Neoplasms Commons^™

Investigating Corollaries Between Streptococcus Gallolyticus Subsp. Gallolyticus Virulence And Colorectal Cancer, Tyler G. Myers

Pursuit - The Journal of Undergraduate Research at The University of Tennessee

Streptococcus gallolyticus subsp. gallolyticus (Sgg) is a gram-positive, non-beta-hemolytic bacterium that belongs to the Lancefield group D of streptococcal pathogens. For the past several decades, associations between Sgg bacteremia and colorectal cancer (CRC) have been apparent, with gastroenterologists routinely recommending colonoscopies for positive cases of Sgg in either blood or stool samples. However, current research has not wholly established whether Sgg acts as a causative agent of CRC or if pre-existing cancers make the lumen of the colon more hospitable to its colonization. Regardless, Sgg has been implicated in the modulation of host inflammatory pathways and subsequent remodeling …

Metabolic Responses To Freund’S Adjuvants And Oncolytic Viruses: Implications On Vaccines And Tumor Immunity, Kiruthiga Mone

Dissertations and Doctoral Documents, University of Nebraska-Lincoln, 2023–

Freund’s adjuvants have been extensively used in experimental research, and they modulate immune responses through various mechanisms. While both complete Freund’s adjuvant (CFA) and incomplete Freund’s adjuvant (IFA) contain the same mineral oil base, CFA contains the killed extract of Mycobacterium tuberculosis (M. tb) as an additional ingredient. Because the CFA contains mycobacterial content similar to that of Bacillus Calmette-Guérin (BCG), which induces trained immunity (TI), we tested the hypothesis that CFA may elicit TI-like features. To test this hypothesis, we investigated the metabolic and epigenetic reprogramming induced by CFA, with IFA and BCG as controls, in inbred …

Synergistic Anti-Tumor Activity Of Ciclopirox Olamine And Metformin In Triple-Negative Breast Cancer, Yakun Wu, Hui Lyu, Congcong Tan, Margaret E. Larsen, Shou Ching Tang, Shile Huang, Bolin Liu

School of Graduate Studies Faculty Publications

No abstract provided.

The Effects Of Bone-Remodeling Therapy On Survival, Pain, And Skeletal Related Events In The Setting Of Renal Cell Carcinoma With Bone Metastases: A Multicenter Investigation From A Large Global Health Research Network (Trinetx), Brian H. Im, Kevin K. Zarrabi, Aaron R. Hochberg, Mihir M. Shah, Md, James R. Mark, Joseph K. Izes, Patrick T. Gomella, Costas D. Lallas, Leonard G. Gomella, Adam R. Metwalli

Department of Urology Faculty Papers

INTRODUCTION: Renal cell carcinoma (RCC) is the most common renal malignancy-bone metastases (BM) are indicative of aggressive disease with a poor prognosis. We aim to evaluate the overall mortality of patients with RCC with and without BM, and to elucidate the effects of bone-remodeling therapy on mortality, incidence of skeletal-related events, and opioid usage patterns in patients with BM.

METHODS: A retrospective cohort study was conducted using TriNetX, a large, collaborative network sourced from electronic medical records of over 110 million patients from over 100 healthcare organizations. All adult patients with RCC and RCC with BM were queried.

RESULTS: There …

The Vascular Density/Angiogenesis Marker Cd31/Pecam1 Does Not Correlate With Overall Survival In Neuroendocrine Tumors, Nicholas J. Skill, Kenneth Avanzino, Yvette Bren-Mattison, J. Philip Boudreaux, Ramcharan Thiagarajan, Mary Maluccio

School of Medicine Faculty Publications

Abstract: Neuroendocrine neoplasms (NENs) are rare cancers. CD31/PECAM1 is an adhesion molecule that modulates endothelial cell-to-cell contact. Increased CD31 expression is a marker for tumor growth, and cancer aggressiveness. The purpose of this study was to better understand the prognostic value of CD31 expression in primary and metastatic NEN tumors in terms of correlations with overall survival and pathological metrics, tumor grade, and tumor primary/metastatic location. As NENs are highly vascular tumors, the hypothesis is that CD31 staining is an important prognostic biomarker and target. This is based on prior correlations between CD31 staining and 3-year recurrence-free survival in pancreas …

Investigating The Role Of Traditional Chinese Herbal Medicine For Cancer Symptom Management In Older Adults: A Rapid Review, Isabelle C. Karshner

Honors Undergraduate Theses

Background: Patients with cancer often experience symptoms related to disease, complications, and treatment. One potential method of alleviating these symptoms is traditional Chinese herbal medications (TCHM). This rapid review explores the role of traditional Chinese herbal medications in treating cancer-related symptoms in older adults.

