Cancer Biology Commons^™

P300/Cbp Inhibition With Inobrodib In Combination With Gilteritinib And Venetoclax Targets Leukemia Stem Cells In Epigenetic Mutant Aml, Melanie L. Goetz, Jennifer S. Romer-Seibert, Amanda M. Versace, Scott Kogan, Chetan Jeurkar, Robert L. Bowman, Nigel Brooks, Kris Frese, Sara E. Meyer

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Acute myeloid leukemia (AML) is a fatal blood cancer with cytotoxic chemotherapy offering at best 25% 5-year survival. While targeted BCL2 and FLT3 inhibitors venetoclax and gilteritinib are used upfront in the treatment of a subset of adult patients with AML and help to extend the survival of some patients, a curative treatment combination with minimal side effects has yet to be discovered. We find that use of the dual histone acetyltransferase p300/CBP bromodomain inhibitor CCS1477 (inobrodib), together with venetoclax and gilteritinib, virtually eliminates leukemia stem cells in an aggressive preclinical model of DNMT3A/FLT3-mutant AML by impairing pro-oncogenic survival and …

Diacylglycerol Kinase Eta As A Novel Target In Nras Mutant Melanoma, Haley P. Wilson, Casey D. Stefanski, Signe Caksa, Glenn L. Mersky, Scott D. Varney, Jelan I. Haj, Dan A. Erkes, Timothy J. Purwin, Vivian Chua, Andrew E. Aplin

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

NRAS mutations occur in 10%-30% of cutaneous melanomas and are associated with high tumor mutational burden. Mutant NRAS signaling drives aberrant cell growth and proliferation, in part, through activation of the RAF-MEK-ERK1/2 kinase pathway; however, targeted therapies to this pathway have limited effectiveness in patients with NRAS mutant melanoma. The role of other targetable signaling pathways in NRAS mutant melanoma is poorly characterized. Here, we demonstrated that one isoform of diacylglycerol kinase, diacylglycerol kinase eta (DGKη), a lipid signaling regulator, was highly expressed in NRAS mutant melanoma patient samples. Knockdown of DGKH in NRAS mutant melanoma cell lines resulted in …

Synthetic Lethality Between Rb-Loss And E2f3 Inhibition In Small Cell Cancers Targeted By Pyrimidine Synthesis Blockade, Evan R. Abt, Liang Wang, Grigor Varuzhanyan, Jack Freeland, Tian He, Guadalupe M. Peña-Garcia, Lauryn Ruegg, Jami Mclaughlin, Donghui Cheng, Nikolas G. Balanis, Chia-Chun Chen, Yang Xu, Yi Xing, Sanaz Memarzadeh, Caius G. Radu, Thomas G. Graeber, Owen N. Witte

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Small cell carcinoma is a highly lethal cancer variant often found with neuroendocrine (NE) features, as exemplified by small cell lung cancer and small cell NE prostate cancer (SCPC). A genome-wide CRISPR dependency screen using SCPC models generated through human prostate cell transformation identifies a requirement for the transcription factor E2F3. E2F3 dependency is linked to RB inactivation, a near universal occurrence across small cell cancers. The requirement for E2F3 is shared by RB-deficient cells originating from the prostate, lung, and adnexa. In RB-deficient cancer cells, E2F3 inhibition restrains cell cycle progression, proliferation, and tumor growth in vivo. Inhibition of …

Advancements In Extracellular Vesicle Research, Lucia R. Languino

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

The AAEV (American Association of Extracellular Vesicles) Annual Meeting at the John P. McGovern Commons in Houston, TX convened over 300 leading re- searchers, clinicians, and industry experts from around the world to advance the rapidly evolving field of extracellular vesicle (EV) science. EVs, nanoscale lipid- bound particles released by all prokaryotic and eukaryotic cells, have emerged as crucial mediators of intercellular communication, trans- porting proteins, nucleic acids, and lipids that influence a wide spectrum of physiological and pathological processes. Their involvement in immune modulation, tissue regeneration, cancer progression, metabolic regulation, and other complex biological functions positions EVs as promising …

Updating Misev: When, What, How, And Why?, Naveed Akbar, Dylan Burger, Benedetta Bussolati, Edit Buzás, Randy Carney, Young-Eun Cho, Tom Driedonks, Juan Manuel Falcon-Perez, Yu Fujita, Deborah Goberdhan, An Hendrix, Yiyao Huang, Suresh Mathivanan, Mỹ Mahoney, Sujata Mohanty, Andreas Möller, Nicole Noren Hooten, Stefano Pluchino, Carlos Salomon, Ana Claudia Torrecilhas, Sara Veiga, Kenneth Witwer

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

No abstract provided.

