Medical Microbiology Commons^™

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, …

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 …

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 …

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. …

Radiofrequency Ablation In Combination With Cd73 Inhibitor Ab680 Reduces Tumor Growth And Enhances Anti-Tumor Immunity In A Syngeneic Model Of Pancreatic Ductal Adenocarcinoma, Erika Y Faraoni, Lincoln N Strickland, Baylee J O'Brien, Joseph F Barraza, Nirav C Thosani, Curtis J Wray, Tingting W Mills, Jennifer M Bailey-Lundberg

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma presents a 5-year overall survival rate of 11%, placing an imperative need for the discovery and application of innovative treatments. Radiofrequency ablation represents a promising therapy for PDA, as studies show it induces coagulative necrosis and a host adaptive immune response. In this work we evaluated the effects of RFA treatment in vivo by establishing a syngeneic mouse model of PDA and performing tumor ablation in one flank. Our studies revealed RFA acutely impaired PDA tumor growth; however, such effects were not sustained one week after treatment. Adenosine (ADO) pathway represents a strong immunosuppressive mechanism that was …

Single-Cell Rna Sequencing Reveals Intratumoral Heterogeneity And Potential Mechanisms Of Malignant Progression In Prostate Cancer With Perineural Invasion, Bao Zhang, Shenghan Wang, Zhichao Fu, Qiang Gao, Lin Yang, Zhentao Lei, Yuqiang Shi, Kai Le, Jie Xiong, Siyao Liu, Jiali Zhang, Junyan Su, Jing Chen, Mengyuan Liu, Beifang Niu

Faculty, Staff and Student Publications

Background: Prostate cancer (PCa) is the second most common cancer among men worldwide. Perineural invasion (PNI) was a prominent characteristic of PCa, which was recognized as a key factor in promoting PCa progression. As a complex and heterogeneous disease, its true condition is difficult to explain thoroughly with conventional bulk RNA sequencing. Thus, an improved understanding of PNI-PCa progression at the single-cell level is needed.

Methods: In this study, we performed scRNAseq on tumor tissues of three PNI-PCa patients. Principal component analysis (PCA) and Uniform manifold approximation and projection (UMAP) were used to reduce dimensionality and visualize the cellular composition …

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 …

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 …

Socioeconomic, Clinical, And Molecular Features Of Breast Cancer Influence Overall Survival Of Latin American Women, Liz Maria De Almeida, Sandra Cortés, Marta Vilensky, Olivia Valenzuela, Laura Cortes-Sanabria, Mirian De Souza, Rafael Alonso Barbeito, Eliana Abdelhay, Nora Artagaveytia, Adrian Daneri-Navarro, Andrea S Llera, Bettina Müller, Osvaldo L Podhajcer, Carlos Velazquez, Elsa Alcoba, Isabel Alonso, Alicia I Bravo, Natalia Camejo, Dirce Maria Carraro, Mónica Castro, Sandra Cataldi, Alfonso Cayota, Mauricio Cerda, Alicia Colombo, Susanne Crocamo, Alicia Del Toro-Arreola, Raul Delgadillo-Cristerna, Lucia Delgado, Marisa Dreyer Breitenbach, Elmer Fernández, Jorge Fernández, Wanda Fernández, Ramon A Franco-Topete, Fancy Gaete, Jorge Gómez, Leivy P Gonzalez-Ramirez, Marisol Guerrero, Susan A Gutierrez-Rubio, Beatriz Jalfin, Alejandra Lopez-Vazquez, Dora Loria, Silvia Míguez, Andres De J Moran-Mendoza, Gilberto Morgan-Villela, Carina Mussetti, Maria Aparecida Nagai, Antonio Oceguera-Villanueva, Rui M Reis, Javier Retamales, Robinson Rodriguez, Cristina Rosales, Efrain Salas-Gonzalez, Laura Segovia, Juan M Sendoya, Aida A Silva-Garcia, Stella Viña, Livia Zagame, Beth Jones, Moysés Szklo, United States-Latin American Cancer Research Network (Us-Lacrn)

