Medical Cell Biology Commons^™

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 …

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 …

Concerted Type I Interferon Signaling In Microglia And Neural Cells Promotes Memory Impairment Associated With Amyloid Β Plaques, Ethan R Roy, Gabriel Chiu, Sanming Li, Nicholas E Propson, Rupa Kanchi, Baiping Wang, Cristian Coarfa, Hui Zheng, Wei Cao

Faculty, Staff and Students Publications

The principal signals that drive memory and cognitive impairment in Alzheimer's disease (AD) remain elusive. Here, we revealed brain-wide cellular reactions to type I interferon (IFN-I), an innate immune cytokine aberrantly elicited by amyloid β plaques, and examined their role in cognition and neuropathology relevant to AD in a murine amyloidosis model. Using a fate-mapping reporter system to track cellular responses to IFN-I, we detected robust, Aβ-pathology-dependent IFN-I activation in microglia and other cell types. Long-term blockade of IFN-I receptor (IFNAR) rescued both memory and synaptic deficits and resulted in reduced microgliosis, inflammation, and neuritic pathology. Microglia-specific Ifnar1 deletion attenuated …

The Ep300/Tp53 Pathway, A Suppressor Of The Hippo And Canonical Wnt Pathways, Is Activated In Human Hearts With Arrhythmogenic Cardiomyopathy In The Absence Of Overt Heart Failure, Leila Rouhi, Siyang Fan, Sirisha M Cheedipudi, Aitana Braza-Boïls, Maria Sabater Molina, Yan Yao, Matthew J Robertson, Cristian Coarfa, Juan R Gimeno, Pilar Molina, Priyatansh Gurha, Esther Zorio, Ali J Marian

Faculty, Staff and Students Publications

AIMS: Arrhythmogenic cardiomyopathy (ACM) is a primary myocardial disease that typically manifests with cardiac arrhythmias, progressive heart failure, and sudden cardiac death (SCD). ACM is mainly caused by mutations in genes encoding desmosome proteins. Desmosomes are cell-cell adhesion structures and hubs for mechanosensing and mechanotransduction. The objective was to identify the dysregulated molecular and biological pathways in human ACM in the absence of overt heart failure.

METHODS AND RESULTS: Transcriptomes in the right ventricular endomyocardial biopsy samples from three independent individuals carrying truncating mutations in the DSP gene and five control samples were analysed by RNA-Seq (discovery group). These cases …

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 …

Phgdh Heterogeneity Potentiates Cancer Cell Dissemination And Metastasis, Matteo Rossi, Patricia Altea-Manzano, Margherita Demicco, Ginevra Doglioni, Laura Bornes, Marina Fukano, Anke Vandekeere, Alejandro M Cuadros, Juan Fernández-García, Carla Riera-Domingo, Cristina Jauset, Mélanie Planque, H Furkan Alkan, David Nittner, Dongmei Zuo, Lindsay A Broadfield, Sweta Parik, Antonino Alejandro Pane, Francesca Rizzollo, Gianmarco Rinaldi, Tao Zhang, Shao Thing Teoh, Arin B Aurora, Panagiotis Karras, Ines Vermeire, Dorien Broekaert, Joke Van Elsen, Maximilian M L Knott, Martin F Orth, Sofie Demeyer, Guy Eelen, Lacey E Dobrolecki, Ayse Bassez, Thomas Van Brussel, Karl Sotlar, Michael T Lewis, Harald Bartsch, Manfred Wuhrer, Peter Van Veelen, Peter Carmeliet, Jan Cools, Sean J Morrison, Jean-Christophe Marine, Diether Lambrechts, Massimiliano Mazzone, Gregory J Hannon, Sophia Y Lunt, Thomas G P Grünewald, Morag Park, Jacco Van Rheenen, Sarah-Maria Fendt

Faculty, Staff and Students Publications

Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs1. Genetic, transcriptional and translational heterogeneity contributes to this dynamic process2,3. Metabolic heterogeneity has also been observed4, yet its role in cancer progression is less explored. Here, we discover that loss of phosphoglycerate dehydrogenase (PHGDH) potentiates metastatic dissemination. Specifically, we find that heterogeneous or low PHGDH expression in primary tumors of breast cancer patients is associated with decreased metastasis free survival time. In mice, circulating tumor cells and early metastatic lesions are enriched with PHGDH low cancer …

