Neoplasms Commons^™

Malt1 Protease Inhibition Restrains Glioblastoma Progression By Reversing Tumor-Associated Macrophage-Dependent Immunosuppression In Mice, Juliana Hofstätter Azambuja, Saigopalakrishna Yerneni, Lisa Maurer, Hannah Crentsil, Gabriela Debom, Linda Klei, Mei Smyers, Chaim Sneiderman, Kristina Schwab, Rajesh Acharya, Aivi Nguyen, Josie Emery, John Little, Jeffrey Meridew, Yijen Lin Wu, Prasanna Ekambaram, Dong Hu, Pete Gough, John Bertin, Ari Melnick, Gary Kohanbash, Riyue Bao, Peter Lucas, Linda Mcallister-Lucas

College of Life Sciences Faculty Papers

MALT1 protease is an intracellular signaling molecule that promotes tumor progression via cancer cell-intrinsic and cancer cell-extrinsic mechanisms. MALT1 has been mostly studied in lymphocytes, and little is known about its role in tumor-associated macrophages. We show that MALT1 is expressed in glioblastoma (GBM)-associated macrophages. Mechanistically, GBM tumor cells induce a MALT1-NF-κB signaling axis in macrophages, leading to enhanced macrophage migration and polarization toward an immunosuppressive ('M2-like') phenotype. Inactivation of MALT1 protease promotes transcriptional reprogramming that reduces migration and restores a macrophage anti-tumor 'M1-like' phenotype. Preclinical in vivo analysis shows that MALT1 inhibitor treatment results in immuno-reactivity of GBM-associated macrophages …

Human Kallikrein 2: A Novel Lineage-Specific Surface Target In Prostate Cancer, Fei Shen, Ryan Smith, Theresa Mcdevitt, Krista Menard, Shaozhou Tian, Gerald Chu, Ruchi Chaudhary, Jennifer Mccann, Halley Oyer, Sherry C. Wang, Steven Max, Peter Francis, William K. Kelly, Charles G. Drake

Kimmel Cancer Center Faculty Papers

PURPOSE: Targeted therapies for metastatic prostate cancer are limited, highlighting the need for novel drug targets and mechanisms of action (MoA). Human kallikrein 2 (KLK2) is a prostate-specific antigen expressed across the prostate cancer disease continuum. However, it was not recognized as a therapeutic target for prostate cancer in the past due to limited evidence of its cell surface expression. In this study, we systematically characterized KLK2 expression in prostate cancer, confirmed its cell surface expression, and demonstrated the preclinical efficacy of three KLK2-targeting therapeutics with distinct MoA.

EXPERIMENTAL DESIGN: The KLK2 expression profile in different stages of prostate cancer …

Runx2 Cooperates With Srebp1 To Rewire Cancer Metabolism And Promote Aggressiveness, Emanuele Vitale, Mila Gugnoni, Veronica Manicardi, Silvia Muccioli, Federica Torricelli, Benedetta Donati, Simonetta Piana, Gloria Manzotti, Elisa Salviato, Francesca Reggiani, Cristian Ascione, Rebecca Vezzani, Moira Ragazzi, Mattia Forcato, Oriana Romano, Silvio Bicciato, Aaron Goldman, Marco Tigano, Alessia Ciarrocchi

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Embryonic Transcription Factors (TFs) are often reactivated in cancer, driving developmental gene programs that support phenotypic plasticity. Metabolic adaptation fuels this plasticity by supplying energy and molecular building blocks for growth. RUNX2, the master regulator of bone morphogenesis, is ectopically expressed in epithelial cancer, promoting metastasis through trans-differentiation processes like Epithelial-to-Mesenchymal Transition (EMT) and osteomimicry. By combining omics data with functional validation, we demonstrated that RUNX2 drives cancer cell metabolic rewiring by repressing mitochondrial respiration while promoting anabolic processes. We showed that RUNX2 upregulates key genes of lipid biosynthesis by regulating and cooperating with SREBP1. In vivo expression analysis in …

