Medical Cell Biology Commons^™

Targeting Syndecan-1: New Opportunities In Cancer Therapy, Zecheng Yang, Shuaitong Chen, Haoqiang Ying, Wantong Yao

Faculty, Staff and Student Publications

Syndecan-1 (SDC1, CD138) is one of the heparan sulfate proteoglycans and is essential for maintaining normal cell morphology, interacting with the extracellular and intracellular protein repertoire, as well as mediating signaling transduction upon environmental stimuli. The critical role of SDC1 in promoting tumorigenesis and metastasis has been increasingly recognized in various cancer types, implying a promising potential of utilizing SDC1 as a novel target for cancer therapy. This review summarizes the current knowledge on SDC1 structure and functions, including its role in tumor biology. We also discuss the highlights and limitations of current SDC1-targeted therapies as well as the obstacles …

Mycn-Driven Fatty Acid Uptake Is A Metabolic Vulnerability In Neuroblastoma, Ling Tao, Mahmoud A Mohammad, Giorgio Milazzo, Myrthala Moreno-Smith, Tajhal D Patel, Barry Zorman, Andrew Badachhape, Blanca E Hernandez, Amber B Wolf, Zihua Zeng, Jennifer H Foster, Sara Aloisi, Pavel Sumazin, Youli Zu, John Hicks, Ketan B Ghaghada, Nagireddy Putluri, Giovanni Perini, Cristian Coarfa, Eveline Barbieri

Faculty, Staff and Students Publications

Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. MYCN amplification is found in half of high-risk NB patients; however, no available therapies directly target MYCN. Using multi-dimensional metabolic profiling in MYCN expression systems and primary patient tumors, we comprehensively characterized the metabolic landscape driven by MYCN in NB. MYCN amplification leads to glycerolipid accumulation by promoting fatty acid (FA) uptake and biosynthesis. We found that cells expressing amplified MYCN depend highly on FA uptake for survival. Mechanistically, MYCN directly upregulates FA transport protein 2 (FATP2), encoded by SLC27A2. Genetic depletion of SLC27A2 impairs NB survival, and …

Ros And Mirna Dysregulation In Ovarian Cancer Development, Angiogenesis And Therapeutic Resistance, David C Stieg, Yifang Wang, Ling-Zhi Liu, Bing-Hua Jiang

Kimmel Cancer Center Faculty Papers

The diverse repertoires of cellular mechanisms that progress certain cancer types are being uncovered by recent research and leading to more effective treatment options. Ovarian cancer (OC) is among the most difficult cancers to treat. OC has limited treatment options, especially for patients diagnosed with late-stage OC. The dysregulation of miRNAs in OC plays a significant role in tumorigenesis through the alteration of a multitude of molecular processes. The development of OC can also be due to the utilization of endogenously derived reactive oxygen species (ROS) by activating signaling pathways such as PI3K/AKT and MAPK. Both miRNAs and ROS are …

Aberrant Uterine Folding In Mice Disrupts Implantation Chamber Formation And Alignment Of Embryo-Uterine Axes, Manoj K Madhavan, Francesco J Demayo, John P Lydon, Niraj R Joshi, Asgerally T Fazleabas, Ripla Arora

Faculty, Staff and Students Publications

The uterine luminal epithelium folds characteristically in mammals, including humans, horses and rodents. Improper uterine folding in horses results in pregnancy failure, but the precise function of folds remains unknown. Here, we uncover dynamic changes in the 3D uterine folding pattern during early pregnancy with the entire lumen forming pre-implantation transverse folds along the mesometrial-antimesometrial axis. Using a time course, we show that transverse folds are formed before embryo spacing, whereas implantation chambers form as the embryo begins attachment. Thus, folds and chambers are two distinct structures. Transverse folds resolve to form a flat implantation region, after which an embryo …

Skin Fibrosis And Recovery Is Dependent On Wnt Activation Via Dpp4, Anna R Jussila, Brian Zhang, Elizabeth Caves, Sakin Kirti, Miarasa Steele, Emily Hamburg-Shields, John Lydon, Yan Ying, Robert Lafyatis, Sanjay Rajagopalan, Valerie Horsley, Radhika P Atit