Faculty, Staff and Students Publications

Molecular profile of breast cancer in Latin-American women was studied in five countries: Argentina, Brazil, Chile, Mexico, and Uruguay. Data about socioeconomic characteristics, risk factors, prognostic factors, and molecular subtypes were described, and the 60-month overall cumulative survival probabilities (OS) were estimated. From 2011 to 2013, 1,300 eligible Latin-American women 18 years or older, with a diagnosis of breast cancer in clinical stage II or III, and performance status ≦̸1 were invited to participate in a prospective cohort study. Face-to-face interviews were conducted, and clinical and outcome data, including death, were extracted from medical records. Unadjusted associations were evaluated by …

Mapk6-Akt Signaling Promotes Tumor Growth And Resistance To Mtor Kinase Blockade, Qinbo Cai, Wolong Zhou, Wei Wang, Bingning Dong, Dong Han, Tao Shen, Chad J Creighton, David D Moore, Feng Yang

Faculty, Staff and Students Publications

Mitogen-activated protein kinase 6 (MAPK6) is an atypical MAPK. Its function in regulating cancer growth remains elusive. Here, we reported that MAPK6 directly activated AKT and induced oncogenic outcomes. MAPK6 interacted with AKT through its C34 region and the C-terminal tail and phosphorylated AKT at S473 independent of mTORC2, the major S473 kinase. mTOR kinase inhibitors have not made notable progress in the clinic. Our identified MAPK6-AKT axis may provide a major resistance pathway. Besides repressing growth, inhibiting MAPK6 sensitized cancer cells to mTOR kinase inhibitors. MAPK6 overexpression is associated with decreased overall survival and the survival of patients with …

Intestinal Dysbiosis – A New Treatment Target In The Prevention Of Colorectal Cancer, Florinela-Andrada Dumitru, Sergiu Ioan Micu, Roxana Emanuela Popoiag, Marilena Musat, Andreea Daniela Caloian, Valentin Calu, Vlad Denis Constantin, Daniela Gabriela Balan, Cornelia Nitipir, Florin Enache

Journal of Mind and Medical Sciences

The gastrointestinal microbiome contains at least 100 trillion microorganisms (bacteria, viruses, fungi), whose distribution varies from the mouth to the rectum spatially and temporally throughout one's lifetime. The microbiome benefits from advancing research due to its major role in human health. Studies indicate that its functions are immunity, metabolic processes and mucosal barrier. The disturbances of these functions, dysbiosis, influence physiology, lead to diabetes, inflammatory bowel disease, obesity and colon tumorigenesis. The third most common form of cancer, colorectal cancer, is the result of many factors and genes, and although the link between dysbiosis and this type of cancer is …

Targeting Parp-1 With Metronomic Therapy Modulates Mdsc Suppressive Function And Enhances Anti-Pd-1 Immunotherapy In Colon Cancer, Mohamed A. Ghonim, Salome V. Ibba, Abdelmetalab F. Tarhuni, Youssef Errami, Hanh H. Luu, Matthew J. Dean, Ali H. El-Bahrawy, Dorota Wyczechowska, Ilyes A. Benslimane, Luis Del Valle, Amir A. Al-Khami, Augusto C. Ochoa, A Hamid Boulares

School of Graduate Studies Faculty Publications

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors (eg, olaparib) are effective against BRCA-mutated cancers at/near maximum tolerated doses by trapping PARP-1 on damaged chromatin, benefitting only small patient proportions. The benefits of targeting non-DNA repair aspects of PARP with metronomic doses remain unexplored. METHODS: Colon epithelial cells or mouse or human bone marrow (BM)-derived-myeloid-derived suppressor cells (MDSCs) were stimulated to assess the effect of partial PARP-1 inhibition on inflammatory gene expression or immune suppression. Mice treated with azoxymethane/four dextran-sulfate-sodium cycles or mice bred into PARP-1 or treated with olaparib were used to examine the role of PARP-1 in colitis-induced or spontaneous colon …