Stat-Independent Functions Of Janus Kinases 1 And 2 Are Obligatory For The Postnatal Development Of Mammary Epithelial Ducts, Rayane Dennaoui, Madison N. Wicker, Carson Moen, Michaela Schlederer, Kerry Vistisen, Aleata A. Triplett, Thomas Rülicke, Hallgeir Rui, Lukas Kenner, Emilio Casanova, Kay-Uwe Wagner

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Janus kinases 1 and 2 and STAT transcription factors are critical signaling nodes for numerous growth factors. In the mammary gland, JAK2 and STAT5a/b are essential for alveolar cell differentiation and lactation, but little is known about the cooperative roles of JAKs and STATs before pregnancy. We examined female mice conditionally deficient in JAK1/2 and discovered that both kinases jointly regulate epithelial cell proliferation and ductal morphogenesis. To assess the role of downstream STATs, we generated genetic models co-deficient in STAT3/5a/5b with or without STAT1 or JAK1. Although loss of STAT3/5a/5b leads to a JAK1-dependent upregulation of STAT1, the formation …

An Antioxidant Cocktail Of Tert-Butylhydroquinone And A Manganese Porphyrin Induces Toxic Levels Of Oxidative Stress In Cancer Cells, Sandra Tamarin, Hannah Jung, Joseph Lamorte, Laura Biesterveld, Gabriel Piñero, Grace Turchetta, Molly Myers, Rebecca Oberley-Deegan, Aimee Eggler

Student Papers, Posters & Projects

Despite significant advancement in cancer treatments, therapies with minimal toxicity to healthy cells are still limited. One targetable weakness of cancer cells is their sensitivity to oxidative stress. We find that the combination of two antioxidants—the common food additive tert-butylhydroquinone (tBHQ) and a manganese porphyrin in clinical trials, MnTnBuOE-2-PyP5+ (MnBuOE)—increases oxidative stress and causes apoptotic death in several cancer cell lines, but not in mouse primary fibroblasts. Investigating the mechanism of cell death, MnBuOE is observed to catalyze the oxidation of tBHQ, producing the electrophilic quinone tert-butylquinone (tBQ). A critical role for tBQ and its electrophilic character was revealed with …

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 …

Htlv-1 And Atll: Epidemiology, Oncogenesis, And Opportunities For Community-Informed Research In The United States, Adrian D. Altieri, Sean P. Reilly, Abu Mansalay, Alan Khoo, Nettie Johnson, Zafar K. Khan, Amy Leader, Pooja Jain, Pierluigi Porcu

Kimmel Cancer Center Faculty Papers

Human T-cell leukemia virus type 1 (HTLV-1), the first oncogenic human retrovirus, causes adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm of mature CD4+ T-cells that is incurable in most patients and is associated with a median survival of less than 1 year. HTLV-1 also causes inflammatory disorders, including HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and uveitis. The estimated lifetime risks of ATLL and HAM/TSP in HTLV-1 carriers are 3-5% and 0.25-1.8%, respectively. Although there is uncertainty about other health effects of HTLV-1, a recent meta-analysis showed an association between HTLV-1 and cardiovascular, cerebrovascular, and metabolic diseases and a 57% increased risk …

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 …

Elevated Nr2f1 Underlies The Persistence Of Invasive Disease After Treatment Of Braf-Mutant Melanoma, Manoela Tiago, Timothy J. Purwin, Casey D. Stefanski, Renaira Oliveira Da Silva, Mitchell E. Fane, Yash Chhabra, Jelan I. Haj, Jessica L. F. Teh, Rama Kadamb, Weijia Cai, Sheera Rosenbaum, Vivian Chua, Nir Hacohen, Michael A. Davies, Jessie Villanueva, Inna Chervoneva, Ashani T. Weeraratna, Dan A. Erkes, Claudia Capparelli, Julio A. Aguirre-Ghiso, Andrew E. Aplin

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Despite the success of targeted inhibitors in cutaneous melanoma, therapeutic responses are limited by the aged tumor microenvironment and drug-tolerant residual cells. Given the similarities between drug tolerance and cellular dormancy, we studied the dormancy marker, nuclear receptor subfamily 2 group F member 1 (NR2F1), in response to BRAF-V600E inhibitors (BRAFi) plus MEK inhibitors (MEKi) in BRAF-mutant melanoma models. Transcriptomic analysis of melanoma patient samples treated with BRAFi + MEKi showed increased NR2F1. NR2F1 was highly expressed in the drug-tolerant invasive cell state of minimal residual disease in patient-derived and mouse-derived xenografts on BRAFi + MEKi. NR2F1 over-expression was sufficient …

