shizuko Sei, Jacklyn Thompson, Mahira Zaheer, Krishna M Sinha, Powel H Brown, Michelle I Savage, Eduardo Vilar, Praveen Rajendran, Roderick H Dashwood

Faculty, Staff and Student Publications

A previously reported clinical trial in familial adenomatous polyposis (FAP) patients treated with erlotinib plus sulindac (ERL + SUL) highlighted immune response/interferon-γ signaling as a key pathway. In this study, we combine intermittent low-dose ERL ± SUL treatment in the polyposis in rat colon (Pirc) model with mechanistic studies on tumor-associated immune modulation. At clinically relevant doses, short-term (16 weeks) and long-term (46 weeks) ERL ± SUL administration results in near-complete tumor suppression in Pirc colon and duodenum (p < 0.0001). We identify a low-dose threshold for significant antitumor activity in Pirc rats given SUL at 125 ppm in the diet plus ERL at 5 mg/kg body weight via twice-weekly oral gavage (SUL125 + ERL5 × 2). Longitudinal analyses show diminished expression of MHC class I and II genes in polyps larger than Grade 5, a novel finding in the Pirc model. Treatment with ERL ± SUL upregulates the corresponding MHC and immune-associated factors in a subset of Pirc colon polyps, Pirc tumor cell lines, murine colon carcinoma cells, and FAP patient-derived organoids, with Nlrc5 playing a critical role in this effect. Imaging mass cytometry reveals that SUL125 + ERL5 × 2 increases tumor-associated Cd4+ T cells by ~2.6-fold (p < 0.05), with no apparent effect on Cd8+ T cells. The treatment also increases tumor-associated Cd68+ cells (p < 0.05) and decreases Foxp3+ (p < 0.01) and Arg1+ (p < 0.05) cells. Thus, intermittent low-dose ERL + SUL treatment enhances tumor-associated MHC expression and remodels the immune cell niche toward a more permissive "helper" immune microenvironment. We conclude that early immune-interception strategies targeting interferon-γ signaling may benefit FAP patients at drug doses below the clinical standard of care.

Sensory Neuron-Expressed Fgf13 Controls Nociceptive Signaling In Diabetic Neuropathy Models, Aditya K Singh, Matteo Bernabucci, Nolan M Dvorak, Zahra Haghighijoo, Jessica Di Re, Nana A Goode, Feni K Kadakia, Laura A Maile, Olumarotimi O Folorunso, Paul A Wadsworth, Cynthia M Tapia, Pingyuan Wang, Jigong Wang, Haiying Chen, Yu Xue, Jully Singh, Kali Hankerd, Isaac J Gamez, Makenna Kager, Vincent Truong, Patrick Walsh, Stephanie I Shiers, Nishka Kuttanna, Hanyue Liao, Margherita Marchi, Erika Salvi, Ilaria D'Amato, Daniela D'Amico, Parsa Arman, Catharina G Faber, Rayaz A Malik, Marina De Tommaso, Dan Ziegler, Krishna Rajarathnam, Thomas A Green, Peter M Grace, Matthew R Sapio, Michael J Iadarola, Gregory D Cuny, Diana S Chow, Giuseppe Lauria Pinter, Steve Davidson, Dustin P Green, Jun-Ho La, Jin Mo Chung, Jia Zhou, Theodore J Price, Elizabeth Salisbury, Subo Yuan, Fernanda Laezza

Faculty, Staff and Student Publications

Nociception involves complex signaling, yet intrinsic mechanisms bidirectionally regulating this process remain unexplored. Here, we show that the fibroblast growth factor 13 (FGF13)/Nav1.7 protein-protein interaction (PPI) complex bidirectionally modulates nociception, and that the FGF13/Nav1.7 ratio is upregulated in type 2 diabetic neuropathy (T2DN). PW164, an FGF13/Nav1.7 channel C-terminal tail domain (CTD) PPI interface inhibitor, which reduces complex assembly, selectively suppressed Na+ currents sensitized by capsaicin-induced activation of TRPV1 channels in human induced pluripotent stem cell-derived (hIPSC-derived) sensory neurons and inhibited mechanical and thermal hyperalgesia in mice. FGF13 silencing mimics PW164 activity in culture and in vivo. Conversely, ZL192, an FGF13 …