Purpose: The purpose of this rapid review is to gain and provide a better understanding of the effects of TCHM on cancer-symptom management in the older adult population. This review explores the association between TCHM and effects on cancer symptoms in older adults, including interactions, toxicity, and signs/symptoms of TCHM use that may be useful information …

Disruption Of Protein-Protein Interaction Hotspots In The C-Terminal Domain Of Mlh1 Confers Mismatch Repair Deficiency, Keri M. Fishwick, Diego Gomez Vieito, Giada Greco, Giulio Collotta, Marco Gatti, Anastasija A. Kulik, Raphaël Guérois, Ivan Corbeski, Ashutosh S. Phadte, Issam Senoussi, Petr Cejka, Anna Pluciennik, Antonio Porro, Alessandro A. Sartori

Department of Biochemistry and Molecular Biology Faculty Papers

MutLα, a heterodimer of MLH1 and PMS2, plays a key role in DNA mismatch repair (MMR), which maintains genomic stability by correcting replication errors. Loss of MLH1 function causes MMR deficiency (MMRd), leading to elevated mutation rates and increased cancer susceptibility. However, MMRd can offer a therapeutic advantage, as high tumour mutational burden enhances the efficacy of immune checkpoint inhibition. MMR also drives somatic expansion of CAG repeats linked to Huntington’s disease (HD) pathogenesis. The C-terminal domain (CTD) of MLH1 contains at least two distinct protein–protein interaction (PPI) sites. The S1 site supports heterodimerization with the PMS2 endonuclease, whereas the …

Inflammatory Co-Regulation Of Voltage-Gated Sodium Channels And Na,K-Atpase In Metastatic Breast Cancer, Steven D. Scahill, Kelly Jean Sherman, Dennis Paul

School of Graduate Studies Faculty Publications

Sodium regulation is a potentially major driver of cancer metastasis. Voltage-gated sodium channels (VGSCs) and Na,K-ATPase are sodium transporters that are upregulated in many advanced carcinomas and are implicated as metastatic drivers. However, little is known about what drives this overexpression, how these proteins influence metastatic behavior, or whether these complementary sodium transporters are co-regulated in cancer. Using sodium transporter regulation in healthy neurons as a model, the present study demonstrated that the inflammatory mediator tumor necrosis factor alpha (TNFα) affects the expression of VGSCs and Na,K-ATPase in an in vitro model of metastatic breast cancer. Acute TNFα challenge increased …

Role Of Gut Microbiome In Oncogenesis And Oncotherapies, Renuka Sri Sai Peddireddi, Sai Kiran Kuchana, Rohith Kode, Saketh Khammammettu, Aishwarya Koppanatham, Supriya Mattigiri, Harshavardhan Gobburi, Suresh K. Alahari

School of Graduate Studies Faculty Publications

The gut microbiome has emerged as a key regulator of human health, influencing not only metabolism and immunity but also the development and treatment of cancer. Mounting evidence suggests that microbial dysbiosis contributes to oncogenesis by driving chronic inflammation, producing genotoxic metabolites, altering bile acid metabolism, and disrupting epithelial barrier integrity. At the same time, the gut microbiome significantly modulates the host response to oncotherapies including chemotherapy, radiotherapy, and especially immunotherapy, where microbial diversity and specific taxa determine treatment efficacy and toxicity. This review synthesizes current evidence on the role of the gut microbiome in both oncogenesis and oncotherapies, focusing …

Regulation Of Insm1 Gene Expression And Neuroendocrine Differentiation In High-Risk Neuroblastoma, Chiachen Chen, Siyuan Cheng, Xiuping Yu, Yisheng Lee, Michael S. Lan

