Medical Genetics Commons^™

Hsp90 Inhibitor Auy922 Suppresses Tumor Growth And Modulates Immune Response Through Yap1-Tead Pathway Inhibition In Gastric Cancer, Katsuhiro Yoshimura, Gengyi Zou, Yibo Fan, Kohei Yamashita, Lingzhi Wang, Jingjing Wu, Ruiping Wang, Shan Shao, Ailing W Scott, Jiankang Jin, Melissa Pool Pizzi, Xiaodan Yao, Calena-Abel Brown, Linghua Wang, Qiong Gan, Rebecca E Waters, Feng Yin, Shumei Song, Shilpa S Dhar, Jaffer A Ajani

Faculty, Staff and Student Publications

Heat shock protein 90 (HSP90), a vital chaperone involved in the folding and stabilization of various cellular proteins, regulates key functions in many tumor cells. In the context of gastric adenocarcinoma (GAC), where HSP90's role remains largely unexplored, we aimed to investigate the significance of HSP90 inhibitor, AUY922, in regulating the YAP1/TEAD pathway and its association with the tumor immune microenvironment (TME). Our results showed that AUY922 effectively inhibited GAC aggressiveness in both the invitro and invivo models, induced apoptosis, and cell-cycle arrest. Various functional assays elucidated that AUY922 potently inhibited the expression and interaction among YAP1/TEAD and HSP90, resulting …

Chemoresistance-Motility Signature Of Molecular Evolution To Chemotherapy In Non-Muscle-Invasive Bladder Cancer And Its Clinical Implications, Mi-So Jeong, Seung-Woo Baek, Gi-Eun Yang, Jeong-Yeon Mun, Jeong Ah Kim, Tae-Nam Kim, Jong-Kil Nam, Yung-Hyun Choi, Ju-Seog Lee, In-Sun Chu, Sun-Hee Leem

Faculty, Staff and Student Publications

Non-muscle-invasive bladder cancer (NMIBC) often recurs and can progress to MIBC due to resistance to treatments like intravesical chemotherapy or Bacillus Calmette-Guérin (BCG). Therefore, we established the Gemcitabine-Resistant Cells (GRCs) to study the molecular evolution under external pressure. A 63-gene Chemoresistance-Motility (CrM) signature was created to identify stage-specific traits of GRCs. This signature was tested on 1846 samples using log-rank tests and Cox regression to evaluate clinical utility. Early and intermediate resistance stages showed increased cell motility and metastatic potential. FAK, PI3K-AKT, and TGFβ pathways were activated first, followed by MAPK signaling. Single-cell analysis and experiments utilizing the CrM signature …

Chemoresistance-Motility Signature Of Molecular Evolution To Chemotherapy In Non-Muscle-Invasive Bladder Cancer And Its Clinical Implications, Mi-So Jeong, Seung-Woo Baek, Gi-Eun Yang, Jeong-Yeon Mun, Jeong Ah Kim, Tae-Nam Kim, Jong-Kil Nam, Yung-Hyun Choi, Ju-Seog Lee, In-Sun Chu, Sun-Hee Leem

Faculty, Staff and Student Publications

Non-muscle-invasive bladder cancer (NMIBC) often recurs and can progress to MIBC due to resistance to treatments like intravesical chemotherapy or Bacillus Calmette-Guérin (BCG). Therefore, we established the Gemcitabine-Resistant Cells (GRCs) to study the molecular evolution under external pressure. A 63-gene Chemoresistance-Motility (CrM) signature was created to identify stage-specific traits of GRCs. This signature was tested on 1846 samples using log-rank tests and Cox regression to evaluate clinical utility. Early and intermediate resistance stages showed increased cell motility and metastatic potential. FAK, PI3K-AKT, and TGFβ pathways were activated first, followed by MAPK signaling. Single-cell analysis and experiments utilizing the CrM signature …

Mitochondrial Uncouplers Inhibit Oncogenic E2f1 Activity And Prostate Cancer Growth, Ohuod Hawsawi, Weinan Xue, Tingting Du, Mengqi Guo, Xiaolin Yu, Mingyi Zhang, Paul S Hoffman, Roni Bollag, Jun Li, Jia Zhou, Hongbo Wang, Junran Zhang, Zheng Fu, Xiaoguang Chen, Chunhong Yan