Comparisons Of Oral, Intestinal, And Pancreatic Bacterial Microbiomes In Patients With Pancreatic Cancer And Other Gastrointestinal Diseases, Mei Chung, Naisi Zhao, Richard Meier, Devin C. Koestler, Guojun Wu, Erika De Castillo, Bruce J. Paster, Kevin Charpentier, Jacques Izard, Karl T. Kelsey, Dominique S. Michaud

Department of Food Science and Technology: Faculty Publications

Background: Oral microbiota is believed to play important roles in systemic diseases, including cancer. Methods: We collected oral samples (tongue, buccal, supragingival, and saliva) and pancreatic tissue or intestinal samples from 52 subjects, and characterized 16S rRNA genes using high-throughput DNA sequencing.

Results: Bray–Curtis plot showed clear separations between bacterial communities in the oral cavity and those in intestinal and pancreatic tissue samples. PERMANOVA tests indicated that bacterial communities from buccal samples were similar to supragingival and saliva samples, and pancreatic duct samples were similar to pancreatic tumor samples, but all other samples were significantly different from each …

Conservation Of Epithelial-To-Mesenchymal Transition Process In Neural Crest Cells And Metastatic Cancer, April Zhang, Hira Aslam, Neha Sharma, Aryeh Warmflash, Walid D Fakhouri

Faculty, Staff and Student Publications

Epithelial to mesenchymal transition (EMT) is a highly conserved cellular process in several species, from worms to humans. EMT plays a fundamental role in early embryogenesis, wound healing, and cancer metastasis. For neural crest cell (NCC) development, EMT typically results in forming a migratory and potent cell population that generates a wide variety of cell and tissue, including cartilage, bone, connective tissue, endocrine cells, neurons, and glia amongst many others. The degree of conservation between the signaling pathways that regulate EMT during development and metastatic cancer (MC) has not been fully established, despite ample studies. This systematic review and meta-analysis …

How Can We Stop Cancer?, Joseph R. Current

The Review: A Journal of Undergraduate Student Research

Cancer is a disease that humans have been struggling to combat for centuries. It originates from the accumulation of several mutations over the life of a cell that causes it to evade cell death and multiply rapidly. It can affect any tissue in the body and can spread to other parts of the body through metastasis. Cancer comes in numerous shapes and sizes with different levels of aggression, growth speeds, and health risks. Many treatments for cancer exist today, three of the most popular being surgery, chemotherapy, and radiation therapy, which can be used in combinations with other treatments to …

Mucosa-Associated Microbiota In Barrett’S Esophagus, Dysplasia, And Esophageal Adenocarcinoma Differ Similarly Compared With Healthy Controls, Shajan Peter, Amanda Pendergraft,, William Vanderpol, Mel Wilcox, Kondal R. Kyanam Kabir Baig, Casey Morrow, Jacques Izard, Peter J. Mannon

Department of Food Science and Technology: Faculty Publications

Introduction: Alterations in the composition of the human gut microbiome and its metabolites have been linked to gut epithelial neoplasia. We hypothesized that differences in mucosa-adherent Barrett’s microbiota could link to risk factors, providing risk of progression to neoplasia.

Methods: Paired biopsies from both diseased and nonaffected esophagus (as well as gastric cardia and gastric juice for comparison) from patients with intestinal metaplasia (n = 10), low grade dysplasia (n = 10), high grade dysplasia (n = 10), esophageal adenocarcinoma (n = 12), and controls (n = 10) were processed for mucosa-associated bacteria …

Non-Thermal Plasma-Induced Immunogenic Cell Death In Cancer: A Topical Review., Marian Khalili, Lynsey Daniels, Abraham Lin, Fred C. Krebs, Adam E. Snook, Sander Bekeschus, Wilbur B. Bowne, Vandana Miller

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Recent advances in biomedical research in cancer immunotherapy have identified the use of an oxidative stress-based approach to treat cancers, which works by inducing immunogenic cell death (ICD) in cancer cells. Since the anti-cancer effects of non-thermal plasma (NTP) are largely attributed to the reactive oxygen and nitrogen species that are delivered to and generated inside the target cancer cells, it is reasonable to postulate that NTP would be an effective modality for ICD induction. NTP treatment of tumors has been shown to destroy cancer cells rapidly and, under specific treatment regimens, this leads to systemic tumor-specific immunity. The translational …