Setdb1 Is Critically Required For Uveal Melanoma Growth And Represents A Promising Therapeutic Target, Imène Krossa, Céline Pisibon, Yann Cheli, Karine Bille, Mélanie Dalmasso, Sabah Hamadat, Chrystel Husser, Marie Irondelle, Julien Cherfils-Vicini, Frédéric Soysouvanh, Sacha Nahon-Esteve, Arnaud Martel, Sandra Lassalle, Jean-Pierre Caujolle, Célia Maschi, Stéphanie Baillif, Dan Hasson, Saul Carcamo, Andrerw E. Aplin, Irwin Davidson, Emily Bernstein, Valeria Naim, Robert Ballotti, Corine Bertolotto, Thomas Strub

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Metastatic uveal melanomas are highly resistant to all existing treatments. To identify actionable vulnerabilities, we conducted a CRISPR-Cas9 knockout screen using a library composed of chromatin regulators. We revealed that the lysine methyltransferase, SETDB1, plays a critical role in metastatic uveal melanoma cell proliferation and survival. Functionally, SETDB1 deficiency induces a DNA damage response, senescence-like state and growth arrest. Knockdown of SETDB1 is associated with a decreased expression of genes related to replication and cell cycle. Moreover, deficiency in CDC6, an essential regulator of DNA replication, phenocopies SETDB1 inhibition. Using a pre-clinical model, we further demonstrated that anti-SETDB1 therapy impairs …

Targeting The Bcl2 Family: Advances And Challenges In Bh3 Mimetic-Based Therapies, Nabanita Mukherjee, James Sheetz, Yiqun Shellman

Student Papers, Posters & Projects

The BCL2 family of proteins plays a pivotal role in regulating apoptosis and cellular homeostasis, making them critical therapeutic targets in cancer and other diseases characterized by pathological cell survival. BH3 mimetics, small molecules that selectively inhibit anti-apoptotic BCL2 family members, have achieved significant clinical success, particularly in hematologic malignancies. However, several challenges remain, including resistance mechanisms, toxicity (such as MCL1 inhibitor-associated cardiotoxicity), and the intricate balance between apoptotic and non-apoptotic functions. This review provides a comprehensive overview of BCL2 family biology, the development and clinical application and outcomes of BH3 mimetics, and the emerging resistance mechanism known as double-bolt …

Bard1: A Friend Or Foe In Pancreatic Ductal Adenocarcinoma?, Lily Zekavat, Aditi Jain

Department of Surgery Faculty Papers

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive solid malignancy with poor overall prognosis and limited response to standard treatments. Growing interest in the modulation of DNA repair mechanisms, including the homologous recombination (HR) repair pathway, has opened new avenues for therapeutic development. BARD1 (BRCA1-Associated RING Domain 1) plays a complex role in tumor biology, functioning either as a tumor suppressor or as an oncogenic driver, depending on isoform expression, cellular context, and regulatory environment. In this review, we examine the dual roles of BARD1, focusing on its regulation and paradoxical activities in PDAC. We summarize evidence that BARD1 and BARD1 …

A Novel Sialylation Pathway Mediated By Extracellular Vesicles In Aggressive Prostate Cancer, Camila A. Bach, Md Niamat Hossain, Ishan J. Chaudhari, Cecilia E. Verrillo, Nicole M. Naranjo, Isabella Amoroso, Anna Testa, Samuel Sey, W. Kevin Kelly, Susan L. Bellis, Aurelio Lorico, Ada G. Blidner, Gabriel A. Rabinovich, Lucia R. Languino

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Altered cell surface glycosylation is a hallmark of cancer; among aberrant glycan structures, hypersialylated proteins contribute to disease progression. The enzyme ST6 β-galactoside α2,6-sialyltransferase 1 (ST6GAL1) mediates α2,6-linked sialylation of N-glycosylated proteins and is upregulated in many cancers, including prostate cancer (PrCa). We propose that ST6GAL1 may be released by cancer cells in small extracellular vesicles (sEVs) in the PrCa tumor microenvironment to potentially modulate cell surface sialylation in recipient cells. We isolated sEVs from PrCa cells by density gradient separation and characterized them by nanoparticle tracking analysis using ZetaView and immunoblotting analysis. We identified ST6GAL1 in both its membrane-bound …