Faculty, Staff and Students Publications

Fibrosis is the life-threatening, excessive accumulation of the extracellular matrix and is sometimes associated with a loss of lipid-filled cells in the skin and other organs. Understanding the mechanisms of fibrosis and associated lipodystrophy and their reversal may reveal new targets for therapeutic intervention. In vivo genetic models are needed to identify key targets that induce recovery from established fibrosis. Wnt signaling is activated in animal and human fibrotic diseases across organs. Here, we developed a genetically inducible and reversible Wnt activation model and showed that it is sufficient to cause fibrotic dermal remodeling, including extracellular matrix expansion and shrinking …

Dedifferentiation-Mediated Stem Cell Niche Maintenance In Early-Stage Ductal Carcinoma In Situ Progression: Insights From A Multiscale Modeling Study, Joseph D Butner, Prashant Dogra, Caroline Chung, Javier Ruiz-Ramírez, Sara Nizzero, Marija Plodinec, Xiaoxian Li, Ping-Ying Pan, Shu-Hsia Chen, Vittorio Cristini, Bulent Ozpolat, George A Calin, Zhihui Wang

Faculty, Staff and Student Publications

We present a multiscale agent-based model of ductal carcinoma in situ (DCIS) to study how key phenotypic and signaling pathways are involved in the early stages of disease progression. The model includes a phenotypic hierarchy, and key endocrine and paracrine signaling pathways, and simulates cancer ductal growth in a 3D lattice-free domain. In particular, by considering stochastic cell dedifferentiation plasticity, the model allows for study of how dedifferentiation to a more stem-like phenotype plays key roles in the maintenance of cancer stem cell populations and disease progression. Through extensive parameter perturbation studies, we have quantified and ranked how DCIS is …

Intraovarian, Isoform-Specific Transcriptional Roles Of Progesterone Receptor In Ovulation, Kirsten M Smith, Doan T Dinh, Lisa K Akison, Matilda Nicholls, Kylie R Dunning, Atsushi Morimoto, John P Lydon, Darryl L Russell, Rebecca L Robker

Faculty, Staff and Students Publications

Progesterone receptor (PGR) activity is obligatory for mammalian ovulation; however, there is no established direct functional pathway explaining how progesterone receptor completely and specifically regulates oocyte release. This study examined the overarching cell- and isoform-specific effects of the PGR within each cellular compartment of the ovary, using mice null for the PGR (PRKO), as well as isoform-specific null mice. The PGR was expressed in ovarian granulosa and stromal cells and although PRKO ovaries showed no visible histological changes in preovulatory ovarian morphology, follicle rupture did not occur. Reciprocal ovarian transplant experiments established the necessity of ovarian PGR expression for ovulation. …

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 …

Applying Mci-062, A Novel Pan-Ras Inhibitor, To Treat Kras-Mutant Lung Cancer., Richard Fu

Poster Presentations

Honors thesis poster presentation.

RAS, one of the most prevalent oncogenes, is mutated in 27% of human cancers. Gainof- function RAS mutations activate multiple downstream pathways, including the RASRAF- MEK-ERK and PI3K/AKT/mTOR pathways, which are critical in tumorigenesis and cancer cell proliferation. The RAS proteins KRAS, HRAS, and NRAS along with their downstream effectors are attractive targets for cancer therapy since they act as frequent drivers in lung, colorectal, and pancreatic cancers. However, RAS proteins have relatively smooth surfaces that lack traditional binding pockets, making inhibitors specific to RAS difficult to create. Recently, a novel small molecule pan-RAS inhibitor named …

Developing Targeted Therapies For T-Cell Acute Lymphoblastic Leukemia, Jianzhong Hu

Theses and Dissertations (ETD)

Introduction Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and risk-adapted chemotherapies have dramatically improved the outcomes of this disease. Compared to B-cell ALL, T-cell ALL (T-ALL) is more aggressive and has worse outcomes from chemotherapy. There is a great unmet need to develop biomarkers and novel targeted therapies for this type of cancer. Working together with internal and external collaborators, we performed a large-scale pharmacotyping assay in over 300 primary ALL samples. By combining pharmacotypying and genomic profiling of these samples, we identified a substantial T-ALL population that showed strong response to dasatinib, a known ABL1 …