From Vaccine Vector To Oncomodulation: Understanding The Complex Interplay Between Cmv And Cancer., Nicole A. Wilski, Christopher M. Snyder

Department of Microbiology and Immunology Faculty Papers

Cytomegalovirus (CMV) is a herpesvirus that establishes a persistent, but generally asymptomatic, infection in most people in the world. However, CMV drives and sustains extremely large numbers of antigen-specific T cells and is, therefore, emerging as an exciting platform for vaccines against infectious diseases and cancer. Indeed, pre-clinical data strongly suggest that CMV-based vaccines can sustain protective CD8+ T cell and antibody responses. In the context of vaccines for infectious diseases, substantial pre-clinical studies have elucidated the effcacy and protective mechanisms of CMV-based vaccines, including in non-human primate models of various infections. In the context of cancer vaccines, however, much …

Long-Term Use Of Antibiotics And Risk Of Colorectal Adenoma, Yin Cao, Kana Wu, Raaj Mehta, David A. Drew, Mingyang Song, Paul Lochhead, Long H. Nguyen, Jacques Izard, Charles S. Fuchs, Wendy S. Garrett, Curtis Huttenhower, Shuji Ogino, Edward L. Giovannucci, Andrew T. Chan

Department of Food Science and Technology: Faculty Publications

Objective: Recent evidence suggests that antibiotic use, which alters the gut microbiome, is associated with an increased risk of colorectal cancer. However, the association between antibiotic use and risk of colorectal adenoma, the precursor for the majority of colorectal cancers, has not been investigated.

Design: We prospectively evaluated the association between antibiotic use at age 20–39 and 40–59 (assessed in 2004) and recent antibiotic use (assessed in 2008) with risk of subsequent colorectal adenoma among 16,642 women aged ≥ 60 enrolled in the Nurses’ Health Study who underwent at least one colonoscopy through 2010. We used multivariate logistic …

Osteoblasts Are "Educated" By Crosstalk With Metastatic Breast Cancer Cells In The Bone Tumor Microenvironment., Alexus D. Kolb, Alison B. Shupp, Dimpi Mukhopadhyay, Frank C. Marini, Karen M. Bussard

Department of Cancer Biology Faculty Papers

INTRODUCTION: In a cancer-free environment in the adult, the skeleton continuously undergoes remodeling. Bone-resorbing osteoclasts excavate erosion cavities, and bone-depositing osteoblasts synthesize osteoid matrix that forms new bone, with no net bone gain or loss. When metastatic breast cancer cells invade the bone, this balance is disrupted. Patients with bone metastatic breast cancer frequently suffer from osteolytic bone lesions that elicit severe bone pain and fractures. Bisphosphonate treatments are not curative. Under ideal circumstances, osteoblasts would synthesize new matrix to fill in erosion cavities caused by osteoclasts, but this is not what occurs. Our prior evidence demonstrated that osteoblasts are …

Inhibition Of Cancer Stem Cells By Glycosaminoglycan Mimetics, Connor P. O'Hara

Theses and Dissertations

Connor O’Hara July 29, 2019

Inhibition of Cancer Stem Cells by Glycosaminoglycan Mimetics

In the United States cancer is the second leading cause of death, with colorectal cancer (CRC) being the third deadliest cancer and expected to cause over 51,000 fatalities in 2019 alone.¹ The current standard of care for CRC depends largely on the staging, location, and presence of metastasis.² As the tumor grows and invades nearby lymph tissue and blood vessels, CRC has the opportunity to invade not only nearby tissue but also metastasize into the liver and lung (most commonly).³ The 5-year survival rate …

Tgf-Β Sustains Tumor Progression Through Biochemical And Mechanical Signal Transduction., Robert L Furler, Douglas F Nixon, Christine A Brantner, Anastas Popratiloff, Christel H Uittenbogaart