The Role Of Liver Macrophages In Viral Liver Pathogenesis, Alexis Brantly, Kyle Yeakle, Michael J. Bouchard, Peter J. Gaskill, Michael R. Nonnemacher

Kimmel Cancer Center Faculty Papers

Liver macrophages play important roles in the pathophysiology of liver fibrosis and hepatocellular carcinoma. However, liver macrophages are a heterogenous population and have differing roles in maintenance of liver function and response in disease. In a healthy liver, macrophages play a critical role in antigen processing, maintaining tolerance to the high levels of gut-derived bacterial products, and regulating inflammation through cytokine response. However, macrophages also play a critical role in liver pathology, specifically in the context of viral infection. The liver is targeted by multiple viruses, including human immunodeficiency virus, hepatitis B virus, and hepatitis C virus, which dysregulate macrophage …

Risk Of Second Primary Lung Cancer Among Cancer Survivors Stratified By The Site Of First Primary Cancer And The Lung Cancer Screening Eligibility Status, Sara Nofal, Edwin J Ostrin, Jianjun Zhang, Jia Wu, Paul Scheet, Mara B Antonoff, John V Heymach, Iakovos Toumazis

Faculty, Staff and Student Publications

Personal history of cancer is an independent risk factor for developing lung cancer. However, it is not considered in the current US lung cancer screening (LCS) guidelines. In this study, we assessed the risk of developing lung cancer among cancer survivors across 24 different sites of first primary cancer stratified by their LCS eligibility status. Using data from the Patient History Database at the University of Texas MD Anderson Cancer Center, we calculated and compared the cumulative incidence of second primary lung cancer, the overall and the LCS eligibility status-specific, stratified by the site of first primary cancer among cancer …

Evolution Of Esophageal Adenocarcinoma From Precursor Lesion Stem Cells, Wa Xian, Shan Wang, Jingzhong Xie, Yusuke Yamamoto, Melina Khorrami, Yanting Zhang, Raul Caballero Montes, Caycel Desales, Melika Khorrami, Zaal Mory, Ashley Hoffman, Amber Su, Crystal Nguyen, Peter J A Davies, Clifford Stephan, Shuang Pan, Wengen Wu, Yuxin Liu, Jeremy Siegelman, Rebecca E Waters, William A Ross, Shumei Song, Mark Metersky, David G Beer, Christopher P Crum, Alexander J Stewart, Matthew Vincent, Richard Russell, Robert A Izard, Khek Yu Ho, Jack Hung-Sen Lai, William W Bachovchin, Jaffer A Ajani, Frank D Mckeon

Faculty, Staff and Student Publications

Background & aims: Metastatic cancers arise from a decades-long succession of increasingly virulent precursor lesions, each of which represents prospective targets for therapeutic intervention. This evolutionary process has been particularly vivid in esophageal adenocarcinoma (EAC), as this cancer and associated precursor lesions, including Barrett's esophagus (BE), low-grade dysplasia (LGD), and high-grade dysplasia (HGD), coexist in an accessible, 2-dimensional pattern in esophageal mucosa. Given the durability of these precursor lesions, it is likely that they, like EAC, rely on stem cells for their regenerative growth. To assess the role of stem cells in the evolution of EAC, we apply technology that …

Irradiation Of Prostate Cancer Alters Circulating Small Extracellular Vesicle Functions, Aejaz Sayeed, Vaughn Garcia, Cecilia E. Verrillo, Rachel M. Derita, Md Niamat Hossain, Shiv R. Krishn, Samuel Sey, Christopher D. Shields, Adrian D. Altieri, Qin Liu, Khalid Sossey-Alaoui, William K. Kelly, Lucia R. Languino