Fgfr3-Induced Y158 Parp1 Phosphorylation Promotes Parp Inhibitor Resistance Via Brg1/Mre11-Mediated Dna Repair In Breast Cancer Models, Mei-Kuang Chen, Hirohito Yamaguchi, Yuan Gao, Weiya Xia, Jeffrey T Chang, Yu-Chun Hsiao, Tewodros W Shegute, Zong-Shin Lin, Chen-Shiou Wu, Yu-Han Wang, Jennifer K Litton, Qingqing Ding, Yongkun Wei, Yu-Yi Chu, Funda Meric-Bernstam, Helen Piwnica-Worms, Banu Arun, Jordi Rodon Ahnert, Jinsong Liu, Jun Yao, Wei-Chao Chang, Hung-Ling Wang, Coya Tapia, Constance T Albarracin, Khandan Keyomarsi, Shao-Chun Wang, Ying-Nai Wang, Gabriel N Hortobagyi, Chunru Lin, Liuqing Yang, Dihua Yu, Mien-Chie Hung

Faculty, Staff and Student Publications

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are used to treat BRCA-mutated (BRCAm) cancer patients; however, resistance has been observed. Therefore, biomarkers to indicate PARPi resistance and combination therapy to overcome that are urgently needed. We identified a high prevalence of activated FGF receptor 3 (FGFR3) in BRCAm triple-negative breast cancer (TNBC) cells with intrinsic and acquired PARPi resistance. FGFR3 phosphorylated PARP1 at tyrosine 158 (Y158) to recruit BRG1 and prolong chromatin-loaded MRE11, thus promoting homologous recombination (HR) to enhance PARPi resistance. FGFR inhibition prolonged PARP trapping and synergized with PARPi in vitro and in vivo. High-level PARP1 Y158 phosphorylation (p-Y158) positively …

Blunted Cd40-Responsive Enhancer Activation In Crebbp-Mutant Lymphomas Can Be Restored By Enforced Cd4 T-Cell Engagement, Haopeng Yang, Wenchao Zhang, Vida Ravanmehr, Guiling Cui, Kevin Bowman, Ruidong Chen, Jared M Henderson, Shyanne Lockman, Estela Rojas, Ashley Wilson, Sydney Parsons, Ariel Mechaly, Leslie Regad, Ahmed Haouz, Christopher R Flowers, Sattva Neelapu, Loretta Nastoupil, R Eric Davis, Qing Deng, Fernando Rodrigues-Lima, Michael R Green

Faculty, Staff and Student Publications

The CREBBP lysine acetyltransferase (KAT) is frequently mutated in follicular lymphoma and diffuse large B-cell lymphoma and has been studied using gene knockout in murine and human cells. However, most CREBBP mutations encode amino acid substitutions within the catalytic KAT domain (CREBBP KAT-PM) that retain an inactive protein and have not been extensively characterized. Using CRISPR gene editing and extensive epigenomic characterization of lymphoma cell lines, we found that CREBBP KAT-PM lead to unloading of CREBBP from chromatin, loss of enhancer acetylation, and prevention of EP300 compensation. These enhancers were enriched for those that are dynamically loaded by CREBBP in …

Extracellular Vesicles In Cancer: From Isolation And Characterization To Metastasis, Drug Resistance, And Clinical Applications, Ancuta Jurj, Doru Paul, George A Calin

Faculty, Staff and Student Publications

Cancer progression, along with other hallmarks of cancer, is sustained through bidirectional cell-to-cell communication. This function is primarily facilitated by lipid-rich nanoparticles expelled into the extracellular matrix by stromal and/or malignant cells. These entities, known as extracellular vesicles, contain a vast repertoire of bioactive molecules and hold promise as potential biomarkers and nanovehicles for drug delivery. Intriguingly, the cellular and molecular mechanisms governing the functions of extracellular vesicles remain poorly understood. In the present manuscript, we highlight the intracellular and intercellular journey of extracellular vesicles, from their inception to the present day, their implications in various hallmarks of cancer, and …

Pi(4)P Recruits Cide Proteins To Promote The Formation Of Unilocular Lipid Droplets During Adipogenesis And Hepatic Steatosis, Jin Wu, Mingming Gao, Xiaoqin Wu, Yang Liu, Taiping Zhang, Yan Liang, Haixia Yang, Chengxin Ma, Youpi Ye, Chunmei Chang, Peng Li, Feng-Jung Chen, Hongyuan Yang