The Disordered N-Terminal Domain Of Dnmt3a Recognizes H2ak119ub And Is Required For Postnatal Development, Tianpeng Gu, Dapeng Hao, Junsung Woo, Teng-Wei Huang, Lei Guo, Xueqiu Lin, Anna G Guzman, Ayala Tovy, Carina Rosas, Mira Jeong, Yubin Zhou, Benjamin Deneen, Yun Huang, Wei Li, Margaret A Goodell

Faculty, Staff and Students Publications

DNA methyltransferase 3a (DNMT3A) plays a crucial role during mammalian development. Two isoforms of DNMT3A are differentially expressed from stem cells to somatic tissues, but their individual functions remain largely uncharacterized. Here we report that the long isoform DNMT3A1, but not the short DNMT3A2, is essential for mouse postnatal development. DNMT3A1 binds to and regulates bivalent neurodevelopmental genes in the brain. Strikingly, Dnmt3a1 knockout perinatal lethality could be partially rescued by DNMT3A1 restoration in the nervous system. We further show that the intrinsically disordered N terminus of DNMT3A1 is required for normal development and DNA methylation at DNMT3A1-enriched regions. Mechanistically, …

The Effects Of Paclitaxel On Cellular Migration And The Cytoskeleton, Ashley Salguero-Gonzalez

Thinking Matters Symposium

In a clinical setting, some patients are exposed to an anti-cancer chemotherapy agent, paclitaxel. Cancerous cells undergo rapid, continuous cell division without control. Chemotherapy treatments try to slow and stop the uncontrollable cell division cycles and eliminate cancerous cells in the process. Paclitaxel serves as a treatment for some types of cancers, including lung, melanoma, bladder, and esophageal. Because it targets the cytoskeleton, paclitaxel can also influence cell migration. This project utilizes a cellular migration assay and an immunohistochemistry assay to analyze the effects of paclitaxel on the movement of cells and on the cytoskeleton of neuroglia rat cells with …

Ocular Adnexal Metastases From Renal Cell Carcinoma: An Update And Comprehensive Literature Review, Tejal Magan, Tejus Pradeep, Madalina Tuluc, Jurij R. Bilyk, Tatyana Milman

Wills Eye Hospital Papers

PURPOSE: The purpose of this study was to review the clinical presentation, systemic work-up, and outcomes of all previously reported ocular adnexal (OA) metastases from renal cell carcinoma (RCC). METHODS: This was a literature review. PubMed and Google Scholar databases were searched for all well-documented cases of OA metastases from RCC. RESULTS: Final analysis identified 44 patients with either biopsy-confirmed (41/44, 93%) or treatment response-documented (3/44, 6%) OA metastases from RCC. Thirty-four (77%) patients were male. The median age was 60 years (mean: 60, range: 22-87 years). The most common presenting signs were proptosis (19/44, 43%) and OA mass (14/44, …

Spata7 Is Required For Maintenance Of The Retinal Connecting Cilium, Jiaxiong Lu, Kaitlyn Xiong, Xinye Qian, Jongsu Choi, Yoon-Kyung Shim, Jacob Burnett, Graeme Mardon, Rui Chen

Faculty, Staff and Students Publications

SPATA7, an early onset LCA3 retinal disease gene, encodes a putative scaffold protein that is essential for the proper assembly of the connecting cilium (CC) complex in photoreceptors. Previous studies have shown that SPATA7 interacts with other photoreceptor-specific ciliary proteins, such as RPGR and RPGRIP1, and maintains the integrity of CC integrity. However, although it is known that Spata7 is required for early formation of the CC, it is unclear if Spata7 is also required for the maintenance of the CC. To investigate Spata7 function in the retina at the adult stage, loss of function was induced in the …

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 …

Perturbed Hematopoiesis In Individuals With Germline Dnmt3a Overgrowth Tatton-Brown-Rahman Syndrome, Ayala Tovy, Carina Rosas, Amos S Gaikwad, Geraldo Medrano, Linda Zhang, Jaime M Reyes, Yung-Hsin Huang, Tastuhiko Arakawa, Kristen Kurtz, Shannon E Conneely, Anna G Guzman, Rogelio Aguilar, Anne Gao, Chun-Wei Chen, Jean J Kim, Melissa T Carter, Amaia Lasa-Aranzasti, Irene Valenzuela, Lionel Van Maldergem, Lorenzo Brunetti, M John Hicks, Andrea N Marcogliese, Margaret A Goodell, Rachel E Rau