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

It is known that β1 integrins and a downstream signaling molecule c-Src are upregulated in prostate cancer (PrCa) tissues, are co-expressed in circulating small extracellular vesicles (sEVs) and contribute to cancer progression. Here, we demonstrate that sEVs from PrCa patients show robust expression of both β1 integrins and c-Src. The impact of irradiation, a widely used therapy for the treatment of PrCa, on circulating sEVs is however not fully understood. We show that sEVs isolated from the plasma of transgenic adenocarcinoma of mouse prostate (TRAMP) mice, stimulate migration and anchorage-independent growth of recipient cancer cells, but sEVs are not active …

Impacts Of Radiation On Metabolism And Vascular Cell Senescence, Junichi Abe, Khanh Chau, Anahita Mojiri, Guangyu Wang, Masayoshi Oikawa, Venkata S K Samanthapudi, Abigail M Osborn, Keila C Ostos-Mendoza, Karla N Mariscal-Reyes, Tammay Mathur, Abhishek Jain, Joerg Herrmann, Syed Wamique Yusuf, Sunil Krishnan, Anita Deswal, Steven H Lin, Sivareddy Kotla, John P Cooke, Nhat-Tu Le

Faculty, Staff and Student Publications

Significance: This review investigates how radiation therapy (RT) increases the risk of delayed cardiovascular disease (CVD) in cancer survivors. Understanding the mechanisms underlying radiation-induced CVD is essential for developing targeted therapies to mitigate these effects and improve long-term outcomes for patients with cancer.

Recent Advances: Recent studies have primarily focused on metabolic alterations induced by irradiation in various cancer cell types. However, there remains a significant knowledge gap regarding the role of chronic metabolic alterations in normal cells, particularly vascular cells, in the progression of CVD after RT.

Critical Issues: This review centers on RT-induced metabolic alterations in vascular cells …

Neovascular Pruning By Ido1 Inhibitors Can Potentiate Immunogenic Cytotoxicity Of Ischemia-Targeted Agents To Synergistically Enhance Anti-Pd-1 Responsiveness, Shih-Chun Shen, Souvik Dey, James B. Duhadaway, Erika Sutanto-Ward, Maurice T. Hampton, Serguei V. Kozlov, George C. Prendergast, Alexander J. Muller

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Strategies for deploying indoleamine 2,3-dioxygenase 1 (IDO1)-targeted therapies for use against cancer have focused on IDO1's role in promoting peripheral immune tolerance that shields tumors from effector T cells. However, preclinical investigation of both primary and metastatic tumor development in the lungs has uncovered a previously unappreciated role for IDO1 in directing a counterregulatory response to interferon (IFN)-γ that realigns the local inflammatory environment to promote tumor neovascularization. Understanding how to therapeutically leverage the ability of IDO1 inhibitors to subvert inflammatory neovascularization within the tumor microenvironment has potential ramifications for future clinical development of these compounds.

METHODS: Pulmonary metastases …

Targeting Bard1 Suppresses A Myc-Dependent Transcriptional Program And Tumor Growth In Pancreatic Ductal Adenocarcinoma, Sohum Patel, Eleanor Jenkins, Rutuj P. Kusurkar, Sherry Lee, Wei Jiang, Avinoam Nevler, Matthew Mccoy, Michael J. Pishvaian, Rosalie C. Sears, Jonathan R. Brody, Charles J. Yeo, Aditi Jain

Department of Surgery Faculty Papers

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers demanding better and more effective therapies. BARD1 or BRCA1-Associated -Ring Domain-1 plays a pivotal role in homologous recombination repair (HRR). However, its function and the underlying molecular mechanisms in PDAC are still not fully elucidated. Here, we demonstrate that BARD1 is overexpressed in PDAC and its genetic inhibition suppresses c-Myc and disrupts c-Myc dependent transcriptional program. Mechanistically, BARD1 stabilizes c-Myc through ubiquitin-proteasome system by regulating FBXW7. Importantly, targeting BARD1 using either siRNAs or CRISPR/Cas9 deletion blocks PDAC growth in vitro and in vivo, without any signs of toxicity to mice. …

The Tumor Microenvironment Is An Ecosystem Sustained By Metabolic Interactions, Emily Jane Kay, Sara Zanivan