Faculty, Staff and Student Publications

Mitochondrial uncouplers dissipate proton gradients and deplete ATP production from oxidative phosphorylation (OXPHOS). While the growth of prostate cancer depends on OXPHOS-generated ATP, the oncogenic pathway mediated by the transcription factor E2F1 is crucial for the progression of this deadly disease. Here, we report that mitochondrial uncouplers, including tizoxanide (TIZ), the active metabolite of the Food and Drug Administration (FDA)-approved anthelmintic nitazoxanide (NTZ), inhibit E2F1-mediated expression of genes involved in cell cycle progression, DNA synthesis, and lipid synthesis. Consequently, NTZ/TIZ induces S-phase kinase-associated protein 2 (SKP2)-mediated G1 arrest while impeding DNA synthesis, lipogenesis, and the growth of prostate cancer cells. …

Functional Characterization Of Qt Interval Associated Scn5a Enhancer Variants Identify Combined Additive Effects, Lavanya Gunamalai, Parul Singh, Brian Berg, Leilei Shi, Ernesto Sanchez, Alexa Smith, Ghislain Breton, Mark T Bedford, Darius Balciunas, Ashish Kapoor

Faculty, Staff and Student Publications

Several empirical and theoretical studies suggest the presence of multiple enhancers per gene that collectively regulate gene expression, and that common sequence variation impacting on the activities of these enhancers is a major source of inter-individual gene expression variability. However, for the vast majority of genes, enhancers and the underlying regulatory variation remains unknown. Even for the genes with well-characterized enhancers, the nature of the combined effects from multiple enhancers and their variants, when known, on gene expression regulation remains unexplored. Here, we have evaluated the combined effects from five SCN5A enhancers and their regulatory variants that are known to …

Comprehensive Characterization Of The Transcriptional Landscape In Alzheimer’S Disease (Ad) Brains, Chengxuan Chen, Zhao Zhang, Yuan Liu, Wei Hong, Hande Karahan, Jun Wang, Wenbo Li, Lixia Diao, Meichen Yu, Andrew J Saykin, Kwangsik Nho, Jungsu Kim, Leng Han

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is the leading dementia among the elderly with complex origins. Despite extensive investigation into the AD-associated protein-coding genes, the involvement of noncoding RNAs (ncRNAs) and posttranscriptional modification (PTM) in AD pathogenesis remains unclear. Here, we comprehensively characterized the landscape of ncRNAs and PTM events in 1460 samples across six brain regions sourced from the Mount Sinai/JJ Peters VA Medical Center Brain Bank Study and Mayo cohorts, encompassing 33,321 long ncRNAs, 92,897 enhancer RNAs, 53,763 alternative polyadenylation events, and 900,221 A-to-I RNA editing events. We additionally identified 25,351 aberrantly expressed ncRNAs and altered PTM events associated with AD …

Nucleus-Translocated Gclm Promotes Chemoresistance In Colorectal Cancer Through A Moonlighting Function, Jin-Fei Lin, Ze-Xian Liu, Dong-Liang Chen, Ren-Ze Huang, Fen Cao, Kai Yu, Ting Li, Hai-Yu Mo, Hui Sheng, Zhi-Bing Liang, Kun Liao, Yi Han, Shan-Shan Li, Zhao-Lei Zeng, Song Gao, Huai-Qiang Ju, Rui-Hua Xu

Faculty, Staff and Student Publications

Metabolic enzymes perform moonlighting functions during tumor progression, including the modulation of chemoresistance. However, the underlying mechanisms of these functions remain elusive. Here, utilizing a metabolic clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 knockout library screen, we observe that the loss of glutamate-cysteine ligase modifier subunit (GCLM), a rate-limiting enzyme in glutathione biosynthesis, noticeably increases the sensitivity of colorectal cancer (CRC) cells to platinum-based chemotherapy. Mechanistically, we unveil a noncanonical mechanism through which nuclear GCLM competitively interacts with NF-kappa-B (NF-κB)-repressing factor (NKRF), to promote NF-κB activity and facilitate chemoresistance. In response to platinum drug treatment, GCLM is phosphorylated by P38 …

Atrx Silences Cartpt Expression In Osteoblastic Cells During Skeletal Development, Yi-Ting Chen, Ming-Ming Jiang, Carolina Leynes, Mary Adeyeye, Camilla F Majano, Barakat Ibrahim, Urszula Polak, George Hung, Zixue Jin, Denise G Lanza, Lan Liao, Brian Dawson, Yuqing Chen-Evenson, Oscar E Ruiz, Richard J Gibbons, Jason D Heaney, Yangjin Bae, Brendan Lee

