Medical Specialties Commons^™

Small Extracellular Vesicle-Mediated Itgb6 Sirna Delivery Downregulates The Αvβ6 Integrin And Inhibits Adhesion And Migration Of Recipient Prostate Cancer Cells, Shiv Ram Krishn, Vaughn Garcia, Nicole M Naranjo, Fabio Quaglia, Christopher D Shields, Maisha A Harris, Andrew V Kossenkov, Qin Liu, Eva Corey, Dario C Altieri, Lucia R Languino

Department of Cancer Biology Faculty Papers

The αVβ6 integrin, an epithelial-specific cell surface receptor absent in normal prostate and expressed during prostate cancer (PrCa) progression, is a therapeutic target in many cancers. Here, we report that transcript levels of ITGB6 (encoding the β6 integrin subunit) are significantly increased in metastatic castrate-resistant androgen receptor-negative prostate tumors compared to androgen receptor-positive prostate tumors. In addition, the αVβ6 integrin protein levels are significantly elevated in androgen receptor-negative PrCa patient derived xenografts (PDXs) compared to androgen receptor-positive PDXs. In vitro, the androgen receptor-negative PrCa cells express high levels of the αVβ6 integrin compared to androgen receptor-positive PrCa cells. Additionally, …

Stabilized Core Gene And Pathway Election Uncovers Pan-Cancer Shared Pathways And A Cancer-Specific Driver, Pathum Kossinna, Weijia Cai, Xuewen Lu, Carrie S Shemanko, Qingrun Zhang

Department of Cancer Biology Faculty Papers

Approaches systematically characterizing interactions via transcriptomic data usually follow two systems: (i) coexpression network analyses focusing on correlations between genes and (ii) linear regressions (usually regularized) to select multiple genes jointly. Both suffer from the problem of stability: A slight change of parameterization or dataset could lead to marked alterations of outcomes. Here, we propose Stabilized COre gene and Pathway Election (SCOPE), a tool integrating bootstrapped least absolute shrinkage and selection operator and coexpression analysis, leading to robust outcomes insensitive to variations in data. By applying SCOPE to six cancer expression datasets (BRCA, COAD, KIRC, LUAD, PRAD, and THCA) in …

The Nogo Receptor Ngr2, A Novel Αvβ3 Integrin Effector, Induces Neuroendocrine Differentiation In Prostate Cancer, Fabio Quaglia, Shiv Ram Krishn, Khalid Sossey-Alaoui, Priyanka Shailendra Rana, Elzbieta Pluskota, Pyung Hun Park, Christopher D. Shields, Stephen Lin, Peter Mccue, Andrew V. Kossenkov, Yanqing Wang, David W. Goodrich, Sheng-Yu Ku, Himisha Beltran, William K. Kelly, Eva Corey, Maja Klose, Christine Bandtlow, Qin Liu, Dario C. Altieri, Edward F. Plow, Lucia R. Languino

Department of Cancer Biology Faculty Papers

Androgen deprivation therapies aimed to target prostate cancer (PrCa) are only partially successful given the occurrence of neuroendocrine PrCa (NEPrCa), a highly aggressive and highly metastatic form of PrCa, for which there is no effective therapeutic approach. Our group has demonstrated that while absent in prostate adenocarcinoma, the αVβ3 integrin expression is increased during PrCa progression toward NEPrCa. Here, we show a novel pathway activated by αVβ3 that promotes NE differentiation (NED). This novel pathway requires the expression of a GPI-linked surface molecule, NgR2, also known as Nogo-66 receptor homolog 1. We show here that NgR2 is upregulated by αVβ3, …

Ctpathway: A Crosstalk-Based Pathway Enrichment Analysis Method For Cancer Research, Haizhou Liu, Mengqin Yuan, Ramkrishna Mitra, Xu Zhou, Min Long, Wanyue Lei, Shunheng Zhou, Yu-E Huang, Fei Hou, Christine M. Eischen, Wei Jiang

Department of Cancer Biology Faculty Papers

Background: Pathway enrichment analysis (PEA) is a common method for exploring functions of hundreds of genes and identifying disease-risk pathways. Moreover, different pathways exert their functions through crosstalk. However, existing PEA methods do not sufficiently integrate essential pathway features, including pathway crosstalk, molecular interactions, and network topologies, resulting in many risk pathways that remain uninvestigated.