Faculty, Staff and Student Publications

Cancer-associated fibroblasts (CAFs) and immune cells make up two major components of the tumor microenvironment (TME), contributing to an ecosystem that can either support or restrain cancer progression. Metabolism is a key regulator of the TME, providing a means for cells to communicate with and influence each other, modulating tumor progression and anti-tumor immunity. Cells of the TME can metabolically interact directly through metabolite secretion and consumption or by influencing other aspects of the TME that, in turn, stimulate metabolic rewiring in target cells. Recent advances in understanding the subtypes and plasticity of cells in the TME both open up …

Genetics And Biology Of Pancreatic Ductal Adenocarcinoma, Haoqiang Ying, Alec C Kimmelman, Nabeel Bardeesy, Raghu Kalluri, Anirban Maitra, Ronald A Depinho

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) poses a grim prognosis for patients. Recent multidisciplinary research efforts have provided critical insights into its genetics and tumor biology, creating the foundation for rational development of targeted and immune therapies. Here, we review the PDAC genomic landscape and the role of specific oncogenic events in tumor initiation and progression, as well as their contributions to shaping its tumor biology. We further summarize and synthesize breakthroughs in single-cell and metabolic profiling technologies that have illuminated the complex cellular composition and heterotypic interactions of the PDAC tumor microenvironment, with an emphasis on metabolic cross-talk across cancer and …

Targeted Inhibition Of Aurora Kinase A Promotes Immune Checkpoint Inhibition Efficacy In Human Papillomavirus-Driven Cancers, Soma Ghosh, Madison P O'Hara, Pragya Sinha, Tuhina Mazumdar, Lacin Yapindi, Jagannadha K Sastry, Faye M Johnson

Faculty, Staff and Student Publications

Background: Human papillomavirus (HPV)-driven cancers include head and neck squamous cell carcinoma and cervical cancer and represent approximately 5% of all cancer cases worldwide. Standard-of-care chemotherapy, radiotherapy, and immune checkpoint inhibitors (ICIs) are associated with adverse effects and limited responses in patients with HPV-driven cancers. The integration of targeted therapies with ICIs may improve outcomes. In a previous study, we demonstrated that Aurora kinase A (AURKA, Aurora A) inhibitors lead to apoptosis of human HPV-positive cancer cells in vitro and in vivo. Here, we explored the potential of Aurora A inhibition to enhance response to ICIs in immune-competent …

Predicting Sinonasal Inverted Papilloma Attachment Using Machine Learning: Current Lessons And Future Directions, Sean P Mckee, Xiaomin Liang, William C Yao, Brady Anderson, Jumah G Ahmad, David Z Allen, Salman Hasan, Andy J Chua, Chinmay Mokashi, Samia Islam, Amber U Luong, Martin J Citardi, Luca Giancardo

Faculty, Staff and Student Publications

Background: Hyperostosis is a common radiographic feature of inverted papilloma (IP) tumor origin on computed tomography (CT). Herein, we developed a machine learning (ML) model capable of analyzing CT images and identifying IP attachment sites.

Methods: A retrospective review of patients treated for IP at our institution was performed. The tumor attachment site was manually segmented on CT scans by the operating surgeon. We used a nnU-Net model, a state-of-the-art deep learning-based segmentation algorithm that automatically configures image preprocessing, network architecture, training, and post-processing to identify the IP attachment site. The model was trained and evaluated using a 5-fold cross …

Effects Of Cadherin Mediated Contact Normalization On Oncogenic Src Kinase Mediated Gene Expression And Protein Phosphorylation, Rachel E Nicoletto, Cayla J Holdcraft, Ariel C Yin, Edward P Retzbach, Stephanie A Sheehan, Amanda A Greenspan, Christopher M Laugier, Jason Trama, Caifeng Zhao, Haiyan Zheng, Gary S Goldberg

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Nontransformed cells form heterotypic cadherin junctions with adjacent transformed cells to inhibit tumor cell growth and motility. Transformed cells must override this form of growth control, called "contact normalization", to invade and metastasize during cancer progression. Heterocellular cadherin junctions between transformed and nontransformed cells are needed for this process. However, specific mechanisms downstream of cadherin signaling have not been clearly elucidated. Here, we utilized a β-catenin reporter construct to determine if contact normalization affects Wnt signaling in transformed cells. β-catenin driven GFP expression in Src transformed mouse embryonic cells was decreased when cultured with cadherin competent nontransformed cells compared to …