Development And Characterization Of Anti-Galectin-9 Antibodies That Protect T Cells From Galectin-9-Induced Cell Death, Riyao Yang, Linlin Sun, Ching-Fei Li, Yu-Han Wang, Weiya Xia, Boning Liu, Yu-Yi Chu, Laura Bover, Long Vien, Mien-Chie Hung

Faculty, Staff and Student Publications

Antibodies that target immune checkpoint proteins such as programmed cell death protein 1, programmed death ligand 1, and cytotoxic T-lymphocyte-associated antigen 4 in human cancers have achieved impressive clinical success; however, a significant proportion of patients fail to respond to these treatments. Galectin-9 (Gal-9), a β-galactoside-binding protein, has been shown to induce T-cell death and facilitate immunosuppression in the tumor microenvironment by binding to immunomodulatory receptors such as T-cell immunoglobulin and mucin domain-containing molecule 3 and the innate immune receptor dectin-1, suggesting that it may have potential as a target for cancer immunotherapy. Here, we report the development of two …

Cistrome And Transcriptome Analysis Identifies Unique Androgen Receptor (Ar) And Ar-V7 Splice Variant Chromatin Binding And Transcriptional Activities, Paul Basil, Matthew J Robertson, William E Bingman, Amit K Dash, William C Krause, Ayesha A Shafi, Badrajee Piyarathna, Cristian Coarfa, Nancy L Weigel

Faculty, Staff and Students Publications

The constitutively active androgen receptor (AR) splice variant, AR-V7, plays an important role in resistance to androgen deprivation therapy in castration resistant prostate cancer (CRPC). Studies seeking to determine whether AR-V7 is a partial mimic of the AR, or also has unique activities, and whether the AR-V7 cistrome contains unique binding sites have yielded conflicting results. One limitation in many studies has been the low level of AR variant compared to AR. Here, LNCaP and VCaP cell lines in which AR-V7 expression can be induced to match the level of AR, were used to compare the activities of AR and …

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 …

Ezh2 And Endometrial Cancer Development: Insights From A Mouse Model, Xin Fang, Nan Ni, Xiaofang Wang, Yanan Tian, Ivan Ivanov, Monique Rijnkels, Kayla J Bayless, John P Lydon, Qinglei Li

Faculty, Staff and Students Publications

Enhancer of zeste homolog 2 (EZH2), a core component of polycomb repressive complex 2, plays an important role in cancer development. As both oncogenic and tumor suppressive functions of EZH2 have been documented in the literature, the objective of this study is to determine the impact of Ezh2 deletion on the development and progression of endometrial cancer induced by inactivation of phosphatase and tensin homolog (PTEN), a tumor suppressor gene frequently dysregulated in endometrial cancer patients. To this end, we created mice harboring uterine deletion of both Ezh2 and Pten using Cre recombinase driven by the progesterone receptor …

Human Endothelial Cells Promote Arsenic-Transformed Lung Epithelial Cells To Induce Tumor Growth And Angiogenesis Through Interleukin-8 Induction, Lei Zhao, Yi-Fang Wang, Jie Liu, Bing-Hua Jiang, Ling-Zhi Liu

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Arsenic exposure is associated with lung cancer. Angiogenesis is essential for tumor development. However, the role and mechanism of human vascular endothelial cells in tumor growth and angiogenesis induced by arsenic-transformed bronchial epithelial (As-T) cells remain to be elucidated. In this study, we found that endothelial cells significantly increased As-T cell-induced tumor growth compared to those induced by As-T cells alone. To understand the molecular mechanism, we found that endothelial cells co-cultured with As-T cells or cultured in conditioned medium (CM) prepared from As-T cells showed much higher cell migration, proliferation, and tube formation compared to those co-cultured with BEAS-2B …

Combination Of Tipifarnib And Sunitinib Overcomes Renal Cell Carcinoma Resistance To Tyrosine Kinase Inhibitors Via Tumor-Derived Exosome And T Cell Modulation, Jacob W. Greenberg, Hogyoung Kim, Miae Ahn, Ahmed A. Moustafa, He Zhou, Pedro C. Barata, A. Hamid Boulares, Asim B. Abdel-Mageed, Louis S. Krane