School of Graduate Studies Faculty Publications

Neuroblastoma (NB), a pediatric cancer of sympatho-adrenal (SA) lineage, is marked by disrupted differentiation and cellular heterogeneity. INSM1, a zinc-finger transcription factor, is highly expressed in NB and developing SA tissues, where it regulates neuroendocrine differentiation, especially in chromaffin cells. We investigated INSM1's role in maintaining an undifferentiated, progenitor-like state in NB and its regulation via metabolic and epigenetic mechanisms. Transcriptomic profiling, promoter assays, and metabolic flux analysis revealed that INSM1 expression correlates with methionine cycle activity, particularly the S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio. Disruption of SAM/SAH balance altered INSM1 promoter activity and histone methylation, implicating epigenetic control in NB cell …

Radiogenomic Profiling Of Prostate Tumors Prior To External Beam Radiotherapy Converges On A Transcriptomic Signature Of Tgf-Β Activity Driving Tumor Recurrence, Anson T. Ku, Uma Shankavaram, Shana Y. Trostel, Hong Zhang, Sumeyra Kartal, Houssein A. Sater, Stephanie A. Harmon, Nicole V. Carrabba, Yang Liu, Hyunnam Ryu, James A. Proudfoot, Boon Hao Hong, Bradford J. Wood, Peter A. Pinto, Peter L. Choyke, Mack Roach, Howard M. Sandler, Stephanie L. Pugh, Kenneth L. Zeitzer, Lucas C. Mendez, Nirav S. Kapadia, William A. Hall, Anand B. Desai, Radka S. Stoyanova, Alan Pollack, Elai Davicioni, Melvin L. K. Chua, Baris Turkbey, Adam G. Sowalsky, Deborah E. Citrin

Einstein Health Papers

PURPOSE: Clinical risk grouping based on PSA, tumor grade, and disease extent guides treatment intensity for localized prostate cancer. However, many patients with intermediate- or high-risk disease treated with external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) still develop biochemical recurrence (BCR). Early identification of patients at high risk for BCR could enable personalized treatment strategies.

EXPERIMENTAL DESIGN: We prospectively enrolled 29 patients with intermediate- or high-risk prostate cancer undergoing EBRT and ADT. Pretreatment biopsies (n = 60) underwent whole-transcriptome microarray and whole-exome sequencing. Patients received multiparametric MRI at baseline and 6 months after treatment, with a median follow-up …

Genomic Ascertainment Of Chek2 -Related Cancer Predisposition, Sunyoung Kim, Jung Kim, Mark Ramos, Jeremy Haley, Diane Smelser, H. Shanker Rao, Uyenlinh L. Mirshahi, Katherine L. Nathanson, Barry I. Graubard, Hormuzd A. Katki, David Carey, Douglas R. Stewart

School of Graduate Studies Faculty Publications

Importance: There is clear evidence that deleterious germline variants in CHEK2 increase risk for breast and prostate cancers; there is limited or conflicting evidence for other cancers. Objective: To quantify the prevalence of as well as cancer risk and survival associated with CHEK2 germline pathogenic and likely pathogenic variants using genomic ascertainment. Design, Setting, and Participants: This case-control study used 2 electronic health record-linked and exome-sequenced biobanks: UK Biobank (n = 469765) and Geisinger MyCode (adults only; n = 167050). Variants were classified according to American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Cases …

Dermal Lymphatic Carcinomatosis As A Cutaneous Metastasis From Epidermal Growth Factor Receptor-Positive Lung Adenocarcinoma: A Case Report, Sarah A. Hemelt, Jonathan M. Joseph, Nicholas Culotta

School of Medicine Faculty Publications

Cutaneous metastases are an uncommon but clinically significant manifestation of internal malignancies. We present a rare case of dermal lymphatic carcinomatosis arising from epidermal growth factor receptor (EGFR)-positive lung adenocarcinoma, a presentation that may closely mimic inflammatory dermatoses and indicate therapeutic resistance or disease progression. We describe the clinical course of a 65-year-old woman who developed a violaceous cutaneous metastatic lesion beneath the left breast during treatment for metastatic lung adenocarcinoma. This case highlights the importance of recognizing cutaneous signs as indicators of disease progression and emphasizes the diagnostic challenges and prognostic implications of cutaneous metastases in lung cancer.