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 …

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. …

5-Hydroxymethylcytosine Sequencing Of Plasma Cell-Free Dna Identifies Epigenomic Features In Prostate Cancer Patients Receiving Androgen Deprivation Therapies, Qianxia Li, Chiang-Ching Huang, Shane Huang, Yijun Tian, Jinyong Huang, Amirreza Bitaraf, Xiaowei Dong, Marja T. Nevalainen, Manishkumar Patel, Jodie Wong, Jingsong Zhang, Brandon J Manley, Jong Y. Park, Manish Kohli, Elizabeth M. Gore, Deepak Kilari, Liang Wang

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

BACKGROUND: We evaluated whether 5hmC signatures in cell-free DNA (cfDNA) are associated with treatment failure to androgen-deprivation therapies (ADT) among men with hormone-naive prostate cancer.

METHODS: We collected a total of 139 serial plasma samples from 55 prostate cancer patients receiving ADT at 3 time points including baseline (before initiating ADT, n = 55); 3 months (after initiating ADT, n = 55); and disease progression (n = 15) within 24 months or 24 months if no progression was detected (n = 14). We used selective chemical labeling sequencing to quantify 5hmC abundance across the genome and Kaplan-Meier analysis to assess …

Sigma1 Inhibitor Suppression Of Adaptive Immune Resistance Mechanisms Mediated By Cancer Cell Derived Extracellular Vesicles, Paola A. Castagnino, Derick A. Haas, Luca Musante, Nathalia A. Tancler, Bach V. Tran, Rhonda Kean, Alexandra R. Steck, Luis A. Martinez, Elahe A. Mostaghel, D. Craig Hooper, Felix J. Kim

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Adaptive immune resistance in cancer describes the various mechanisms by which tumors adapt to evade anti-tumor immune responses. IFN-γ induction of programmed death-ligand 1 (PD-L1) was the first defined and validated adaptive immune resistance mechanism. The endoplasmic reticulum (ER) is central to adaptive immune resistance as immune modulatory secreted and integral membrane proteins are dependent on ER. Sigma1 is a unique ligand-regulated integral membrane scaffolding protein enriched in the ER of cancer cells. PD-L1 is an integral membrane glycoprotein that is translated into the ER and processed through the cellular secretory pathway. At the cell surface, PD-L1 is an immune …

Comprehensive Investigation Of Proteoglycan Gene Expression In Breast Cancer: Discovery Of A Unique Proteoglycan Gene Signature Linked To The Malignant Phenotype, Simone Buraschi, Gabriel Pascal, Federico Liberatore, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Solid tumors present a formidable challenge in oncology, necessitating innovative approaches to improve therapeutic outcomes. Proteoglycans, multifaceted molecules within the tumor microenvironment, have garnered attention due to their diverse roles in cancer progression. Their unique ability to interact with specific membrane receptors, growth factors, and cytokines provides a promising avenue for the development of recombinant proteoglycan-based therapies that could enhance the precision and efficacy of cancer treatment. In this study, we performed a comprehensive analysis of the proteoglycan gene landscape in human breast carcinomas. Leveraging the available wealth of genomic and clinical data regarding gene expression in breast carcinoma and …

Adiposity Throughout Adulthood And Risk Of Young-Onset Breast Cancer Tumor Subtypes In The Young Women's Health History Study, Lydia Marcus Post, Dorothy R. Pathak, Ann S. Hamilton, Kelly A. Hirko, Richard T. Houang, Emily H. Guseman, Dan Sanfelippo, Nicole Bohme Carnegie, L. Karl Olson, Hallgeir Rui, Ann G. Schwartz, Ellen M. Velie

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

BACKGROUND: The role of adult adiposity in young-onset breast cancer (YOBC) subtype risk is not well understood.