School of Graduate Studies Faculty Publications

Background: Tyrosine kinase inhibitors (TKI) were initially demonstrated as an efficacious treatment for renal cell carcinoma (RCC). However, after a median treatment length of 14 months, a vast majority of patients develop resistance. This study analyzed a combination therapy of tipifarnib (Tipi) + sunitinib that targeted exosome-conferred drug resistance. Methods: 786-O, 786-O-SR (sunitinib resistant), A498, A498-SR, Caki-2, Caki-2-SR, and 293T cells were cultured. Ex-osomes were collected using differential ultracentrifugation. Cell proliferation, Jurkat T cell immune assay, and immunoblot analysis were used for downstream analysis. Results: SR exosomes treatment displayed a cytotoxic effect on immune cells. This cytotoxic effect was associated …

Interplay Between Soluble Cd74 And Macrophage-Migration Inhibitory Factor Drives Tumor Growth And Influences Patient Survival In Melanoma, Yasunari Fukuda, Matias A Bustos, Sung-Nam Cho, Jason Roszik, Suyeon Ryu, Victor M Lopez, Jared K Burks, Jeffrey E Lee, Elizabeth A Grimm, Dave S B Hoon, Suhendan Ekmekcioglu

Faculty, Staff and Student Publications

Soluble forms of receptors play distinctive roles in modulating signal-transduction pathways. Soluble CD74 (sCD74) has been identified in sera of inflammatory diseases and implicated in their pathophysiology; however, few relevant data are available in the context of cancer. Here we assessed the composition and production mechanisms, as well as the clinical significance and biological properties, of sCD74 in melanoma. Serum sCD74 levels were significantly elevated in advanced melanoma patients compared with normal healthy donors, and the high ratio of sCD74 to macrophage-migration inhibitory factor (MIF) conferred significant predictive value for prolonged survival in these patients (p = 0.0035). Secretion of …

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 …

Quality Control For Single Cell Imaging Analytics Using Endocrine Disruptor-Induced Changes In Estrogen Receptor Expression, Fabio Stossi, Pankaj K Singh, Ragini M Mistry, Hannah L Johnson, Radhika D Dandekar, Maureen G Mancini, Adam T Szafran, Arvind U Rao, Michael A Mancini

Faculty, Staff and Students Publications

BACKGROUND: Diverse toxicants and mixtures that affect hormone responsive cells [endocrine disrupting chemicals (EDCs)] are highly pervasive in the environment and are directly linked to human disease. They often target the nuclear receptor family of transcription factors modulating their levels and activity. Many high-throughput assays have been developed to query such toxicants; however, single-cell analysis of EDC effects on endogenous receptors has been missing, in part due to the lack of quality control metrics to reproducibly measure cell-to-cell variability in responses.

OBJECTIVE: We began by developing single-cell imaging and informatic workflows to query whether the single cell distribution of the …

Δnp63 Regulates A Common Landscape Of Enhancer Associated Genes In Non-Small Cell Lung Cancer, Marco Napoli, Sarah J Wu, Bethanie L Gore, Hussein A Abbas, Kyubum Lee, Rahul Checker, Shilpa Dhar, Kimal Rajapakshe, Aik Choon Tan, Min Gyu Lee, Cristian Coarfa, Elsa R Flores

Faculty, Staff and Students Publications

Distinct lung stem cells give rise to lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). ΔNp63, the p53 family member and p63 isoform, guides the maturation of these stem cells through the regulation of their self-renewal and terminal differentiation; however, the underlying mechanistic role regulated by ∆Np63 in lung cancer development has remained elusive. By utilizing a ΔNp63-specific conditional knockout mouse model and xenograft models of LUAD and LUSC, we found that ∆Np63 promotes non-small cell lung cancer by maintaining the lung stem cells necessary for lung cancer cell initiation and progression in quiescence. ChIP-seq analysis of lung basal cells, …