Identification Of Predictive Pretreatment Biomarkers For Neoadjuvant Chemotherapy Response In Latino Invasive Breast Cancer Patients, Hedda Michelle Guevara-Nieto, Rafael Parra-Medina, Carlos A. Orozco, Sandra Diaz-Casas, Jone Garai, Jovanny Zabaleta, Liliana López-Kleine, Alba L. Combita

School of Medicine Faculty Publications

Background: Breast cancer (BC) exhibits significant heterogeneity in incidence and mortality worldwide. Neoadjuvant chemotherapy (NAC) is the standard treatment for locally advanced BC; however, its efficacy varies by subtype. This study examined the gene expression profiles associated with NAC response in Colombian women with invasive BC. Methods: RNA sequencing of pre-treatment tissues from 58 patients (29 responders and 29 non-responders) identified differentially expressed genes (DEGs) for each molecular subtype, and prognostic performance was evaluated using risk scores. Results: Functional enrichment analysis highlighted the immune system pathways in non-responders. Changes in cytokine target activity and immune cell populations were analyzed to …

Proteome-Wide Association Study Of Prostate Cancer Risk Across Populations, Hua Zhong, Jingjing Zhu, Shuai Liu, Chong Wu, Liang Wang, Seamus P. Whelton, Catherine H. Marshall, Michael J. Blaha, Peter Durda, Xiuqing Guo, Craig W. Johnson, Henry J. Lin, Kent D. Taylor, Russell P. Tracy, Ronit I. Yarden, Ani W. Manichaikul, Stephen S. Rich, Jerome I. Rotter, Rajat Deo, Ruth F. Dubin, Peter Ganz, Lang Wu

School of Graduate Studies Faculty Publications

There is insufficient understanding of the molecular basis of prostate cancer (PCa) across different populations. We perform a large-scale proteome-wide association study (PWAS) to identify proteins with genetically regulated expression in plasma to be associated with PCa risk across populations. We develop genetic prediction models for expression of 1578, 1993, 1218, and 1390 proteins for African (n = 450), European (n = 758), Asian (n = 289), and Hispanic/Latino (n = 474) males, respectively, and evaluate associations of genetically regulated protein expression with PCa risk in 19,391 PCa cases and 61,608 controls of African population, 122,188 cases and 604,640 controls …

Phosphorylation At S1288 Of Leukemia Associated Rhogef (Larg/Arhgef12) Induces Plasma Membrane Localization And Promotes Binding And Activation Of Rhoa, Won Seok Yang, Neda Z. Ghanem, Steven D. Scahill, Maisel J. Caliva, Hannah Röttig, Annika Fitz, Michelle L. Matter, Joe W. Ramos

School of Graduate Studies Faculty Publications

Leukemia-associated RhoGEF (LARG) is a guanine nucleotide exchange factor (GEF) known for its specificity toward Ras homolog family member A (RhoA). LARG plays a crucial regulatory role in various cellular processes such as migration, proliferation, invasion, and metastasis by facilitating the exchange of GDP to GTP on RhoA. Phosphorylation of LARG at S1288 by ribosomal S6 kinase 2 (RSK2) promotes RhoA activation. However, the precise mechanism remains unclear. Here, we demonstrate the essential role and mechanism by which S1288 phosphorylation facilitates LARG-mediated invasiveness in response to epidermal growth factor (EGF). Upon EGF stimulation, RSK2 phosphorylates LARG at S1288, thereby promoting …

Mucosal Melanoma: Mechanisms Of Its Etiology, Progression, Resistance And Therapy, Sofie-Yasmin Hassan, Thomas W. Flanagan, Sarah-Lilly Hassan, Sybille Facca, Youssef Haikel, Mohamed Hassan

School of Graduate Studies Faculty Publications

Mucosal melanoma (MM) is a rare, aggressive cancer whose incidence has increased continuously over the years. This subtype of melanoma arises from melanocytes on hairless surfaces, typically in the respiratory tract, gastrointestinal (GI) tract, and urogenital tract. The most common sites of occurrence include the head and neck, the anorectal region, and the vulvovaginal region, while the rare sites of MM are the urinary tract and the upper and lower GI tract, including the esophagus, duodenum and the gallbladder. MM arises in melanocytes of the ectodermal mucosa that originate from neural crest cells and migrate through embryonic mesenchyme to their …

Sulindac Sulfide Suppresses Oncogenic Transformation Through Let-7b-Mediated Repression Of K-Ras Signaling, Zhipin Liang, Ruixia Ma, Bin Yi, Adam I. Riker, Yaguang Xi

School of Graduate Studies Faculty Publications

No abstract provided.