Cd8Α Structural Domains Enhance Gucy2c Car-T Cell Efficacy, Trevor R. Baybutt, Ariana A. Entezari, Adi Caspi, Ross E. Staudt, Robert D. Carlson, Scott A. Waldman, Adam E. Snook

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Despite success in treating some hematological malignancies, CAR-T cells have not yet produced similar outcomes in solid tumors due, in part, to the tumor microenvironment, poor persistence, and a paucity of suitable target antigens. Importantly, the impact of the CAR components on these challenges remains focused on the intracellular signaling and antigen-binding domains. In contrast, the flexible hinge and transmembrane domains have been commoditized and are the least studied components of the CAR. Here, we compared the hinge and transmembrane domains derived from either the CD8ɑ or CD28 molecule in identical GUCY2C-targeted third-generation designs for colorectal cancer. While these structural …

The P-Myh9/Usp22/Hif-1Α Axis Promotes Lenvatinib Resistance And Cancer Stemness In Hepatocellular Carcinoma, Qiaonan Shan, Lu Yin, Qifan Zhan, Jiongjie Yu, Sheng Pan, Jianyong Zhuo, Wei Zhou, Jiaqi Bao, Lincheng Zhang, Jiachen Hong, Jianan Xiang, Qingyang Que, Kangchen Chen, Shengjun Xu, Jingrui Wang, Yangbo Zhu, Bin He, Jingbang Wu, Haiyang Xie, Shusen Zheng, Tingting Feng, Sunbin Ling, Xiao Xu

Faculty, Staff and Student Publications

Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma (HCC). A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed. In this study, we aimed to dissect the underlying mechanism of lenvatinib resistance (LR) and provide effective treatment strategies. We established an HCC model of acquired LR. Cell counting, migration, self-renewal ability, chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells. Molecular and biochemical strategies such as RNA-sequencing, immunoprecipitation, mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms. Patient-derived HCC models and HCC samples …

Mitochondrial Reprogramming By Activating Oxphos Via Glutamine Metabolism In African American Patients With Bladder Cancer, Karthik Reddy Kami Reddy, Danthasinghe Waduge Badrajee Piyarathna, Jun Hyoung Park, Vasanta Putluri, Chandra Sekhar Amara, Abu Hena Mostafa Kamal, Jun Xu, Daniel Kraushaar, Shixia Huang, Sung Yun Jung, Livia S Eberlin, Jabril R Johnson, Rick A Kittles, Leomar Y Ballester, Krishna Parsawar, M Minhaj Siddiqui, Jianjun Gao, Adriana Langer Gramer, Roni J Bollag, Martha K Terris, Yair Lotan, Chad J Creighton, Seth P Lerner, Arun Sreekumar, Benny Abraham Kaipparettu, Nagireddy Putluri

Faculty, Staff and Students Publications

Bladder cancer (BLCA) mortality is higher in African American (AA) patients compared with European American (EA) patients, but the molecular mechanism underlying race-specific differences are unknown. To address this gap, we conducted comprehensive RNA-Seq, proteomics, and metabolomics analysis of BLCA tumors from AA and EA. Our findings reveal a distinct metabolic phenotype in AA BLCA characterized by elevated mitochondrial oxidative phosphorylation (OXPHOS), particularly through the activation of complex I. The results provide insight into the complex I activation-driven higher OXPHOS activity resulting in glutamine-mediated metabolic rewiring and increased disease progression, which was also confirmed by [U]13C-glutamine tracing. Mechanistic studies further …