METHODS: In this population-based case (n = 1812)-control (n = 1,381) study of invasive YOBC (ages <50 >years), cases were identified from the Los Angeles County and Metropolitan Detroit Surveillance, Epidemiology, and End Results registries, 2010 to 2015. Area-based, frequency-matched controls were sampled from the 2010 Census. General adiposity [body mass index (BMI)] and central adiposity (waist circumference and waist-to-height ratio) across adulthood and covariates were collected from in-person interviews and measurements. ORs and 95% confidence intervals (CI) for adiposity and YOBC tumor subtypes …

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 …

Bp1003 Decreases Stat3 Expression And Its Pro-Tumorigenic Functions In Solid Tumors And The Tumor Microenvironment, Maria Gagliardi, Rhonda Kean, Bingbing Dai, Jithesh Augustine, Michael Roberts, Jason Fleming, D. Craig Hooper, Ana Ashizawa

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Overexpression and aberrant activation of signal transducer and activator of transcription 3 (STAT3) contribute to tumorigenesis, drug resistance, and tumor-immune evasion, making it a potential cancer therapeutic target. BP1003 is a neutral liposome incorporated with a nuclease-resistant P-ethoxy antisense oligodeoxynucleotide (ASO) targeting the STAT3 mRNA. Its unique design enhances BP1003 stability, cellular uptake, and target affinity. BP1003 efficiently reduces STAT3 expression and enhances the sensitivity of breast cancer cells (HER2⁺, triple negative) and ovarian cancer cells (late stage, invasive ovarian cancer) to paclitaxel and 5-fluorouracil (5-FU) in both 2D and 3D cell cultures. Similarly, ex vivo and in …

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 …

Expression Of The Αvβ3 Integrin Affects Prostate Cancer Sev Cargo And Density And Promotes Sev Pro-Tumorigenic Activity In Vivo Through A Gpi-Anchored Receptor, Ngr2, Cecilia Verrillo, Fabio Quaglia, Christopher Shields, Stephen Lin, Andrew Kossenkov, Hsin-Yao Tang, David Speicher, Nicole Naranjo, Anna Testa, William Kelly, Qin Liu, Benjamin Leiby, Luca Musante, Khalid Sossey-Alaoui, Navneet Dogra, Tzu-Yi Chen, Dario Altieri, Lucia Languino

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

It is known that small extracellular vesicles (sEVs) are released from cancer cells and contribute to cancer progression via crosstalk with recipient cells. We have previously reported that sEVs expressing the αVβ3 integrin, a protein upregulated in aggressive neuroendocrine prostate cancer (NEPrCa), contribute to neuroendocrine differentiation (NED) in recipient cells. Here, we examine the impact of αVβ3 expression on sEV protein content, density and function. sEVs used in this study were isolated by iodixanol density gradients and characterized by nanoparticle tracking analysis, immunoblotting and single vesicle analysis. Our proteomic profile of sEVs containing αVβ3 shows downregulation of typical effectors involved …

Altered Extracellular Matrix Correlates With An Immunosuppressive Tumor Microenvironment And Disease Progression In Younger Adults With Oral Cavity Squamous Cell Carcinoma, Leonard Estephan, Gaurav Kumar, Matthew Stewart, Raphael Banoub, Alban Linnenbach, Larry Harshyne, Ubaldo Martinez-Outshoorn, My Mahoney, Joseph Curry, Jennifer Johnson, Andrew South, Adam Luginbuhl

Kimmel Cancer Center Faculty Papers

INTRODUCTION: Oral cavity squamous cell carcinoma (OSCC) occurs most frequently in patients >60 years old with a history of tobacco and alcohol use. Epidemiological studies describe increased incidence of OSCC in younger adults (years). Despite its poor prognosis, knowledge of OSCC tumor microenvironment (TME) characteristics in younger adults is scarce and could help inform possible resistance to emerging treatment options.

METHODS: Patients with OSCC were evaluated using TCGA-HNSC (n=121) and a stage and subsite-matched institutional cohort (n=8) to identify differential gene expression focusing on the extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT) processes in younger (≤45 years) vs. older adults …

Identifying Targetable Vulnerabilities To Circumvent Or Overcome Venetoclax Resistance In Diffuse Large B-Cell Lymphoma, Clare M. Adams, Amanda Mcbride, Peter Michener, Irina Shkundina, Ramkrishna Mitra, Hyun Hwan An, Pierluigi Porcu, Christine M. Eischen

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Clinical trials with single-agent venetoclax/ABT-199 (anti-apoptotic BCL2 inhibitor) revealed that diffuse large B-cell lymphoma (DLBCL) is not solely dependent on BCL2 for survival. Gaining insight into pathways/proteins that increase venetoclax sensitivity or unique vulnerabilities in venetoclax-resistant DLBCL would provide new potential treatment avenues. Therefore, we generated acquired venetoclax-resistant DLBCL cells and evaluated these together with intrinsically venetoclax-resistant and -sensitive DLBCL lines. We identified resistance mechanisms, including alterations in BCL2 family members that differed between intrinsic and acquired venetoclax resistance and increased dependencies on specific pathways. Although combination treatments with BCL2 family member inhibitors may overcome venetoclax resistance, RNA-sequencing and drug/compound …