Methods: To overcome these limitations, we develop a new crosstalk-based PEA method, CTpathway, based on a global pathway crosstalk map (GPCM) with >440,000 edges by combing pathways from eight resources, transcription factor-gene regulations, and large-scale protein-protein interactions. Integrating gene differential expression and crosstalk effects in …

Lysine Methyltransferase Nsd1 And Cancers: Any Role In Melanoma?, Imène Krossa, Thomas Strub, Andrew E Aplin, Robert Ballotti, Corine Bertolotto

Department of Cancer Biology Faculty Papers

Epigenetic regulations, that comprise histone modifications and DNA methylation, are essential to processes as diverse as development and cancer. Among the histone post-translational modifications, lysine methylation represents one of the most important dynamic marks. Here, we focused on methyltransferases of the nuclear binding SET domain 1 (NSD) family, that catalyze the mono- and di-methylation of histone H3 lysine 36. We review the loss of function mutations of NSD1 in humans that are the main cause of SOTOS syndrome, a disease associated with an increased risk of developing cancer. We then report the role of NSD1 in triggering tumor suppressive or …

A Genome-Wide Screen Identifies Pdpk1 As A Target To Enhance The Efficacy Of Mek1/2 Inhibitors, Weijia Cai, Nicole A. Wilski, Timothy J. Purwin, Megane Vernon, Manoela Tiago, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

Melanomas frequently harbor activating NRAS mutations. However, limited advance has been made in developing targeted therapy options for NRAS mutant melanoma patients. MEK inhibitors (MEKi) show modest efficacy in the clinic and their actions need to be optimized. In this study, we performed a genome-wide CRISPR-Cas9-based screen and demonstrated that loss of Phosphoinositide-dependent kinase-1 (PDPK1) enhances the efficacy of MEKi. The synergistic effects of PDPK1 loss and MEKi was validated in NRAS mutant melanoma cell lines using pharmacological and molecular approaches. Combined PDPK1 inhibitors (PDPK1i) with MEKi suppressed NRAS mutant xenograft growth and induced gasdermin E-associated pyroptosis. In an immune-competent …

The Future Of Targeted Kinase Inhibitors In Melanoma, Signe Caksa, Usman Baqai, A E Aplin

Department of Cancer Biology Faculty Papers

Melanoma is a cancer of the pigment-producing cells of the body and its incidence is rising. Targeted inhibitors that act against kinases in the MAPK pathway are approved for BRAF-mutant metastatic cutaneous melanoma and increase patients' survival. Response to these therapies is limited by drug resistance and is less durable than with immune checkpoint inhibition. Conversely, rare melanoma subtypes have few therapeutic options for advanced disease and MAPK pathway targeting agents show minimal anti-tumor effects. Nevertheless, there is a future for targeted kinase inhibitors in melanoma: in new applications such as adjuvant or neoadjuvant therapy and in novel combinations with …

Targeting Sox10-Deficient Cells To Reduce The Dormant-Invasive Phenotype State In Melanoma, Claudia Capparelli, Timothy J. Purwin, Mckenna Glasheen, Signe Caksa, Manoela Tiago, Nicole A. Wilski, Danielle Pomante, Sheera Rosenbaum, Mai Q Nguyen, Weijia Cai, Janusz Franco-Barraza, R. Zheng, Md, Gaurav Kumar, I Chervoneva, Ayako Shimada, Vito W Rebecca, Adam E. Snook, Kim Hookim, Xiaowei Xu, Edna Cukierman, Meenhard Herlyn, A E Aplin