Targeting Igf2 To Reprogram The Tumor Microenvironment For Enhanced Viro-Immunotherapy, Min Hye Noh, Jin Muk Kang, Alexandra A Miller, Grace Nguyen, Minxin Huang, Ji Seon Shim, Alberto J Bueso-Perez, Sara A Murphy, Kimberly A Rivera-Caraballo, Yoshihiro Otani, Eunju Kim, Seung-Hee Yoo, Yuanqing Yan, Yeshavanth Banasavadi-Siddegowda, Hiroshi Nakashima, E Antonio Chiocca, Balveen Kaur, Zhongming Zhao, Tae Jin Lee, Ji Young Yoo

Faculty, Staff and Student Publications

BACKGROUND: The FDA approval of oncolytic herpes simplex-1 virus (oHSV) therapy underscores its therapeutic promise and safety as a cancer immunotherapy. Despite this promise, the current efficacy of oHSV is significantly limited to a small subset of patients largely due to the resistance in tumor and tumor microenvironment (TME).

METHODS: RNA sequencing (RNA-Seq) was used to identify molecular targets of oHSV resistance. Intracranial human and murine glioma or breast cancer brain metastasis (BCBM) tumor-bearing mouse models were employed to elucidate the mechanism underlying oHSV therapy-induced resistance.

RESULTS: Transcriptome analysis identified IGF2 as one of the top-secreted proteins following oHSV treatment. …

Neoadjuvant Parpi Or Chemotherapy In Ovarian Cancer Informs Targeting Effector Treg Cells For Homologous-Recombination-Deficient Tumors, Yikai Luo, Yu Xia, Dan Liu, Xiong Li, Huayi Li, Jiahao Liu, Dongchen Zhou, Yu Dong, Xin Li, Yiyu Qian, Cheng Xu, Kangjia Tao, Guannan Li, Wen Pan, Qing Zhong, Xingzhe Liu, Sen Xu, Zhi Wang, Ronghua Liu, Wei Zhang, Wanying Shan, Tian Fang, Siyuan Wang, Zikun Peng, Ping Jin, Ning Jin, Shennan Shi, Yuxin Chen, Mengjie Wang, Xiaofei Jiao, Mengshi Luo, Wenjian Gong, Ya Wang, Yue Yao, Yi Zhao, Xinlin Huang, Xuwo Ji, Zhaoren He, Guangnian Zhao, Rong Liu, Mingfu Wu, Gang Chen, Li Hong, Cocpo Consortium, Ding Ma, Yong Fang, Han Liang, Qinglei Gao

Faculty, Staff and Student Publications

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD …

Role Of Kindlin 2 In Prostate Cancer, Katarzyna Bialkowska, Lamyae El Khalki, Priyanka Rana, Wei Wang, Daniel Lindner, Yvonne Parker, Lucia Languino, Dario Altieri, Elzbieta Pluskota, Khalid Sossey-Alaoui, Edward Plow

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Kindlin-2 is a cytoskeletal adapter protein that is present in many different cell types. By virtue of its interaction with multiple binding partners, Kindlin-2 intercalates into numerous signaling pathways and cytoskeletal nodes. A specific interaction of Kindlin-2 that is of paramount importance in many cellular responses is its direct binding to the cytoplasmic tails of integrins, an interaction that controls many of the adhesive, migratory and signaling responses mediated by members of the integrin family of cell-surface heterodimers. Kindlin-2 is highly expressed in many cancers and is particularly prominent in prostate cancer cells. CRISPR/cas9 was used as a primary approach …

Whole Genome And Reverse Protein Phase Array Landscapes Of Patient Derived Osteosarcoma Xenograft Models, Chia-Chin Wu, Licai Huang, Zhongting Zhang, Zhenlin Ju, Xingzhi Song, E Anders Kolb, Wendong Zhang, Jonathan Gill, Min Ha, Malcolm A Smith, Peter Houghton, Christopher L Morton, Raushan Kurmasheva, John Maris, Yael Mosse, Yiling Lu, Richard Gorlick, P Andrew Futreal, Hannah C Beird

Faculty, Staff and Student Publications

Osteosarcoma is the most common primary bone malignancy in children and young adults, and it has few treatment options. As a result, there has been little improvement in survival outcomes in the past few decades. The need for models to test novel therapies is especially great in this disease since it is both rare and does not respond to most therapies. To address this, an NCI-funded consortium has characterized and utilized a panel of patient-derived xenograft models of osteosarcoma for drug testing. The exomes, transcriptomes, and copy number landscapes of these models have been presented previously. This study now adds …