Faculty, Staff and Students Publications

ATP-dependent chromatin remodeling protein ATRX is an essential regulator involved in maintenance of DNA structure and chromatin state and regulation of gene expression during development. ATRX was originally identified as the monogenic cause of X-linked α-thalassemia mental retardation (ATR-X) syndrome. Affected individuals display a variety of developmental abnormalities and skeletal deformities. Studies from others investigated the role of ATRX in skeletal development by tissue-specific Atrx knockout. However, the impact of ATRX during early skeletal development has not been examined. Using preosteoblast-specific Atrx conditional knockout mice, we observed increased trabecular bone mass and decreased osteoclast number in bone. In vitro coculture …

High-Grade B-Cell Lymphoma Not Otherwise Specified, With Diffuse Large B-Cell Lymphoma Gene Expression Signatures: Genomic Analysis And Potential Therapeutics, Waseem Lone, Alyssa Bouska, Tyler A Herek, Catalina Amador, Joo Song, Alexander M Xu, Dylan Jochum, Issa Ismail Issa, Dennis D Weisenburger, Xuan Zhang, Sharath Kumar Bhagavathi, Tayla B Heavican-Foral, Sunandini Sharma, Ab Rauf Shah, Abdul Rouf Mir, Aisha Ahmad Alkhinji, Dalia El-Gamal, Bhavana J Dave, Keenan Hartert, Jiayu Yu, Mallick Saumyaranjan, Timothy C Greiner, Julie Vose, Timothy W Mckeithan, Kai Fu, Michael Green, Chengfeng Bi, Akil Merchant, Wing C Chan, Javeed Iqbal

Faculty, Staff and Student Publications

High-grade B-cell lymphoma not otherwise specified (HGBCL, NOS) has overlapping morphological and genetic features with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL), leading to uncertainty in its diagnosis and clinical management. Using functional genomic approaches, we previously characterized HGBCL and NOS, that demonstrate gene expression profiling (GEP), and genetic signatures similar to BL. Herein, we characterize distinct HGBCL, NOS, cohort (n = 55) in adults (n = 45) and in children (n = 10), and compared the GEP, genomic DNA copy number (CN), and mutational spectrum with de novo DLBCL (n = 85) and BL (n = 52). …

Wnt7a, Naomi M Calhoun, Richard R Behringer

Faculty, Staff and Student Publications

WNT7A regulates numerous developmental processes. It can activate canonical and non-canonical signaling depending on context. It is expressed in the developing central nervous system, limb buds, reproductive organs, and other tissues. Spontaneous and targeted Wnt7a mutations in mouse models resulted in abnormal limbs, defects in male and female reproductive tract organs, infertility, and defects in cerebellar axon remodeling. In zebrafish, wnt7aa mutants exhibited neurogenesis and angiogenesis defects in the central nervous system. In humans, recessive WNT7A missense and nonsense mutations resulted in severe limb and pelvic bone defects. Alterations in WNT7A expression correlated with multiple types of cancer.

Integrating Multi-Omics Data To Uncover Prostate Tissue Dna Methylation Biomarkers And Target Genes For Prostate Cancer Risk, Shuai Liu, Jingjing Zhu, Dylan Green, Hua Zhong, Quan Long, Chong Wu, Liang Wang, Youping Deng, Lang Wu

Faculty, Staff and Student Publications

Previous studies have indicated that specific CpG sites may be linked to the risk of prostate cancer (PCa) by regulating the expression of PCa target genes. However, most existing studies aim to identify DNA methylation (DNAm) biomarkers through blood tissue genetic instruments, which impedes the identification of relevant biomarkers in prostate tissue. To identify PCa risk-associated CpG sites in prostate tissue, we established genetic prediction models of DNAm levels using data from normal prostate samples in the GTEx (N = 108) and assessed associations between genetically predicted DNAm in prostate and PCa risk by studying 122,188 cases and 604,640 controls. …

The Dna Demethylase Tet1 Modifies The Impact Of Maternal Folic Acid Status On Embryonic Brain Development, Lehua Chen, Bernard K Van Der Veer, Qiuying Chen, Spyridon Champeris Tsaniras, Wannes Brangers, Harm H M Kwak, Rita Khoueiry, Yunping Lei, Robert Cabrera, Steven S Gross, Richard H Finnell, Kian Peng Koh

Faculty, Staff and Students Publications

Folic acid (FA) is well known to prevent neural tube defects (NTDs), but we do not know why many human NTD cases still remain refractory to FA supplementation. Here, we investigate how the DNA demethylase TET1 interacts with maternal FA status to regulate mouse embryonic brain development. We determined that cranial NTDs display higher penetrance in non-inbred than in inbred Tet1−/− embryos and are resistant to FA supplementation across strains. Maternal diets that are either too rich or deficient in FA are linked to an increased incidence of cranial deformities in wild type and Tet1+/− offspring and to …