Department of Cancer Biology Faculty Papers

Cellular plasticity contributes to intra-tumoral heterogeneity and phenotype switching, which enable adaptation to metastatic microenvironments and resistance to therapies. Mechanisms underlying tumor cell plasticity remain poorly understood. SOX10, a neural crest lineage transcription factor, is heterogeneously expressed in melanomas. Loss of SOX10 reduces proliferation, leads to invasive properties, including the expression of mesenchymal genes and extracellular matrix, and promotes tolerance to BRAF and/or MEK inhibitors. We identify the class of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) inhibitors as inducing cell death selectively in SOX10-deficient cells. Targeted therapy selects for SOX10 knockout cells underscoring their drug tolerant properties. Combining cIAP1/2 inhibitor …

Ghost Mitochondria Drive Metastasis Through Adaptive Gcn2/Akt Therapeutic Vulnerability, Jagadish C Ghosh, Michela Perego, Ekta Agarwal, Irene Bertolini, Yuan Wang, Aaron R Goldman, Hsin-Yao Tang, Andrew V Kossenkov, Catherine J Libby, Lucia R Languino, Edward F Plow, Annamaria Morotti, Luisa Ottobrini, Marco Locatelli, David W Speicher, M Cecilia Caino, Joel Cassel, Joseph M Salvino, Marie E Robert, Valentina Vaira, Dario C Altieri

Department of Cancer Biology Faculty Papers

Cancer metabolism, including in mitochondria, is a disease hallmark and therapeutic target, but its regulation is poorly understood. Here, we show that many human tumors have heterogeneous and often reduced levels of Mic60, or Mitofilin, an essential scaffold of mitochondrial structure. Despite a catastrophic collapse of mitochondrial integrity, loss of bioenergetics, and oxidative damage, tumors with Mic60 depletion slow down cell proliferation, evade cell death, and activate a nuclear gene expression program of innate immunity and cytokine/chemokine signaling. In turn, this induces epithelial-mesenchymal transition (EMT), activates tumor cell movements through exaggerated mitochondrial dynamics, and promotes metastatic dissemination in vivo. In …

Dna-Pkcs: A Targetable Protumorigenic Protein Kinase., Emanuela Dylgjeri, Karen E Knudsen

Department of Cancer Biology Faculty Papers

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a pleiotropic protein kinase that plays critical roles in cellular processes fundamental to cancer. DNA-PKcs expression and activity are frequently deregulated in multiple hematologic and solid tumors and have been tightly linked to poor outcome. Given the potentially influential role of DNA-PKcs in cancer development and progression, therapeutic targeting of this kinase is being tested in preclinical and clinical settings. This review summarizes the latest advances in the field, providing a comprehensive discussion of DNA-PKcs functions in cancer and an update on the clinical assessment of DNA-PK inhibitors in cancer therapy.

Ras-Mediated Tumor Stress Adaptation And The Targeting Opportunities It Presents, Alexandra Redding, A E Aplin, Elda Grabocka

Department of Cancer Biology Faculty Papers

Cellular stress is known to function in synergistic cooperation with oncogenic mutations during tumorigenesis to drive cancer progression. Oncogenic RAS is a strong inducer of a variety of pro-tumorigenic cellular stresses, and also enhances the ability of cells to tolerate these stresses through multiple mechanisms. Many of these oncogenic, RAS-driven, stress-adaptive mechanisms have also been implicated in tolerance and resistance to chemotherapy and to therapies that target the RAS pathway. Understanding how oncogenic RAS shapes cellular stress adaptation and how this functions in drug resistance is of vital importance for identifying new therapeutic targets and therapeutic combinations to treat RAS-driven …

Novel Oncogenic Transcription Factor Cooperation In Rb-Deficient Cancer, Amy C. Mandigo, Ayesha A Shafi, Jennifer J Mccann, Wei Yuan, Talya Laufer, Denisa Bogdan, Lewis Gallagher, Emanuela Dylgjeri, Galina Semenova, Irina A Vasilevskaya, M J Schiewer, Chris M Mcnair, Johann S De Bono, Karen E Knudsen