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Transforming growth factor β (TGF-β) signaling transduces immunosuppressive biochemical and mechanical signals in the tumor microenvironment. In addition to canonical SMAD transcription factor signaling, TGF-β can promote tumor growth and survival by inhibiting proinflammatory signaling and extracellular matrix (ECM) remodeling. In this article, we review how TGF-β activated kinase 1 (TAK1) activation lies at the intersection of proinflammatory signaling by immune receptors and anti-inflammatory signaling by TGF-β receptors. Additionally, we discuss the role of TGF-β in the mechanobiology of cancer. Understanding how TGF-β dampens proinflammatory responses and induces pro-survival mechanical signals throughout cancer development is critical for designing therapeutics that …

Limited Immune Surveillance In Lymphoid Tissue By Cytolytic Cd4+ T Cells During Health And Hiv Disease., Marcus Buggert, Son Nguyen, Laura M. Mclane, Maria Steblyanko, Nadia Anikeeva, Dominic Paquin-Proulx, Perla M Del Rio Estrada, Yuria Ablanedo-Terrazas, Kajsa Noyan, Morgan A. Reuter, Korey Demers, Johan K. Sandberg, Michael A. Eller, Hendrik Streeck, Marianne Jansson, Piotr Nowak, Anders Sönnerborg, David H. Canaday, Ali Naji, E. John Wherry, Merlin L. Robb, Steven G Deeks, Gustavo Reyes-Teran, Yuri Sykulev, Annika C. Karlsson, Michael R. Betts

Department of Medical Oncology Faculty Papers

CD4+ T cells subsets have a wide range of important helper and regulatory functions in the immune system. Several studies have specifically suggested that circulating effector CD4+ T cells may play a direct role in control of HIV replication through cytolytic activity or autocrine β-chemokine production. However, it remains unclear whether effector CD4+ T cells expressing cytolytic molecules and β-chemokines are present within lymph nodes (LNs), a major site of HIV replication. Here, we report that expression of β-chemokines and cytolytic molecules are enriched within a CD4+ T cell population with high levels of the T-box transcription factors T-bet and …

Stromal Cyclin D1 Promotes Heterotypic Immune Signaling And Breast Cancer Growth, Timothy G. Pestell, Xuanmao Jiao, Mukesh Kumar, Amy R. Peck, Marco Prisco, Shengqiong Deng, Zhiping Li, Adam Ertel, Matthew C. Casimiro, Xiaoming Ju, Agnese Di Rocco, Gabriele Di Sante, Sanjay Katiyar, Alison Shupp, Michael P. Lisanti, Pooja Jain, Kongming Wu, Hallgeir Rui, Douglas Craig Hooper, Zuoren Yu, Aaron R. Goldman, David W. Speicher, Lisa Laury-Kleintop, Richard G. Pestell

Department of Cancer Biology Faculty Papers

The cyclin D1 gene encodes the regulatory subunit of a holoenzyme that drives cell autonomous cell cycle progression and proliferation. Herein we show cyclin D1 abundance is increased > 30-fold in the stromal fibroblasts of patients with invasive breast cancer, associated with poor outcome. Cyclin D1 transformed hTERT human fibroblast to a cancer-associated fibroblast phenotype. Stromal fibroblast expression of cyclin D1 (cyclin D1^Stroma) in vivo, enhanced breast epithelial cancer tumor growth, restrained apoptosis, and increased autophagy. Cyclin D1^Stroma had profound effects on the breast tumor microenvironment increasing the recruitment of F4/80⁺ and CD11b⁺ macrophages and increasing …

Inhibiting Dna Methylation Activates Cancer Testis Antigens And Expression Of The Antigen Processing And Presentation Machinery In Colon And Ovarian Cancer Cells., Cornelia Siebenkäs, Katherine B Chiappinelli, Angela A Guzzetta, Anup Sharma, Jana Jeschke, Rajita Vatapalli, Stephen B Baylin, Nita Ahuja