Immunogenomic Diversity Of Triple-Negative Breast Cancers In Obese And Non-Obese Black And White Women, Fokhrul Hossain, Denise Danos, Jovanny Zabaleta, Xiao-Cheng Wu, Luis Del Valle, Chindo Hicks, Jiande Wu, Jerneja Tomsic, Susan Neuhausen, Yuan Chun Ding, Kavitha Mukund, Zahra Mesrizadeh, Shankar Subramaniam, Augusto Ochoa, Victoria Seewaldt, Lucio Miele

School of Medicine Faculty Publications

Racial disparities in incidence and outcomes of triple-negative breast cancer (TNBC) have been attributed to ancestry, socioeconomic factors and/or obesity. We studied 253 TNBCs from 128 Black and 125 White women. Arms were balanced for age, AJCC stage, histological grade and molecular subtypes, and differed significantly in BMI distribution, obesity, and Area Deprivation Index. We examined survival rates, whole-transcriptome RNASeq and genetic ancestry. In our sample, Black race or obesity were not intrinsically predictive of poor outcomes. TNBC molecular portraits varied with stage and biological aggressiveness, irrespective of race. We identified a novel group of TNBCs with a distinctive luminal-like …

Her3 Promotes Triple-Negative Breast Cancer Progression By Upregulating Phf8 Via Mir-34b-5p-Dependent Mechanism, Hui Lyu, Cong Cong Tan, Yakun Wu, Margaret E. Larsen, Qingzhao Yu, Guobin Kang, Charles Wood, Shou Ching Tang, Bolin Liu

School of Graduate Studies Faculty Publications

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, with limited targeted treatment options and poor clinical outcomes. HER3 has recently emerged as a promising therapeutic target, with HER3-directed antibody–drug conjugates advancing to Phase III clinical trials for non-small cell lung cancer. However, the downstream molecular mechanisms by which HER3 promotes TNBC progression remain poorly defined. In this study, we uncovered a previously unrecognized HER3/miR-34b-5p/PHF8 signaling axis that drives TNBC cell proliferation and tumor growth. Mechanistically, HER3 activation suppresses the tumor-suppressive microRNA miR-34b-5p, resulting in the upregulation of the histone demethylase PHF8 (KDM7B), which in …

Human Kallikrein 2: A Novel Lineage-Specific Surface Target In Prostate Cancer, Fei Shen, Ryan Smith, Theresa Mcdevitt, Krista Menard, Shaozhou Tian, Gerald Chu, Ruchi Chaudhary, Jennifer Mccann, Halley Oyer, Sherry C. Wang, Steven Max, Peter Francis, William K. Kelly, Charles G. Drake

Kimmel Cancer Center Faculty Papers

PURPOSE: Targeted therapies for metastatic prostate cancer are limited, highlighting the need for novel drug targets and mechanisms of action (MoA). Human kallikrein 2 (KLK2) is a prostate-specific antigen expressed across the prostate cancer disease continuum. However, it was not recognized as a therapeutic target for prostate cancer in the past due to limited evidence of its cell surface expression. In this study, we systematically characterized KLK2 expression in prostate cancer, confirmed its cell surface expression, and demonstrated the preclinical efficacy of three KLK2-targeting therapeutics with distinct MoA.

EXPERIMENTAL DESIGN: The KLK2 expression profile in different stages of prostate cancer …

Genomic Profiling Of Intraocular Leiomyomas Reveals Recurrent Copy Number Alterations, Vivian Tang, Yubai Chou, Cuyan Demirkesen, Michele M. Bloomer, Joseph B. Crawford, Ahmet M. Sarici, Carol L. Shields, Ralph C. Eagle Jr., Codrin E. Iacob, Walter P. Devine, Tatyana Milman, Melike Pekmezci

Wills Eye Hospital Papers

PURPOSE: Leiomyomas are benign smooth muscle tumors that commonly present in the uterus, soft tissue, skin, and gastrointestinal tract but in rare cases can also arise within the eye. Notably, intraocular leiomyomas often show slightly different histopathologic and immunohistochemical features, referred to as mesectodermal morphology, given their presumed neural crest origin. Genetic and cytogenetic alterations of intraocular leiomyomas, as well as their association with various clinical and histopathologic features, have not been previously studied.