Department of Cancer Biology Faculty Papers

The retinoblastoma tumor suppressor (RB) is a critical regulator of E2F-dependent transcription, controlling a multitude of protumorigenic networks including but not limited to cell-cycle control. Here, genome-wide assessment of E2F1 function after RB loss in isogenic models of prostate cancer revealed unexpected repositioning and cooperation with oncogenic transcription factors, including the major driver of disease progression, the androgen receptor (AR). Further investigation revealed that observed AR/E2F1 cooperation elicited novel transcriptional networks that promote cancer phenotypes, especially as related to evasion of cell death. These observations were reflected in assessment of human disease, indicating the clinical relevance of the AR/E2F1 cooperome …

Sox10 Requirement For Melanoma Tumor Growth Is Due, In Part, To Immune-Mediated Effects, Sheera Rosenbaum, Manoela Tiago, Signe Caksa, Claudia Capparelli, Timothy J. Purwin, Gaurav Kumar, Mckenna Glasheen, Danielle Pomante, Daniel Kotas, I Chervoneva, A E Aplin

Department of Cancer Biology Faculty Papers

Developmental factors may regulate the expression of immune modulatory proteins in cancer, linking embryonic development and cancer cell immune evasion. This is particularly relevant in melanoma because immune checkpoint inhibitors are commonly used in the clinic. SRY-box transcription factor 10 (SOX10) mediates neural crest development and is required for melanoma cell growth. In this study, we investigate immune-related targets of SOX10 and observe positive regulation of herpesvirus entry mediator (HVEM) and carcinoembryonic-antigen cell-adhesion molecule 1 (CEACAM1). Sox10 knockout reduces tumor growth in vivo, and this effect is exacerbated in immune-competent models. Modulation of CEACAM1 expression but not HVEM elicits modest …

Targeted Treatment Of Head And Neck (Pre)Cancer: Preclinical Target Identification And Development Of Novel Therapeutic Applications, Anne Van Harten, Ruud H. Brakenhoff

Department of Cancer Biology Faculty Papers

Head and neck squamous cell carcinomas (HNSCC) develop in the mucosal lining ofthe upper-aerodigestive tract. In carcinogen-induced HNSCC, tumors emerge from premalignantmucosal changes characterized by tumor-associated genetic alterations, also coined as ‘fields’ that areoccasionally visible as leukoplakia or erythroplakia lesions but are mostly invisible. Consequently,HNSCC is generally diagnosedde novoat more advanced stages in about 70% of new diagnosis.Despite intense multimodality treatment protocols, the overall 5-years survival rate is 50–60% forpatients with advanced stage of disease and seems to have reached a plateau. Of notable concern isthe lack of further improvement in prognosis despite advances in treatment. This can be attributedto …

Mircorrnet: Machine Learning-Based Integration Of Mirna And Mrna Expression Profiles, Combined With Feature Grouping And Ranking., Malik Yousef, Gokhan Goy, Ramkrishna Mitra, Christine M. Eischen, Amhar Jabeer, Burcu Bakir-Gungor

Department of Cancer Biology Faculty Papers

A better understanding of disease development and progression mechanisms at the molecular level is critical both for the diagnosis of a disease and for the development of therapeutic approaches. The advancements in high throughput technologies allowed to generate mRNA and microRNA (miRNA) expression profiles; and the integrative analysis of these profiles allowed to uncover the functional effects of RNA expression in complex diseases, such as cancer. Several researches attempt to integrate miRNA and mRNA expression profiles using statistical methods such as Pearson correlation, and then combine it with enrichment analysis. In this study, we developed a novel tool called miRcorrNet, …