Stanniocalcin 2 Governs Cancer Cell Adaptation To Nutrient Insufficiency Through Alleviation Of Oxidative Stress, Shuo Qie, Haijuan Xiong, Yaqi Liu, Chenhui Yan, Yalei Wang, Lifeng Tian, Chenguang Wang, Nianli Sang

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Solid tumours often endure nutrient insufficiency during progression. How tumour cells adapt to temporal and spatial nutrient insufficiency remains unclear. We previously identified STC2 as one of the most upregulated genes in cells exposed to nutrient insufficiency by transcriptome screening, indicating the potential of STC2 in cellular adaptation to nutrient insufficiency. However, the molecular mechanisms underlying STC2 induction by nutrient insufficiency and subsequent adaptation remain elusive. Here, we report that STC2 protein is dramatically increased and secreted into the culture media by Gln-/Glc- deprivation. STC2 promoter contains cis-elements that are activated by ATF4 and p65/RelA, two transcription factors activated by …

Onecut2 Acts As A Lineage Plasticity Driver In Adenocarcinoma As Well As Neuroendocrine Variants Of Prostate Cancer, Chen Qian, Qian Yang, Mirja Rotinen, Rongrong Huang, Hyoyoung Kim, Brad Gallent, Yiwu Yan, Radu M Cadaneanu, Baohui Zhang, Salma Kaochar, Stephen J Freedland, Edwin M Posadas, Leigh Ellis, Dolores Di Vizio, Colm Morrissey, Peter S Nelson, Lauren Brady, Ramachandran Murali, Moray J Campbell, Wei Yang, Beatrice S Knudsen, Elahe A Mostaghel, Huihui Ye, Isla P Garraway, Sungyong You, Michael R Freeman

Faculty, Staff and Students Publications

Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic …

The Janus Kinase 1 Is Critical For Pancreatic Cancer Initiation And Progression, Hridaya Shrestha, Patrick Rädler, Rayane Dennaoui, Madison Wicker, Nirakar Rajbhandari, Yunguang Sun, Amy Peck, Kerry Vistisen, Aleata Triplett, Rafic Beydoun, Esta Sterneck, Dieter Saur, Hallgeir Rui, Kay-Uwe Wagner

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Interleukin-6 (IL-6)-class inflammatory cytokines signal through the Janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) pathway and promote the development of pancreatic ductal adenocarcinoma (PDAC); however, the functions of specific intracellular signaling mediators in this process are less well defined. Using a ligand-controlled and pancreas-specific knockout in adult mice, we demonstrate in this study that JAK1 deficiency prevents the formation of KRAS^G12D-induced pancreatic tumors, and we establish that JAK1 is essential for the constitutive activation of STAT3, whose activation is a prominent characteristic of PDAC. We identify CCAAT/enhancer binding protein δ (C/EBPδ) as a biologically relevant …

T-Cell Redirecting Bispecific Antibodies: A Review Of A Novel Class Of Immuno-Oncology For Advanced Prostate Cancer, Julia Palecki, Amman Bhasin, Andrew Bernstein, Patrick Mille, William Tester, William Kelly, Kevin Zarrabi

Kimmel Cancer Center Faculty Papers

Novel T-cell immunotherapies such as bispecific T-cell engagers (BiTEs) are emerging as promising therapeutic strategies for prostate cancer. BiTEs are engineered bispecific antibodies containing two distinct binding domains that allow for concurrent binding to tumor-associated antigens (TAAs) as well as immune effector cells, thus promoting an immune response against cancer cells. Prostate cancer is rich in tumor associated antigens such as, but not limited to, PSMA, PSCA, hK2, and STEAP1 and there is strong biologic rationale for employment of T-cell redirecting BiTEs within the prostate cancer disease space. Early generation BiTE constructs employed in clinical study have demonstrated meaningful antitumor …