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Innovative therapies for solid tumors are urgently needed. Recently, therapies that harness the host immune system to fight cancer cells have successfully treated a subset of patients with solid tumors. These responses have been strong and durable but observed in subsets of patients. Work from our group and others has shown that epigenetic therapy, specifically inhibiting the silencing DNA methylation mark, activates immune signaling in tumor cells and can sensitize to immune therapy in murine models. Here we show that colon and ovarian cancer cell lines exhibit lower expression of transcripts involved in antigen processing and presentation to immune cells …

The Significance Of A Common Idiotype (1f7) On Antibodies Against Human Immune Deficiency Virus Type 1 And Hepatitis C Virus, Sybille Muller, Matthew S. Parsons, Heinz Kohler, Michael Grant

Microbiology, Immunology, and Molecular Genetics Faculty Publications

In this review, we trace the concept and potential functional role of regulatory idiotypes in the immune response to human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus, and hepatitis C virus (HCV). A major idiotype involved in these viral infections is recognized and defined by a murine monoclonal antibody (1F7). Antibodies expressing the idiotype defined by 1F7 are dominant in HIV-1 infection and are also found on many broadly neutralizing antibodies against HIV-1. This regulatory idiotypic axis offers opportunities for exploitation in vaccine development for HIV-1, HCV, and other chronic viral infections.

Microbiota, Oral Microbiome, And Pancreatic Cancer, Dominique S. Michaud, Jacques Izard

Department of Food Science and Technology: Faculty Publications

Only 30% of patients diagnosed with pancreatic cancer survive one year post-diagnosis. Progress in understanding the causes of pancreatic cancer has been made, including solidifying the associations with obesity and diabetes, and a proportion of cases should be preventable through lifestyle modifications. Unfortunately, identifying reliable biomarkers of early pancreatic cancer has been extremely challenging, and no effective screening modality is currently available for this devastating form of cancer. Recent data suggest the microbiota may play a role in the disease process, but many questions remain. Future studies focusing on the human microbiome, both etiologically and as a marker of disease …

Systematic Analysis Of A Xenograft Mice Model For Kshv+ Primary Effusion Lymphoma (Pel), Lu Dai, Jimena Trillo-Tinoco, Lihua Bai, Baoli Kang, Zengguang Xu, Xiaofei Wen, Luis Del Valle, Zhiqiang Qin

School of Medicine Faculty Publications

Kaposi's sarcoma-associated herpesvirus is the causative agent of primary effusion lymphoma (PEL), which arises preferentially in the setting of infection with human immunodeficiency virus (HIV). Even with standard cytotoxic chemotherapy, PEL continues to cause high mortality rates, requiring the development of novel therapeutic strategies. PEL xenograft models employing immunodeficient mice have been used to study the in vivo effects of a variety of therapeutic approaches. However, it remains unclear whether these xenograft models entirely reflect clinical presentations of KSHV(+) PEL, especially given the recent description of extracavitary solid tumor variants arising in patients. In addition, effusion and solid tumor cells …

A Melanin-Independent Interaction Between Mc1r And Met Signalling Pathways Is Required For Hgf-Dependent Melanoma, Agnieszka Wolnicka-Głubisz, Faith M. Strickland, Albert Wielgus, Miriam Anver, Glenn Merlino, Edward C. De Fabo, Frances P. Noonan

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Melanocortin 1 receptor (MC1R) signaling stimulates black eumelanin production through a cAMP-dependent pathway. MC1R polymorphisms can impair this process, resulting in a predominance of red phaeomelanin. The red hair, fair skin and UV sensitive phenotype is a well-described melanoma risk factor. MC1R polymorphisms also confer melanoma risk independent of pigment. We investigated the effect of Mc1r deficiency in a mouse model of UV-induced melanoma. C57BL/6-Mc1r+/+-HGF transgenic mice have a characteristic hyperpigmented black phenotype with extra-follicular dermal melanocytes located at the dermal/epidermal junction. UVB induces melanoma, independent of melanin pigmentation, but UVA-induced and spontaneous melanomas are dependent on black eumelanin. We …