The Quandary Of Dna-Based Treatment Assessment In De Novo Metastatic Prostate Cancer In The Era Of Precision Oncology., Sigve Nakken, Wolfgang Lilleby, Marta D. Switlyk, Karen E Knudsen, Oscar Lilleby, Sen Zhao, Fatemeh Kaveh, Per O. Ekstrøm, Alfonso Urbanucci, Eivind Hovig

Department of Cancer Biology Faculty Papers

Guidelines for genetic testing have been established for multiple tumor types, frequently indicating the most confident molecularly targeted treatment options. However, considering the often-complex presentation of individual cancer patients, in addition to the combinatorial complexity and inherent uncertainties of molecular findings, deriving optimal treatment strategies frequently becomes very challenging. Here, we report a comprehensive analysis of a 68-year-old male with metastatic prostate cancer, encompassing pathology and MRI findings, transcriptomic results, and key genomics findings from whole-exome sequencing, both somatic aberrations and germline variants. We identify multiple somatic aberrations that are known to be enriched in prostate cancer, including a deletion …

Redefining Cancer Of Unknown Primary: Is Precision Medicine Really Shifting The Paradigm?, Timothée Olivier, Eugenio Fernandez, Intidhar Labidi-Galy, Pierre-Yves Dietrich, Veronica Rodriguez-Bravo, Giulia Baciarello, Karim Fizazi, Anna Patrikidou

Department of Cancer Biology Faculty Papers

The concept of Cancer of Unknown Primary (CUP) has evolved with the advent of medical oncology. CUP can be difficult to diagnose and represents 2 to 5% of new cancers, therefore not exceptionally rare. Within CUPs can be identified a subset of favourable prognosis tumours, however the vast majority of CUP patients belongs to a poor prognosis group. CUP features significant oncological challenges, such as unravelling biological and transversal issues, and most importantly, improving patient's outcomes. In that regard, CUP patients’ outcomes regrettably showed minimal improvement for decades and CUP remains a cancer group of very poor prognosis. The biology …

Printing The Pathway Forward In Bone Metastatic Cancer Research: Applications Of 3d Engineered Models And Bioprinted Scaffolds To Recapitulate The Bone-Tumor Niche., Anne M. Hughes, Alexus D. Kolb, Alison B. Shupp, Kristy M. Shine, Karen M. Bussard

Department of Cancer Biology Faculty Papers

Breast cancer commonly metastasizes to bone, resulting in osteolytic lesions and poor patient quality of life. The bone extracellular matrix (ECM) plays a critical role in cancer cell metastasis by means of the physical and biochemical cues it provides to support cellular crosstalk. Current two-dimensional in-vitro models lack the spatial and biochemical complexities of the native ECM and do not fully recapitulate crosstalk that occurs between the tumor and endogenous stromal cells. Engineered models such as bone-on-a-chip, extramedullary bone, and bioreactors are presently used to model cellular crosstalk and bone-tumor cell interactions, but fall short of providing a bone-biomimetic microenvironment. …

Differential Expression Of Αvβ3 And Αvβ6 Integrins In Prostate Cancer Progression, Fabio Quaglia, Shiv Ram Krishn, Yanqing Wang, David W Goodrich, Peter Mccue, Andrew Kossenkov, Amy C Mandigo, Karen Knudsen, Paul H Weinreb, Eva Corey, William Kevin Kelly, Lucia R Languino

Department of Cancer Biology Faculty Papers

Neuroendocrine prostate cancer (NEPrCa) arises de novo or after accumulation of genomic alterations in pre-existing adenocarcinoma tumors in response to androgen deprivation therapies. We have provided evidence that small extracellular vesicles released by PrCa cells and containing the αVβ3 integrin promote neuroendocrine differentiation of PrCa in vivo and in vitro. Here, we examined αVβ3 integrin expression in three murine models carrying a deletion of PTEN (SKO), PTEN and RB1 (DKO), or PTEN, RB1 and TRP53 (TKO) genes in the prostatic epithelium; of these three models, the DKO and TKO tumors develop NEPrCa with a gene signature comparable to those of …