A Human Breast Cancer-Derived Xenograft And Organoid Platform For Drug Discovery And Precision Oncology, Katrin P Guillen, Maihi Fujita, Andrew J Butterfield, Sandra D Scherer, Matthew H Bailey, Zhengtao Chu, Yoko S Derose, Ling Zhao, Emilio Cortes-Sanchez, Chieh-Hsiang Yang, Jennifer Toner, Guoying Wang, Yi Qiao, Xiaomeng Huang, Jeffery A Greenland, Jeffery M Vahrenkamp, David H Lum, Rachel E Factor, Edward W Nelson, Cindy B Matsen, Jane M Poretta, Regina Rosenthal, Anna C Beck, Saundra S Buys, Christos Vaklavas, John H Ward, Randy L Jensen, Kevin B Jones, Zheqi Li, Steffi Oesterreich, Lacey E Dobrolecki, Satya S Pathi, Xing Yi Woo, Kristofer C Berrett, Mark E Wadsworth, Jeffrey H Chuang, Michael T Lewis, Gabor T Marth, Jason Gertz, Katherine E Varley, Bryan E Welm, Alana L Welm

Faculty, Staff and Students Publications

Microscaled proteogenomics was deployed to probe the molecular basis for differential response to neoadjuvant carboplatin and docetaxel combination chemotherapy for triple-negative breast cancer (TNBC). Proteomic analyses of pretreatment patient biopsies uniquely revealed metabolic pathways, including oxidative phosphorylation, adipogenesis, and fatty acid metabolism, that were associated with resistance. Both proteomics and transcriptomics revealed that sensitivity was marked by elevation of DNA repair, E2F targets, G₂–M checkpoint, interferon-gamma signaling, and immune-checkpoint components. Proteogenomic analyses of somatic copy-number aberrations identified a resistance-associated 19q13.31–33 deletion where LIG1, POLD1, and XRCC1 are located. In orthogonal datasets, LIG1 (DNA ligase I) gene …

Reactive Oxygen Species Reprogram Macrophages To Suppress Antitumor Immune Response Through The Exosomal Mir-155-5p/Pd-L1 Pathway, Xiang Li, Shaomin Wang, Wei Mu, Jennifer Barry, Anna Han, Richard L Carpenter, Bing-Hua Jiang, Stephen C Peiper, M G Mahoney, A E Aplin, Hong Ren, Jun He

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background: Cancer cells have an imbalance in oxidation-reduction (redox) homeostasis. Understanding the precise mechanisms and the impact of the altered redox microenvironment on the immunologic reaction to tumors is limited.

Methods: We isolated exosomes from ovarian cancer cells through ultracentrifuge and characterized by Western-blots and Nanoparticle Tracking Analysis. 2D, 3D-coculture tumor model, and 3D live cell imaging were used to study the interactions between tumor cells, macrophages and CD3 T cells in vitro. The role of exosomal miR-155-5p in tumor growth was evaluated in xenograft nude mice models and immune-competent mice models. Flow cytometry and flow sorting were used to …

Rspo2 And Rankl Signal Through Lgr4 To Regulate Osteoclastic Premetastatic Niche Formation And Bone Metastasis, Zhiying Yue, Xin Niu, Zengjin Yuan, Qin Qin, Wenhao Jiang, Liang He, Jingduo Gao, Yi Ding, Yanxi Liu, Ziwei Xu, Zhenxi Li, Zhengfeng Yang, Rong Li, Xiwen Xue, Yankun Gao, Fei Yue, Xiang H-F Zhang, Guohong Hu, Yi Wang, Yi Li, Geng Chen, Stefan Siwko, Alison Gartland, Ning Wang, Jianru Xiao, Mingyao Liu, Jian Luo

Faculty, Staff and Students Publications

Therapeutics targeting osteoclasts are commonly used treatments for bone metastasis; however, whether and how osteoclasts regulate premetastatic niche and bone tropism are largely unknown. In this study, we report that osteoclast precursors (OPs) can function as a premetastatic niche component that facilitates breast cancer (BCa) bone metastasis at early stages. At the molecular level, unbiased GPCR ligand/agonist screening in BCa cells suggested that R-spondin 2 (RSPO2) and RANKL, through interaction with their receptor LGR4, promoted osteoclastic premetastatic niche formation and enhanced BCa bone metastasis. This was achieved by RSPO2/RANKL-LGR4 signal modulating the WNT inhibitor DKK1 through Gαq and β-catenin signaling. …