METHODS: We identified eight patients diagnosed with intraocular leiomyoma and performed targeted next-generation sequencing, whole transcriptome RNA sequencing, and chromosomal copy number analysis on those with …

Assessing The Tumor Suppressive Impact And Regulatory Mechanisms Of Spdef Expression In Breast Cancer, Maansi Solanky, Maninder Khosla, Suresh K. Alahari

School of Graduate Studies Faculty Publications

Background/Objectives: Breast cancer is a heterogeneous disease, and the role of the transcription factor SPDEF remains controversial. We aimed to clarify the prognostic value of SPDEF, explore demographic and molecular correlates of its expression, and investigate potential regulatory mechanisms underlying its dysregulation. Methods: Genomic and clinical data for 1218 breast cancer tumors were obtained from The Cancer Genome Atlas (TCGA). SPDEF mRNA expression was compared across intrinsic subtypes, age, and race, and prognostic significance was evaluated by Kaplan–Meier analysis. Promoter methylation patterns and DNA methyltransferase (DNMT) expression were examined as potential regulatory drivers. Co-expression analysis was performed using gene panels …

Runx2 Cooperates With Srebp1 To Rewire Cancer Metabolism And Promote Aggressiveness, Emanuele Vitale, Mila Gugnoni, Veronica Manicardi, Silvia Muccioli, Federica Torricelli, Benedetta Donati, Simonetta Piana, Gloria Manzotti, Elisa Salviato, Francesca Reggiani, Cristian Ascione, Rebecca Vezzani, Moira Ragazzi, Mattia Forcato, Oriana Romano, Silvio Bicciato, Aaron Goldman, Marco Tigano, Alessia Ciarrocchi

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Embryonic Transcription Factors (TFs) are often reactivated in cancer, driving developmental gene programs that support phenotypic plasticity. Metabolic adaptation fuels this plasticity by supplying energy and molecular building blocks for growth. RUNX2, the master regulator of bone morphogenesis, is ectopically expressed in epithelial cancer, promoting metastasis through trans-differentiation processes like Epithelial-to-Mesenchymal Transition (EMT) and osteomimicry. By combining omics data with functional validation, we demonstrated that RUNX2 drives cancer cell metabolic rewiring by repressing mitochondrial respiration while promoting anabolic processes. We showed that RUNX2 upregulates key genes of lipid biosynthesis by regulating and cooperating with SREBP1. In vivo expression analysis in …

Effect Of Valemetostat On The Pharmacokinetics Of Midazolam And Digoxin: A Phase 1 Drug-Drug Interaction Study In Patients With Non-Hodgkin Lymphoma, Masaya Tachibana, Steven Horwitz, Eric Jacobsen, Francine Foss, Pamela Allen, Pierluigi Porcu, Tatyana Feldman, Jia Ruan, Jonathan Brammer, Jie Wang, Shinichi Inaba, Yuka Iko, Keiko Nakajima, Yasuyuki Kakurai, Noriaki Kitami, Yang Chen, Yvonne Lau

Department of Medicine Faculty Papers

Valemetostat tosylate (valemetostat) is an oral, potent, dual inhibitor of enhancer of zeste homolog (EZH)2/1, under investigation in non-Hodgkin lymphomas (NHLs) and solid tumors. In vitro, it inhibits cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) when combined with sensitive CYP3A or P-gp substrates. This drug–drug interaction (DDI) sub-study is part of the phase 1 trial of valemetostat monotherapy (DS3201-A-J101; NCT02732275), assessing the effect of valemetostat on the pharmacokinetics (PK) of sensitive CYP3A and P-gp substrates midazolam and digoxin, respectively, in patients with relapsed or refractory NHL, and its safety and efficacy. Patients received two simultaneous single doses of midazolam and …

Setdb1 Is Critically Required For Uveal Melanoma Growth And Represents A Promising Therapeutic Target, Imène Krossa, Céline Pisibon, Yann Cheli, Karine Bille, Mélanie Dalmasso, Sabah Hamadat, Chrystel Husser, Marie Irondelle, Julien Cherfils-Vicini, Frédéric Soysouvanh, Sacha Nahon-Esteve, Arnaud Martel, Sandra Lassalle, Jean-Pierre Caujolle, Célia Maschi, Stéphanie Baillif, Dan Hasson, Saul Carcamo, Andrerw E. Aplin, Irwin Davidson, Emily Bernstein, Valeria Naim, Robert Ballotti, Corine Bertolotto, Thomas Strub