'Educated' Osteoblasts Reduce Osteoclastogenesis In A Bone-Tumor Mimetic Microenvironment., Alexus D. Kolb, Jinlu Dai, Evan T. Keller, Karen M. Bussard

Department of Cancer Biology Faculty Papers

Breast cancer (BC) metastases to bone disrupt the balance between osteoblasts and osteoclasts, leading to excessive bone resorption. We identified a novel subpopulation of osteoblasts with tumor-inhibitory properties, called educated osteoblasts (EOs). Here we sought to examine the effect of EOs on osteoclastogenesis during tumor progression. We hypothesized that EOs affect osteoclast development in the bone-tumor niche, leading to suppressed pre-osteoclast fusion and bone resorption. Conditioned media (CM) was analyzed for protein expression of osteoclast factors receptor activator of nuclear factor kappa-β ligand (RANKL), osteoprotegerin (OPG), and tumor necrosis factor alpha (TNFα) via ELISA. EOs were co-cultured with pre-osteoclasts on …

Myc Regulates Ribosome Biogenesis And Mitochondrial Gene Expression Programs Through Its Interaction With Host Cell Factor-1., Tessa M. Popay, Jing Wang, Clare M. Adams, Gregory Caleb Howard, Simona G. Codreanu, Stacy D. Sherrod, John A. Mclean, Lance R. Thomas, Shelly L. Lorey, Yuichi J. Machida, April M. Weissmiller, Christine M. Eischen, Qi Liu, William P. Tansey

Department of Cancer Biology Faculty Papers

The oncoprotein transcription factor MYC is a major driver of malignancy and a highly validated but challenging target for the development of anticancer therapies. Novel strategies to inhibit MYC may come from understanding the co-factors it uses to drive pro-tumorigenic gene expression programs, providing their role in MYC activity is understood. Here we interrogate how one MYC co-factor, host cell factor (HCF)-1, contributes to MYC activity in a human Burkitt lymphoma setting. We identify genes connected to mitochondrial function and ribosome biogenesis as direct MYC/HCF-1 targets and demonstrate how modulation of the MYC-HCF-1 interaction influences cell growth, metabolite profiles, global …

The Membrane-Associated Form Of Cyclin D1 Enhances Cellular Invasion, Ke Chen, Xuanmao Jiao, Anthony Ashton, Agnese Di Rocco, Timothy G Pestell, Yunguang Sun, Jun Zhao, Mathew C Casimiro, Zhiping Li, Michael P Lisanti, Peter Mccue, Duanwen Shen, Samuel Achilefu, Hallgeir Rui, Richard G Pestell

Department of Cancer Biology Faculty Papers

The essential G1-cyclin, CCND1, is a collaborative nuclear oncogene that is frequently overexpressed in cancer. D-type cyclins bind and activate CDK4 and CDK6 thereby contributing to G1-S cell-cycle progression. In addition to the nucleus, herein cyclin D1 was also located in the cytoplasmic membrane. In contrast with the nuclear-localized form of cyclin D1 (cyclin D1NL), the cytoplasmic membrane-localized form of cyclin D1 (cyclin D1MEM) induced transwell migration and the velocity of cellular migration. The cyclin D1MEM was sufficient to induce G1-S cell-cycle progression, cellular proliferation, and colony formation. The cyclin D1MEM was sufficient to induce phosphorylation of the serine threonine …

Endogenous Cyclin D1 Promotes The Rate Of Onset And Magnitude Of Mitogenic Signaling Via Akt1 Ser473 Phosphorylation., Ke Chen, Xuanmao Jiao, Agnese Di Rocco, Duanwen Shen, Shaohua Xu, Adam Ertel, Zuoren Yu, Gabriele Di Sante, Min Wang, Zhiping Li, Timothy G Pestell, Mathew C Casimiro, Emmanuel Skordalakes, Samuel Achilefu, Richard G Pestell