Faculty, Staff and Student Publications

Lipid droplets (LDs) are evolutionarily conserved organelles that play important roles in metabolism. Each LD is enclosed by a monolayer of phospholipids, distinct from bilayer membranes. The composition of LD surface phospholipids and their impact on LD growth and function remain to be defined. Phosphoinositides mark cellular organelles and regulate organellar function. Here, we demonstrate that PI(4)P decorates a subset of LDs to recruit and activate CIDE proteins. Enhanced expression of ORP2 and ORP5, LD-associated lipid transfer proteins that remove PI(4)P from LDs, abolished the localization and function of CIDE proteins. Blocking the synthesis of PI(4)P on the LD surface …

Opposing Roles For Myeloid And Smooth Muscle Cell Sting In Pulmonary Hypertension, Ann T Pham, Shiza Virk, Aline C Oliveira, Matthew D Alves, Chunhua Fu, Yutao Zhang, Jimena Alvarez-Castanon, Brian B Lee, Keira L Lee, Radwan Mashina, Katherine E Ray, Patrick Donabedian, Elnaz Ebrahimi, Harsh Patel, Reeha Patel, Duncan Lewis, Zhiguang Huo, Harry Karmouty-Quintana, Li Chen, Lei Jin, Andrew J Bryant

Faculty, Staff and Student Publications

There is an emerging role for stimulator of interferon genes (STING) signaling in pulmonary hypertension (PH) development. Related to this, prior research has demonstrated the relevance of immune checkpoint protein programmed death ligand 1 (PD-L1) expression by immunoregulatory myeloid cells in PH. However, there remains a need to elucidate the cell-specific role of STING expression, and the STING/PD-L1 signaling axis in PH, before readily available disease-modifying therapies can be applied for patients with the disease. Here, through generation of bone marrow chimeric mice, we show that STING-/- mice receiving WT bone marrow were protected against PH secondary to chronic hypoxia. …

Convergent Reduction Of Olfactory Genes And Olfactory Bulb Size In Mammalian Species At Altitude, Allie M Graham, Elysia Saputra, Bogdan Kirilenko, Jason S Presnell, Arianna Harrington, Chad Huff, Michael Hiller, Nathan Clark

Faculty, Staff and Student Publications

The invasion of specialized ecological niches can cause drastic changes to selection regimes, resulting in genomic and phenotypic transformation.

Transcriptomic And Histological Characteristics Of Innate Immune Activation In Brain Parenchyma In A Rat Model Of Neonatal Intraventricular Hemorrhage, Miriam Zamorano, Sanjna Udtha, Aidan M Collier, Erica Underwood, Razan El Sayed, Ankit Agarwal, Devin S Hatchell, Chunfeng Tan, Paul J Nietert, Scott D Olson, Brandon A Miller

Faculty, Staff and Student Publications

Background: Intraventricular hemorrhage (IVH) remains a major complication in preterm infants with lifelong sequelae. There is no effective treatment for IVH other than supportive care and surgery for post-hemorrhagic hydrocephalus. We previously reported that the innate neuroimmune response in an animal model of IVH was dependent on developmental stage, only occurring in older animals.

Methods: This study utilized a lysed-blood injection model of IVH in rats. This model specifically captures the effects of blood products released by IVH on brain parenchyma. We performed RNAseq and differential gene expression analysis on CD11b/c-positive cells in the brain (microglia/macrophages) to define gene expression …

Direct Inhibition Of Ras Reveals The Features Of Oncogenic Signaling Driven By Ras G12 And Q61 Mutations, Michelangelo Marasco, Dinesh Kumar, Santiago Garcia Borrego, Tessa Seale, Giulia Maddalena, Riccardo Mezzadra, Kylie Belanger, Soren Cole, Brayan Perez, Wei Luan, Radha Mukherjee, Ilinca Aricescu, Vladimir Markov, Yuxin Zhu, Sabrina Arena, Alberto Bardelli, Elisa De Stanchina, Scott W Lowe, Richard A Burkhart, Jacquelyn W Zimmerman, Rona Yaeger, Scott E Kopetz, Neal Rosen, Sandra Misale

Faculty, Staff and Student Publications

RAS genes are frequently mutated in cancer, often at codons 12 and 61. With the recent introduction of RAS inhibitors, we can now directly investigate the effects of specific RAS mutations in cancer cells. In this study, we demonstrate that in tumors with RASG12X mutations, mutant RAS can be activated by receptor tyrosine kinases (RTK), and PI3K activation is dependent on mutant RAS. Conversely, RASQ61X mutations activate the MAPK cascade independently of RTKs, and inhibition of RASQ61X impairs MAPK pathway activation but leaves the PI3K pathway unaffected. Our characterization of these distinct features of G12X and Q61X mutations suggests that …