Faculty, Staff and Students Publications

Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth disorder caused by germline heterozygous mutations in the DNA methyltransferase DNMT3A. DNMT3A is a critical regulator of hematopoietic stem cell (HSC) differentiation and somatic DNMT3A mutations are frequent in hematologic malignancies and clonal hematopoiesis. Yet, the impact of constitutive DNMT3A mutation on hematopoiesis in TBRS is undefined. In order to establish how constitutive mutation of DNMT3A impacts blood development in TBRS we gathered clinical data and analyzed blood parameters in 18 individuals with TBRS. We also determined the distribution of major peripheral blood cell lineages by flow cytometric analyses. Our analyses revealed non-anemic macrocytosis, …

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 …

A Non-Coding Insertional Mutation Of Grhl2 Causes Gene Over-Expression And Multiple Structural Anomalies Including Cleft Palate, Spina Bifida And Encephalocele, Georgia Pitsava, Marcia L Feldkamp, Nathan Pankratz, John Lane, Denise M Kay, Kristin M Conway, Charlotte Hobbs, Gary M Shaw, Jennita Reefhuis, Mary M Jenkins, Lynn M Almli, Cynthia Moore, Martha Werler, Marilyn L Browne, Chris Cunniff, Andrew F Olshan, Faith Pangilinan, Lawrence C Brody, Robert J Sicko, Richard H Finnell, Michael J Bamshad, Daniel Mcgoldrick, Deborah A Nickerson, James C Mullikin, Paul A Romitti, James L Mills

Faculty, Staff and Students Publications

BACKGROUND: Sacral agenesis (SA) consists of partial or complete absence of the caudal end of the spine and often presents with additional birth defects. Several studies have examined gene variants for syndromic forms of SA, but only one has examined exomes of children with non-syndromic SA.

METHODS: Using buccal cell specimens from families of children with non-syndromic SA, exomes of 28 child-parent trios (eight with and 20 without a maternal diagnosis of pregestational diabetes) and two child-father duos (neither with diagnosis of maternal pregestational diabetes) were exome sequenced.

RESULTS: Three children had heterozygous missense variants in ID1 (Inhibitor of DNA …

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 …

68-Year Old Man With Progressive Weakness And Ventilator Dependent Respiratory Failure: A Case Report Of Sporadic Late Onset Nemaline Myopathy, P. Kirupaharan, Daniel Kramer, Alan Gandler, Lawrence C. Kenyon, Ross Summer

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background: Neuromuscular pathologies must be considered when caring for patients with persistent or progressive respiratory failure. Pertinent disease states may involve skeletal muscles of respiration or associated neurologic structures including motor neurons, peripheral neurons and the neuromuscular junction. Diagnosis may require pulmonary function testing, neurophysiologic studies, imaging, and/or muscle biopsy.

Case presentation: A 68-year-old male was transferred to our intensive care unit (ICU) for management of ventilator dependent respiratory failure. Upon further historical review, he described gradually worsening gait instability and muscle weakness, which was previously attributed to vascular Parkinsonism in the setting of known cerebrovascular disease. Upon arrival to …

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 …

Defining The Mammalian Coactivation Of Hepatic 12-H Clock And Lipid Metabolism, Huan Meng, Naomi M Gonzales, Sung Yun Jung, Yue Lu, Nagireddy Putluri, Bokai Zhu, Clifford C Dacso, David M Lonard, Bert W O'Malley

Faculty, Staff and Students Publications

The 12-h clock coordinates lipid homeostasis, energy metabolism, and stress rhythms via the transcriptional regulator XBP1. However, the biochemical and physiological bases for integrated control of the 12-h clock and diverse metabolic pathways remain unclear. Here, we show that steroid receptor coactivator SRC-3 coactivates XBP1 transcription and regulates hepatic 12-h cistrome and gene rhythmicity. Mice lacking SRC-3 show abnormal 12-h rhythms in hepatic transcription, metabolic functions, systemic energetics, and rate-limiting lipid metabolic processes, including triglyceride, phospholipid, and cardiolipin pathways. Notably, 12-h clock coactivation is not only preserved, with its cistromic activation priming ahead of the zeitgeber cue of light, but …