Department of Cancer Biology Faculty Papers

Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates RB and functions as a collaborative nuclear oncogene. The serine threonine kinase Akt plays a pivotal role in the control of cellular metabolism, survival, and mitogenic signaling. Herein, Akt1-mediated phosphorylation of downstream substrates in the mammary gland is reduced by cyclin D1 genetic deletion and is induced by mammary-gland-targeted cyclin D1 overexpression. Cyclin D1 is associated with Akt1 and augments the rate of onset and maximal cellular Akt1 activity induced by mitogens. Cyclin D1 is identified in a cytoplasmic-membrane-associated pool, and cytoplasmic-membrane-localized cyclin D1-but not nuclear-localized cyclin D1-recapitulates Akt1 …

Iseqqc: A Tool For Expression-Based Quality Control In Rna Sequencing., Gaurav Kumar, Adam Ertel, George Feldman, Joan Kupper, Paolo Fortina

Department of Cancer Biology Faculty Papers

BACKGROUND: Quality Control in any high-throughput sequencing technology is a critical step, which if overlooked can compromise an experiment and the resulting conclusions. A number of methods exist to identify biases during sequencing or alignment, yet not many tools exist to interpret biases due to outliers.

RESULTS: Hence, we developed iSeqQC, an expression-based QC tool that detects outliers either produced due to variable laboratory conditions or due to dissimilarity within a phenotypic group. iSeqQC implements various statistical approaches including unsupervised clustering, agglomerative hierarchical clustering and correlation coefficients to provide insight into outliers. It can be utilized through command-line (Github: https://github.com/gkumar09/iSeqQC) …

Microrna And Transcription Factor Co-Regulatory Networks And Subtype Classification Of Seminoma And Non-Seminoma In Testicular Germ Cell Tumors., Guimin Qin, Saurav Mallik, Ramkrishna Mitra, Aimin Li, Peilin Jia, Christine M. Eischen, Zhongming Zhao

Department of Cancer Biology Faculty Papers

Recent studies have revealed that feed-forward loops (FFLs) as regulatory motifs have synergistic roles in cellular systems and their disruption may cause diseases including cancer. FFLs may include two regulators such as transcription factors (TFs) and microRNAs (miRNAs). In this study, we extensively investigated TF and miRNA regulation pairs, their FFLs, and TF-miRNA mediated regulatory networks in two major types of testicular germ cell tumors (TGCT): seminoma (SE) and non-seminoma (NSE). Specifically, we identified differentially expressed mRNA genes and miRNAs in 103 tumors using the transcriptomic data from The Cancer Genome Atlas. Next, we determined significantly correlated TF-gene/miRNA and miRNA-gene/TF …

Foxd3 Regulates Vista Expression In Melanoma., Sheera R. Rosenbaum, Meghan Knecht, Mehri Mollaee, Zhijiu Zhong, Dan A. Erkes, Peter A. Mccue, Chervoneva, Adam C. Berger, Jennifer A. Lo, David E. Fisher, Jeffrey E. Gershenwald, Michael A. Davies, Timothy J. Purwin, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

Immune checkpoint inhibitors have improved patient survival in melanoma, but the innate resistance of many patients necessitates the investigation of alternative immune targets. Many immune checkpoint proteins lack proper characterization, including V-domain Ig suppressor of T cell activation (VISTA). VISTA expression on immune cells can suppress T cell activity; however, few studies have investigated its expression and regulation in cancer cells. In this study, we observe that VISTA is expressed in melanoma patient samples and cell lines. Tumor cell-specific expression of VISTA promotes tumor onset in vivo, associated with increased intratumoral T regulatory cells, and enhanced PDL-1 expression on tumor-infiltrating …

Interaction Of The Oncoprotein Transcription Factor Myc With Its Chromatin Cofactor Wdr5 Is Essential For Tumor Maintenance., Lance R. Thomas, Clare M. Adams, Jing Wang, April M. Weissmiller, Joy Creighton, Shelly L. Lorey, Qi Liu, Stephen W. Fesik, Christine M. Eischen, William P. Tansey