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 …

Decorin Suppresses Tumor Lymphangiogenesis: A Mechanism To Curtail Cancer Progression, Dipon K. Mondal, Christopher Xie, Gabriel J. Pascal, Simone Buraschi, Renato V. Iozzo

Kimmel Cancer Center Faculty Papers

The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a prosurvival program and to sustain a proangiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, …

Mcl-1 Mediates Intrinsic Resistance To Raf Inhibitors In Mutant Braf Papillary Thyroid Carcinoma, Maria Cavallo, Jacob Yo, Kayla Gallant, Camille Cunanan, Amirali Amirfallah, Marzieh Daniali, Alyssa Sanders, Andrew Aplin, Edmund Pribitkin, Edward Hartsough

Kimmel Cancer Center Faculty Papers

Papillary thyroid carcinoma (PTC) is the most frequent form of thyroid cancer. PTC commonly presents with mutations of the serine/threonine kinase BRAF (BRAF^V600E), which drive ERK1/2 pathway activation to support growth and suppress apoptosis. PTC patients often undergo surgical resection; however, since the average age of PTC patients is under 50, adverse effects associated with prolonged maintenance therapy following total thyroidectomy are a concern. The development of mutant-selective BRAF inhibitors (BRAFi), like vemurafenib, has been efficacious in patients with metastatic melanoma, but the response rate is low for mutant BRAF PTC patients. Here, we assay the therapeutic response …

A Representative Clinical Course Of Progression, With Molecular Insights, Of Hormone Receptor-Positive, Her2-Negative Bone Metastatic Breast Cancer, Elizabeth Magno, Karen M. Bussard

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Despite treatment advances, breast cancer remains a leading cause of death of women in the United States, mostly due to metastatic disease. Bone is a preferential site for breast cancer metastasis, and most metastatic breast cancer patients experience bone involvement at the time of death. The majority of patients with bone metastatic breast cancer are first diagnosed with and treated for early-stage disease, and from development of early-stage breast cancer to the recurrence of cancer in the bones, up to 30 years may elapse. Throughout this timeframe, a typical patient undergoes many treatments that have effects on the bone microenvironment. …

Immunotherapy Resistance In Solid Tumors: Mechanisms And Potential Solutions, Daniel Lefler, Steven Manobianco, Babar Bashir

Kimmel Cancer Center Faculty Papers

While the emergence of immunotherapies has fundamentally altered the management of solid tumors, cancers exploit many complex biological mechanisms that result in resistance to these agents. These encompass a broad range of cellular activities - from modification of traditional paradigms of immunity via antigen presentation and immunoregulation to metabolic modifications and manipulation of the tumor microenvironment. Intervening on these intricate processes may provide clinical benefit in patients with solid tumors by overcoming resistance to immunotherapies, which is why it has become an area of tremendous research interest with practice-changing implications. This review details the major ways cancers avoid both natural …

A Cyclin D1 Intrinsically Disordered Domain Accesses Modified Histone Motifs To Govern Gene Transcription, Xuanmao Jiao, Gabriele Di Sante, Mathew Casimiro, Agnes Tantos, Anthony Ashton, Zhiping Li, Yen Quach, Dharmendra Bhargava, Agnese Di Rocco, Claudia Pupo, Marco Crosariol, Tamas Lazar, Peter Tompa, Chenguang Wang, Zuoren Yu, Zhao Zhang, Kawthar Aldaaysi, Ratna Vadlamudi, Monica Mann, Emmanuel Skordalakes, Andrew Kossenkov, Yanming Du, Richard Pestell

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

The essential G₁-cyclin, CCND1, is frequently overexpressed in cancer, contributing to tumorigenesis by driving cell-cycle progression. D-type cyclins are rate-limiting regulators of G₁-S progression in mammalian cells via their ability to bind and activate CDK4 and CDK6. In addition, cyclin D1 conveys kinase-independent transcriptional functions of cyclin D1. Here we report that cyclin D1 associates with H2B^S14 via an intrinsically disordered domain (IDD). The same region of cyclin D1 was necessary for the induction of aneuploidy, induction of the DNA damage response, cyclin D1-mediated recruitment into chromatin, and CIN gene transcription. In response to …