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 …

The Allergy Mediator Histamine Confers Resistance To Immunotherapy In Cancer Patients Via Activation Of The Macrophage Histamine Receptor H1, Hongzhong Li, Yi Xiao, Qin Li, Jun Yao, Xiangliang Yuan, Yuan Zhang, Xuedong Yin, Yohei Saito, Huihui Fan, Ping Li, Wen-Ling Kuo, Angela Halpin, Don L Gibbons, Hideo Yagita, Zhongming Zhao, Da Pang, Guosheng Ren, Cassian Yee, J Jack Lee, Dihua Yu

Faculty, Staff and Student Publications

Reinvigoration of antitumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy treatment had significantly improved survival. We uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. …

Common Genomic Aberrations In Mouse And Human Breast Cancers With Concurrent P53 Deficiency And Activated Pten-Pi3k-Akt Pathway, Jarrod D Martinez, Qianxing Mo, Yixiang Xu, Li Qin, Yi Li, Jianming Xu

Faculty, Staff and Students Publications

Simultaneous P53 loss and activation of the PTEN-restricted PI3K-AKT pathway frequently occur in aggressive breast cancers. P53 loss causes genome instability, while PTEN loss and/or activating mutations of PIK3CA and AKT promote cancer cell proliferation that also increases incidences of genomic aberrations. However, the genomic alterations associated with P53 loss and activated PTEN-PI3K-AKT signaling in breast cancer have not been defined. Spatiotemporally controlled breast cancer models with inactivation of both P53 and Pten in adult mice have not been established for studying genomic alterations. Herein, we deleted both floxed Pten and Tp53 genes in the mammary gland epithelial cells in …

Monitoring The Systemic Immune System To Understand And Improve The Efficacy Of Immunotherapy For Metastatic Osteosarcoma, Justin Edward Markel

Graduate Theses, Dissertations, and Problem Reports (ETD)

Osteosarcoma (OS) is a complex tumor with no effective targeted therapies due to its genomic heterogeneity and pleomorphism. The immune response it creates, particularly against metastatic lesions, is considerable; however, various suppressive mechanisms induced by the tumor prohibit its effectiveness. The presence of infiltrating lymphocytes suggests that therapeutic disinhibition through checkpoint blockade could increase antitumor immunity, though none have been successful in clinical trials. The complexities of the immune response to OS tumors have yet to be unraveled; however, there is evidence to suggest that cell-mediated immunity (CMI, specifically T cells, Natural Killer [NK] cells, and myeloid-lineage cells [MLCs]) plays …

Nuclear Progesterone Receptor Expressed By The Cortical Thymic Epithelial Cells Dictates Thymus Involution In Murine Pregnancy, Soo Hyun Ahn, Sean L Nguyen, Tae Hoon Kim, Jae-Wook Jeong, Ripla Arora, John P Lydon, Margaret G Petroff

Faculty, Staff and Students Publications

Progesterone is a gonadal pro-gestational hormone that is absolutely necessary for the success of pregnancy. Most notable actions of progesterone are observed in the female reproductive organs, the uterus and the ovary. Acting through the nuclear progesterone receptor (PGR), progesterone prepares the endometrium for implantation of the embryo. Interestingly, the maternal thymus also is a known expressor of Pgr; its absence is associated with murine pregnancy complications. However, the localization of its expression and its functional importance were not known. Here, we used a transgenic dual fluorescent reporter mouse model and genetic deletion of Pgr in Foxn1+ thymic epithelial …

Targeting The Pro-Survival Protein Bcl-2 To Prevent Breast Cancer, Adelaide Young, Wen Bu, Weiyu Jiang, Amy Ku, Jyoti Kapali, Sagar Dhamne, Lan Qin, Susan G Hilsenbeck, Yi-Chieh Nancy Du, Yi Li

Faculty, Staff and Students Publications

Current chemopreventive strategies require 3-5 years of continuous treatment and have the concerns of significant side effects; therefore, new chemopreventive agents that require shorter and safer treatments are urgently needed. In this study, we developed a new murine model of breast cancer that mimics human breast cancer initiation and is ideal for testing the efficacy of chemopreventive therapeutics. In this model, introduction of lentivirus carrying a PIK3CA gene mutant commonly found in breast cancers infects a small number of the mammary cells, leading to atypia first and then to ductal carcinomas that are positive for both estrogen receptor and progesterone …

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 …