Zic1 Is A Context-Dependent Medulloblastoma Driver In The Rhombic Lip, John J Y Lee, Ran Tao, Zhen You, Parthiv Haldipur, Anders W Erickson, Hamza Farooq, Liam D Hendriske, Namal Abeysundara, Cory M Richman, Evan Y Wang, Neha Das Gupta, Jennifer Hadley, Melissa Batts, Christopher W Mount, Xiaochong Wu, Alex Rasnitsyn, Swneke Bailey, Florence M G Cavalli, Sorana Morrissy, Livia Garzia, Kulandaimanuvel Antony Michealraj, Abhi Visvanathan, Vernon Fong, Jonelle Palotta, Raul Suarez, Bryn G Livingston, Miao Liu, Betty Luu, Craig Daniels, James Loukides, Anne Bendel, Pim J French, Johan M Kros, Andrey Korshunov, Marcel Kool, Fernando Chico Ponce De León, Mario Perezpeña-Diazconti, Boleslaw Lach, Sheila K Singh, Sarah E S Leary, Byung-Kyu Cho, Seung-Ki Kim, Kyu-Chang Wang, Ji-Yeoun Lee, Teiji Tominaga, William A Weiss, Joanna J Phillips, Shizhong Dai, Gelareh Zadeh, Ali G Saad, László Bognár, Almos Klekner, Ian F Pollack, Ronald L Hamilton, Young-Shin Ra, Wieslawa A Grajkowska, Marta Perek-Polnik, Reid C Thompson, Anna M Kenney, Michael K Cooper, Stephen C Mack, Nada Jabado, Mathieu Lupien, Marco Gallo, Vijay Ramaswamy, Mario L Suva, Hiromichi Suzuki, Kathleen J Millen, L Frank Huang, Paul A Northcott, Michael D Taylor

Faculty, Staff and Students Publications

Transcription factors are frequent cancer driver genes, exhibiting noted specificity based on the precise cell of origin. We demonstrate that ZIC1 exhibits loss-of-function (LOF) somatic events in group 4 (G4) medulloblastoma through recurrent point mutations, subchromosomal deletions and mono-allelic epigenetic repression (60% of G4 medulloblastoma). In contrast, highly similar SHH medulloblastoma exhibits distinct and diametrically opposed gain-of-function mutations and copy number gains (20% of SHH medulloblastoma). Overexpression of ZIC1 suppresses the growth of group 3 medulloblastoma models, whereas it promotes the proliferation of SHH medulloblastoma precursor cells. SHH medulloblastoma ZIC1 mutants show increased activity versus wild-type ZIC1, whereas G4 medulloblastoma …

Monoallelic Expression Can Govern Penetrance Of Inborn Errors Of Immunity, O'Jay Stewart, Conor Gruber, Haley E Randolph, Roosheel Patel, Meredith Ramba, Enrica Calzoni, Lei Haley Huang, Jay Levy, Sofija Buta, Angelica Lee, Christos Sazeides, Zoe Prue, David P Hoytema Van Konijnenburg, Ivan K Chinn, Luis A Pedroza, James R Lupski, Erica G Schmitt, Megan A Cooper, Anne Puel, Xiao Peng, Stéphanie Boisson-Dupuis, Jacinta Bustamante, Satoshi Okada, Marta Martin-Fernandez, Jordan S Orange, Jean-Laurent Casanova, Joshua D Milner, Dusan Bogunovic

Faculty, Staff and Students Publications

Inborn errors of immunity (IEIs) are genetic disorders that underlie susceptibility to infection, autoimmunity, autoinflammation, allergy and/or malignancy1. Incomplete penetrance is common among IEIs despite their monogenic basis2. Here we investigate the contribution of autosomal random monoallelic expression (aRMAE), a somatic commitment to the expression of one allele3,4, to phenotypic variability observed in families with IEIs. Using a clonal primary T cell system to assess aRMAE status of genes in healthy individuals, we find that 4.30% of IEI genes and 5.20% of all genes undergo aRMAE. Perturbing H3K27me3 and DNA methylation alters …

Inhibition Of Microrna-660-5p Decreases Breast Cancer Progression Through Direct Targeting Of Tmem41b, Valeria Villarreal-García, José Roberto Estupiñan-Jiménez, Vianey Gonzalez-Villasana, Pablo E Vivas-Mejía, Marienid Flores-Colón, Irma Estefanía Ancira-Moreno, Patricio Adrián Zapata-Morín, Claudia Altamirano-Torres, José Manuel Vázquez-Guillen, Cristina Rodríguez-Padilla, Recep Bayraktar, Mohamed H Rashed, Cristina Ivan, Gabriel Lopez-Berestein, Diana Reséndez-Pérez