Department of Cancer Biology Faculty Papers

The oncoprotein transcription factor MYC is overexpressed in the majority of cancers. Key to its oncogenic activity is the ability of MYC to regulate gene expression patterns that drive and maintain the malignant state. MYC is also considered a validated anticancer target, but efforts to pharmacologically inhibit MYC have failed. The dependence of MYC on cofactors creates opportunities for therapeutic intervention, but for any cofactor this requires structural understanding of how the cofactor interacts with MYC, knowledge of the role it plays in MYC function, and demonstration that disrupting the cofactor interaction will cause existing cancers to regress. One cofactor …

Slc36a1-Mtorc1 Signaling Drives Acquired Resistance To Cdk4/6 Inhibitors., Akihiro Yoshida, Yiwen Bu, Shuo Qie, John Wrangle, E. Ramsay Camp, E. Starr Hazard, Gary Hardiman, Renée De Leeuw, Karen E. Knudsen, J. Alan Diehl

Department of Cancer Biology Faculty Papers

The cyclin-dependent kinase 4/6 (CDK4/6) kinase is dysregulated in melanoma, highlighting it as a potential therapeutic target. CDK4/6 inhibitors are being evaluated in trials for melanoma and additional cancers. While beneficial, resistance to therapy is a concern, and the molecular mechanisms of such resistance remain undefined. We demonstrate that reactivation of mammalian target of rapamycin 1 (mTORC1) signaling through increased expression of the amino acid transporter, solute carrier family 36 member 1 (SLC36A1), drives resistance to CDK4/6 inhibitors. Increased expression of SLC36A1 reflects two distinct mechanisms: (i) Rb loss, which drives SLC36A1 via reduced suppression of E2f; (ii) fragile X …

Identification Of Monocyte-Like Precursors Of Granulocytes In Cancer As A Mechanism For Accumulation Of Pmn-Mdscs., Jérôme Mastio, Thomas Condamine, George Dominguez, Andrew V Kossenkov, Laxminarasimha Donthireddy, Filippo Veglia, Cindy Lin, Fang Wang, Shuyu Fu, Jie Zhou, Patrick Viatour, Sergio Lavilla-Alonso, Alexander T. Polo, Evgenii N. Tcyganov, Charles Mulligan, Brian Nam, Joseph Bennett, Gregory Masters, Michael Guarino, Amit Kumar, Yulia Nefedova, Robert H. Vonderheide, Lucia R. Languino, Scott I. Abrams, Dmitry I. Gabrilovich

Department of Cancer Biology Faculty Papers

We have identified a precursor that differentiates into granulocytes in vitro and in vivo yet belongs to the monocytic lineage. We have termed these cells monocyte-like precursors of granulocytes (MLPGs). Under steady state conditions, MLPGs were absent in the spleen and barely detectable in the bone marrow (BM). In contrast, these cells significantly expanded in tumor-bearing mice and differentiated to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Selective depletion of monocytic cells had no effect on the number of granulocytes in naive mice but decreased the population of PMN-MDSCs in tumor-bearing mice by 50%. The expansion of MLPGs was found to be …

The Bone Extracellular Matrix As An Ideal Milieu For Cancer Cell Metastases., Alexus D. Kolb, Karen M. Bussard

Department of Cancer Biology Faculty Papers

Bone is a preferential site for cancer metastases, including multiple myeloma, prostate, and breast cancers.The composition of bone, especially the extracellular matrix (ECM), make it an attractive site for cancer cell colonization and survival. The bone ECM is composed of living cells embedded within a matrix composed of both organic and inorganic components. Among the organic components, type I collagen provides the tensile strength of bone. Inorganic components, including hydroxyapatite crystals, are an integral component of bone and provide bone with its rigidity. Under normal circumstances, two of the main cell types in bone, the osteoblasts and osteoclasts, help to …