Increased Dna Methylation, Cellular Senescence And Premature Epigenetic Aging In Guinea Pigs And Humans With Tuberculosis, Carly A Bobak, Abhimanyu, Harini Natarajan, Tanmay Gandhi, Sandra L Grimm, Tomoki Nishiguchi, Kent Koster, Santiago Carrero Longlax, Qiniso Dlamini, Jacquiline Kahari, Godwin Mtetwa, Jeffrey D Cirillo, James O'Malley, Jane E Hill, Cristian Coarfa, Andrew R Dinardo

Faculty, Staff and Students Publications

Background: Tuberculosis (TB) is the archetypical chronic infection, with patients having months of symptoms before diagnosis. In the two years after successful therapy, survivors of TB have a three-fold increased risk of death.

Methods: Guinea pigs were infected with Mycobacterium tuberculosis (Mtb) for 45 days, followed by RRBS DNA methylation analysis. In humans, network analysis of differentially expressed genes across three TB cohorts were visualized at the pathway-level. Serum levels of inflammation were measured by ELISA. Horvath (DNA methylation) and RNA-seq biological clocks were used to investigate shifts in chronological age among humans with TB.

Results: Guinea pigs …

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 …

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, …

Isa101 And Nivolumab For Hpv-16+ Cancer: Updated Clinical Efficacy And Immune Correlates Of Response, Luana Guimaraes De Sousa, Kimal Rajapakshe, Jaime Rodriguez Canales, Renee L Chin, Lei Feng, Qi Wang, Tomas Z Barrese, Erminia Massarelli, William William, Faye M Johnson, Renata Ferrarotto, Ignacio Wistuba, Cristian Coarfa, Jack Lee, Jing Wang, Cornelis J M Melief, Michael A Curran, Bonnie S Glisson

Faculty, Staff and Students Publications

BACKGROUND: The combination of ISA101, a human papilloma virus (HPV) 16 peptide vaccine, and nivolumab showed a promising response rate of 33% in patients with incurable HPV-16+ cancer. Here we report long-term clinical outcomes and immune correlates of response.

METHODS: Patients with advanced HPV-16+ cancer and less than two prior regimens for recurrence were enrolled to receive ISA101 (100 µg/peptide) on days 1, 22, and 50 and nivolumab 3 mg/kg every 2 weeks beginning day 8 for up to 1 year. Baseline tumor samples were stained with multiplex immunofluorescence for programmed death-ligand 1 (PD-L1), programmed cell death protein-1 (PD-1), CD3, …

K-Ras And P53 Mouse Model With Molecular Characteristics Of Human Rhabdomyosarcoma And Translational Applications, Kengo Nakahata, Brian W Simons, Enrico Pozzo, Ryan Shuck, Lyazat Kurenbekova, Zachary Prudowsky, Kshiti Dholakia, Cristian Coarfa, Tajhal D Patel, Lawrence A Donehower, Jason T Yustein

Faculty, Staff and Students Publications

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, with overall long-term survival rates of ∼65-70%. Thus, additional molecular insights and representative models are critical for identifying and evaluating new treatment modalities. Using MyoD-Cre-mediated introduction of mutant K-RasG12D and perturbations in p53, we developed a novel genetically engineered mouse model (GEMM) for RMS. The anatomic sites of primary RMS development recapitulated human disease, including tumors in the head, neck, extremities and abdomen. We confirmed RMS histology and diagnosis through Hematoxylin and Eosin staining, and positive immunohistochemical staining for desmin, myogenin, and phosphotungstic acid-Hematoxylin. Cell lines from GEMM tumors …

Maternal Lactobacillus Reuteri Supplementation Shifts The Intestinal Microbiome In Mice And Provides Protection From Experimental Colitis In Female Offspring, Mahesh Krishna, Melinda Engevik, Karen Queliza, Savini Britto, Rajesh Shah, Wenly Ruan, Hongtao Wang, James Versalovic, Richard Kellermayer

Faculty, Staff and Students Publications

The purpose of our experiment was to explore how stochastic (inter-individual variation) gut microbiome composition may link to inflammatory bowel disease (IBD) susceptibility and guide the development of a perinatal preventative probiotic. Dextran sodium sulfate (DSS) was introduced to C57BL/BJ mice to induce acute colitis as a model of IBD. Potentially protective bacteria were identified using a discovery-validation cohort approach toward stochastic DSS susceptibility.