Faculty, Staff and Student Publications

Background: Breast cancer is the most prevalent cancer among women worldwide. Most breast cancer-related deaths result from metastasis and drug resistance. Novel therapies are imperative for targeting metastatic and drug-resistant breast cancer cells. Accumulating evidence suggests that dysregulated microRNAs (miRNAs) promote breast cancer progression, metastasis, and drug resistance. Compared with healthy breast tissue, miR-660-5p is notably overexpressed in breast cancer tumor tissues. However, the downstream effectors of miR-660-5p in breast cancer cells have not been fully elucidated. Our aim was to investigate the role of miR-660-5p in breast cancer cell proliferation, migration, invasion, and angiogenesis and to identify its potential …

Transcriptomic Clustering Of Chronic Lymphocytic Leukemia: Molecular Subtypes Based On Bruton’S Tyrosine Kinase Expression Levels, Gorkem Kismali, Ganiraju Manyam, Nitin Jain, Cristina Ivan, Betty Lamothe, Mary L Ayres, Lakesla R Iles, William G Wierda, Varsha Gandhi

Faculty, Staff and Student Publications

Historically, CLL prognostication relied on disease burden, reflected in clinical stage. Later, chromosome abnormalities and genomics suggested several CLL subtypes which were aligned with response to therapy. Gene expression profiling data identified pathways associated with CLL progression. We hypothesized that transcriptome and proteome may identify functional omics associated with CLL nosology. As a test cohort, we utilized publicly available treatment-naïve CLL transcriptomics data (n = 130) and did consensus clustering that identified BTK-expression-based clusters. The BTK-High and BTK-Low clusters were validated in public and our in-house databases (n = >550 CLL patients). To associate with functional relevance, we took samples …

Cutaneous T Cell Lymphoma Atlas Reveals Malignant Th2 Cells Supported By A B Cell-Rich Tumor Microenvironment, Ruoyan Li, Johanna Strobl, Elizabeth F M Poyner, Aya Balbaa, Fereshteh Torabi, Pavel V Mazin, Nana-Jane Chipampe, Emily Stephenson, Ciro Ramírez-Suástegi, Vijaya Baskar Mahalingam Shanmugiah, Louis Gardner, Bayanne Olabi, Rowen Coulthard, Rachel A Botting, Nina Zila, Elena Prigmore, Nusayhah H Gopee, Marta A Chroscik, Efpraxia Kritikaki, Justin Engelbert, Issac Goh, Hon Man Chan, Harriet F Johnson, Jasmine Ellis, Victoria Rowe, Win Tun, Gary Reynolds, Dexin Yang, April Rose Foster, Laure Gambardella, Elena Winheim, Chloe Admane, Benjamin Rumney, Lloyd Steele, Laura Jardine, Julia Nenonen, Keir Pickard, Jennifer Lumley, Philip Hampton, Simeng Hu, Fengjie Liu, Xiangjun Liu, David Horsfall, Daniela Basurto-Lozada, Louise Grimble, Chris M Bacon, Sophie C Weatherhead, Hanna Brauner, Yang Wang, Fan Bai, Nick J Reynolds, Judith E Allen, Constanze Jonak, Patrick M Brunner, Sarah A Teichmann, Muzlifah Haniffa

Faculty, Staff and Student Publications

Cutaneous T cell lymphoma (CTCL) is a potentially fatal clonal malignancy of T cells primarily affecting the skin. The most common form of CTCL, mycosis fungoides, can be difficult to diagnose, resulting in treatment delay. We performed single-cell and spatial transcriptomics analysis of skin from patients with mycosis fungoides-type CTCL and an integrated comparative analysis with human skin cell atlas datasets from healthy and inflamed skin. We revealed the co-optation of T helper 2 (TH2) cell-immune gene programs by malignant CTCL cells and modeling of the tumor microenvironment to support their survival. We identified MHC-II+ fibroblasts and dendritic cells that …

The Pharmacogenomic And Immune Landscape Of Snornas In Human Cancers, Runhao Wang, Chengxuan Chen, Yuan Liu, Mei Luo, Jingwen Yang, Yamei Chen, Lifei Ma, Liuqing Yang, Chunru Lin, Lixia Diao, Leng Han

Faculty, Staff and Student Publications

Small nucleolar RNAs (snoRNAs) are a class of non-coding RNAs primarily known for their role in the chemical modification of other RNAs. Recent studies suggested that snoRNAs may play a broader role in anti-cancer treatments such as targeted therapies and immunotherapies. Despite these insights, the comprehensive landscape of snoRNA associations with drug response and immunotherapy outcomes remains unexplored. In this study, we identified 79,448 and 75,185 associations between snoRNAs and drug response using data from VAEN and CancerRxTissue, respectively. Additionally, we discovered 29,199 associations between snoRNAs and immune checkpoint genes and 47,194 associations between snoRNAs and immune cell infiltrations. Sixteen …