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Metastatic uveal melanomas are highly resistant to all existing treatments. To identify actionable vulnerabilities, we conducted a CRISPR-Cas9 knockout screen using a library composed of chromatin regulators. We revealed that the lysine methyltransferase, SETDB1, plays a critical role in metastatic uveal melanoma cell proliferation and survival. Functionally, SETDB1 deficiency induces a DNA damage response, senescence-like state and growth arrest. Knockdown of SETDB1 is associated with a decreased expression of genes related to replication and cell cycle. Moreover, deficiency in CDC6, an essential regulator of DNA replication, phenocopies SETDB1 inhibition. Using a pre-clinical model, we further demonstrated that anti-SETDB1 therapy impairs …

Fine Mapping Regulatory Variants By Characterizing Native Cpg Methylation With Nanopore Long-Read Sequencing, Yijun Tian, Shannon K. Mcdonnell, Lang Wu, Nicholas B. Larson, Liang Wang

School of Medicine Faculty Publications

5-Methylcytosine (5mC) is the most common DNA modification in the human genome. Bisulfite conversion combined with short-read sequencing captures this modification at single-nucleotide resolution but introduces PCR duplication bias and limits co-methylation analysis between distant cytosines. To resolve these limitations, we used nanopore long-read sequencing to profile human methylation and performed long-range co-methylation analysis with native DNA modification information. We analyzed the nanopore demo data in the adaptive sampling sequencing targeting the CpG islands and applied the linkage disequilibrium (LD) R to identified methylation haplotype blocks (MHBs). We found that the cancer genome exhibited significantly smaller MHBs, higher CpG density, …

Molecular Determinants Of Neoadjuvant Chemotherapy Resistance In Breast Cancer: An Analysis Of Gene Expression And Tumor Microenvironment, Hedda Michelle Guevara-Nieto, Carlos A. Orozco-Castaño, Rafael Parra-Medina, Jenny Nathaly Poveda-Garavito, Jone Garai, Jovanny Zabaleta, Liliana López-Kleine, Alba Lucia Combita

School of Graduate Studies Faculty Publications

Neoadjuvant chemotherapy (NAC) is a critical component of breast cancer treatment, but the molecular mechanisms underlying resistance remain poorly understood. This study aimed to identify transcriptomic changes associated with NAC resistance across four breast cancer subtypes: Luminal A, Luminal B/HER2-positive, Luminal B/HER2-negative, and Triple-Negative Breast Cancer (TNBC). RNA-seq analysis was performed on paired pre- and post-NAC breast cancer samples from 32 nonresponders. Differentially expressed genes (DEGs) were identified, and functional enrichment analyses were conducted. Protein-protein interaction (PPI) networks were constructed to identify hub genes. Tumor microenvironment (TME) infiltration was estimated using deconvolution algorithms. The results revealed distinct gene expression profiles …

Decreased Risk Of Incident Cancer Among Patients With Vitiligo: A Multicenter Retrospective Cohort Analysis, Rahib K. Islam, Ivan D. Nguyen, Kazi N. Islam, Lacey M. Falgout, Jonathan M. Joseph, Collins T. Langley, Christopher J. Haas

School of Medicine Faculty Publications

No abstract provided.

Integrated Mirna-Mrna Analyses Of Triple-Negative Breast Cancer In Black And White Patients With Or Without Obesity, Fokhrul Hossain, Martha I. Gonzalez-Ramirez, Jone Garai, Diana Polania-Villanueva, Li Li, Farzeen Nafees, Md Manirujjaman, Bolin Liu, Samarpan Majumder, Xiao Cheng Wu, Chindo Hicks, Luis Del Valle, Denise Danos, Augusto Ochoa, Lucio Miele, Jovanny Zabaleta

School of Graduate Studies Faculty Publications

Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous subtype of breast cancer. miRNAs play an essential role in TNBC pathogenesis and prognosis. Obesity is linked with an increased risk for several cancers, including breast cancer. Obesity is also related to the dysregulation of miRNA expression in adipose tissues. However, there is limited knowledge about race- and obesity-specific differential miRNA expression in TNBC. We performed miRNA sequencing of 48 samples (24 tumor and 24 adjacent non-tumor tissues) and RNA sequencing of 24 tumors samples from Black (AA) and White (EA) TNBC patients with or without obesity. We identified 55 miRNAs exclusively …