Focal Deletions Of A Promoter Tether Activate The Irx3 Oncogene In T-Cell Acute Lymphoblastic Leukemia, Sunniyat Rahman, Gianna Bloye, Nadine Farah, Jonas Demeulemeester, Joana R Costa, David O'Connor, Rachael Pocock, Tanya Rapoz-D'Silva, Adam Turna, Lingyi Wang, Soowah Lee, Adele K Fielding, Juliette Roels, Roman Jaksik, Małgorzata Dawidowska, Pieter Van Vlierberghe, Suzana Hadjur, Jim R Hughes, James O J Davies, Alejandro Gutierrez, Michelle A Kelliher, Peter Van Loo, Mark A Dawson, Marc R Mansour

Faculty, Staff and Student Publications

Oncogenes can be activated in cis through multiple mechanisms including enhancer hijacking events and noncoding mutations that create enhancers or promoters de novo. These paradigms have helped parse somatic variation of noncoding cancer genomes, thereby providing a rationale to identify noncanonical mechanisms of gene activation. Here we describe a novel mechanism of oncogene activation whereby focal copy number loss of an intronic element within the FTO gene leads to aberrant expression of IRX3, an oncogene in T-cell acute lymphoblastic leukemia (T-ALL). Loss of this CTCF-bound element downstream to IRX3 (+224 kb) leads to enhancer hijack of an upstream developmentally active …

A Proteogenomic Analysis Of Cervical Cancer Reveals Therapeutic And Biological Insights, Jing Yu, Xiuqi Gui, Yunhao Zou, Qian Liu, Zhicheng Yang, Jusheng An, Xuan Guo, Kaihua Wang, Jiaming Guo, Manni Huang, Shuhan Zhou, Jing Zuo, Yimin Chen, Lu Deng, Guangwen Yuan, Ning Li, Yan Song, Jia Jia, Jia Zeng, Yuxi Zhao, Xianming Liu, Xiaoxian Du, Yansheng Liu, Pei Wang, Bing Zhang, Li Ding, Ana I Robles, Henry Rodriguez, Hu Zhou, Zhen Shao, Lingying Wu, Daming Gao

Faculty, Staff and Students Publications

Although the incidence of cervical cancer (CC) has been reduced in high-income countries due to human papillomavirus (HPV) vaccination and screening strategies, it remains a significant public health issue that poses a threat to women's health in low-income countries. Here, we perform a comprehensive proteogenomic profiling of CC tumors obtained from 139 Chinese women. Integrated proteogenomic analysis links genetic aberrations to downstream pathogenesis-related pathways and reveals the landscape of HPV-associated multi-omic changes. EP300 is found to enhance the acetylation of FOSL2-K222, consequently accelerating the malignant proliferation of CC cells. Proteomic stratification identifies three patient subgroups with distinct features in prognosis, …

Tumor-Associated Antigen Prediction Using A Single-Sample Gene Expression State Inference Algorithm, Xinpei Yi, Hongwei Zhao, Shunjie Hu, Liangqing Dong, Yongchao Dou, Jing Li, Qiang Gao, Bing Zhang

Faculty, Staff and Students Publications

We developed a Bayesian-based algorithm to infer gene expression states in individual samples and incorporated it into a workflow to identify tumor-associated antigens (TAAs) across 33 cancer types using RNA sequencing (RNA-seq) data from the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA). Our analysis identified 212 candidate TAAs, with 78 validated in independent RNA-seq datasets spanning seven cancer types. Eighteen of these TAAs were further corroborated by proteomics data, including 10 linked to liver cancer. We predicted that 38 peptides derived from these 10 TAAs would bind strongly to HLA-A02, the most common HLA allele. Experimental validation confirmed …

Epigenome Reprogramming Through H3k27 And H3k4 Trimethylation As A Resistance Mechanism To Dna Methylation Inhibition In Brafv600e-Mutated Colorectal Cancer, Hey Min Lee, Ajay Kumar Saw, Van K Morris, Stefania Napolitano, Christopher Bristow, Sanjana Srinivasan, Micheal Peoples, Alexey Sorokin, Preeti Kanikarla Marie, Jonathan Schulz, Anand K Singh, Christopher Terranova, Oluwadara Coker, Abhinav Jain, Scott Kopetz, Kunal Rai

Faculty, Staff and Student Publications

Purpose: BRAFV600E-mutated colorectal cancer exhibits a strong correlation with DNA hypermethylation, suggesting that this subgroup of tumors presents unique epigenomic phenotypes. Nonetheless, 5-azacitidine, which inhibits DNA methyltransferase activity, is not efficacious in BRAFV600E colorectal cancer in vivo.

Experimental design: We randomized and treated mice implanted with patient-derived tumor xenografts harboring BRAFV600E mutation with control, 5-azacitidine, vemurafenib (BRAF inhibitor), or the combination. Comprehensive epigenomic profiling was conducted on control and 5-azacitidine-treated tumor samples, including DNA methylation, histone modifications, chromatin accessibility, and gene expression. Combinations of epigenetic agents were explored in preclinical BRAFV600E colorectal cancer models.

Results: A profound reduction of DNA …

Epigenomic And Transcriptomic Profiling Of Solitary Fibrous Tumors Identifies Site-Specific Patterns And Candidate Genes Regulated By Dna Methylation, Hannah C Beird, Jeffrey M Cloutier, Nalan Gokgoz, Christopher Eeles, Anthony M Griffin, Davis R Ingram, Khalida M Wani, Rossana Lazcano Segura, Luca Cohen, Carl Ho, Jay S Wunder, Irene L Andrulis, P Andrew Futreal, Benjamin Haibe-Kains, Alexander J Lazar, Wei-Lien Wang, Joanna Przybyl, Elizabeth G Demicco

Faculty, Staff and Student Publications

A solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that can arise at any anatomical site and is characterized by recurrent NAB2::STAT6 fusions and metastatic progression in 10% to 30%. The cell of origin has not been identified. Despite some progress in understanding the contribution of heterogeneous fusion types and secondary mutations to SFT biology, epigenetic alterations in extrameningeal SFT remain largely unexplored, and most sarcoma research to date has focused on the use of methylation profiling for tumor classification. We interrogated genome-wide DNA methylation in 79 SFTs to identify informative epigenetic changes. RNA-seq data from targeted panels and …

Enriched G4 Forming Repeats In The Human Genome Are Associated With Robust Well-Coordinated Transcription And Reduced Cancer Transcriptome Variation, Ruth B De-Paula, Albino Bacolla, Aleem Syed, John A Tainer

Faculty, Staff and Student Publications

Non-B DNA G-quadruplex (G4) structures with guanine (G) runs of 2 to 4 repeats can trigger opposing experimental transcriptional impacts. Here, we used bioinformatic algorithms to comprehensively assess correlations of steady-state RNA transcript levels with all putative G4 sequence (pG4) locations genome-wide in three mammalian genomes and in normal and tumor human tissues. The human pG4-containing gene set displays higher expression levels than the set without pG4, supporting and extending some prior observations. pG4 enrichment at transcription start sites (TSSs) in human, but not chimpanzee and mouse genomes, suggests possible positive selection pressure for pG4 at human TSS, potentially driving …

Molecular Profiling Of Braf-V600e-Mutant Metastatic Colorectal Cancer In The Phase 3 Beacon Crc Trial, Scott Kopetz, Danielle A Murphy, Jie Pu, Fortunato Ciardiello, Jayesh Desai, Eric Van Cutsem, Harpreet Singh Wasan, Takayuki Yoshino, Hedieh Saffari, Xiaosong Zhang, Phineas Hamilton, Tao Xie, Rona Yaeger, Josep Tabernero

Faculty, Staff and Student Publications

The BEACON CRC study demonstrated that encorafenib (Enco)+cetuximab (Cetux)±binimetinib (Bini) significantly improved overall survival (OS) versus Cetux + chemotherapy in previously treated patients with BRAF-V600E-mutant mCRC, providing the basis for the approval of the Enco+Cetux regimen in the United States and the European Union. A greater understanding of biomarkers predictive of response to Enco+Cetux±Bini treatment is of clinical relevance. In this prespecified, exploratory biomarker analysis of the BEACON CRC study, we characterize genomic and transcriptomic correlates of clinical outcomes and acquired resistance mechanisms through integrated clinical and molecular analysis, including whole-exome and -transcriptome tissue sequencing and circulating tumor DNA genomic …

Microrna-1307-3p Contributes To Breast Cancer Progression Through Prm2, José Roberto Estupiñan-Jiménez, Valeria Villarreal-García, Vianey Gonzalez-Villasana, Pablo E Vivas-Mejia, Jose Manuel Vazquez-Guillen, Patricio Adrián Zapata-Morin, Marienid Flores-Colón, Claudia Altamirano-Torres, Ezequiel Viveros-Valdez, Cristina Ivan, Mohammed H Rashed, Recep Bayraktar, Cristina Rodríguez-Padilla, Gabriel Lopez-Berestein, Diana Resendez-Perez

Faculty, Staff and Student Publications

Background: Despite advances in screening and therapy, breast cancer (BC) remains the predominant cancer in women globally. Dysregulation of microRNAs (miRNAs) is pivotal in carcinogenesis across various cancers, including BC. Evidence indicates that miR-1307-3p is upregulated in BC tumors, yet its target genes are not fully elucidated. This study aimed to explore how miR-1307-3p regulates BC proliferation, migration, invasion, and angiogenesis and to identify potential target genes.

Methods: Basal miR-1307-3p levels were quantified in BC cell lines MDA-MB-231 and MCF-7, as well as MCF-10A using quantitative real-time reverse transcription-PCR (RT-qPCR). The impact of miR-1307-3p inhibition on BC cell proliferation, migration, …

Developmental-Status-Aware Transcriptional Decomposition Establishes A Cell State Panorama Of Human Cancers, Yikai Luo, Han Liang

Faculty, Staff and Student Publications

Background: Cancer cells evolve under unique functional adaptations that unlock transcriptional programs embedded in adult stem and progenitor-like cells for progression, metastasis, and therapeutic resistance. However, it remains challenging to quantify the stemness-aware cell state of a tumor based on its gene expression profile.

Methods: We develop a developmental-status-aware transcriptional decomposition strategy using single-cell RNA-sequencing-derived tissue-specific fetal and adult cell signatures as anchors. We apply our method to various biological contexts, including developing human organs, adult human tissues, experimentally induced differentiation cultures, and bulk human tumors, to benchmark its performance and to reveal novel biology of entangled developmental signaling in …

Unmasking Neuroendocrine Prostate Cancer With A Machine Learning-Driven Seven-Gene Stemness Signature That Predicts Progression, Agustina Sabater, Pablo Sanchis, Rocio Seniuk, Gaston Pascual, Nicolas Anselmino, Daniel F Alonso, Federico Cayol, Elba Vazquez, Marcelo Marti, Javier Cotignola, Ayelen Toro, Estefania Labanca, Juan Bizzotto, Geraldine Gueron

Faculty, Staff and Student Publications

Prostate cancer (PCa) poses a significant global health challenge, particularly due to its progression into aggressive forms like neuroendocrine prostate cancer (NEPC). This study developed and validated a stemness-associated gene signature using advanced machine learning techniques, including Random Forest and Lasso regression, applied to large-scale transcriptomic datasets. The resulting seven-gene signature (KMT5C, DPP4, TYMS, CDC25B, IRF5, MEN1, and DNMT3B) was validated across independent cohorts and patient-derived xenograft (PDX) models. This signature demonstrated strong prognostic value for progression-free, disease-free, relapse-free, metastasis-free, and overall survival. Importantly, the signature not only identified specific NEPC subtypes, …

Yap1 Status Defines Two Intrinsic Subtypes Of Lcnec With Distinct Molecular Features And Therapeutic Vulnerabilities, C Allison Stewart, Lixia Diao, Yuanxin Xi, Runsheng Wang, Kavya Ramkumar, Alejandra G Serrano, Azusa Tanimoto, B Leticia Rodriguez, Benjamin B Morris, Li Shen, Bingnan Zhang, Yan Yang, Samera H Hamad, Robert J Cardnell, Alberto Duarte, Moushumi Sahu, Veronica Y Novegil, Bernard E Weissman, Michael Frumovitz, Neda Kalhor, Luisa Solis Soto, Pedro Da Rocha, Natalie Vokes, Don L Gibbons, Jing Wang, John V Heymach, Bonnie Glisson, Lauren Averett Byers, Carl M Gay

Faculty, Staff and Student Publications

Purpose: Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine malignancy that, like small cell lung cancer (SCLC), is associated with the absence of druggable oncogenic drivers and dismal prognosis. In contrast to SCLC, however, there is little evidence to guide optimal treatment strategies, which are often adapted from SCLC and non-small cell lung cancer approaches.

Experimental design: To better define the biology of LCNEC, we analyzed cell line and patient genomic data and performed IHC and single-cell RNA sequencing of core needle biopsies from patients with LCNEC and preclinical models.

Results: In this study, we demonstrate that the presence …

An Iron-Rich Subset Of Macrophages Promotes Tumor Growth Through A Bach1-Ednrb Axis, Ian W Folkert, William A Molina Arocho, Tsun Ki Jerrick To, Samir Devalaraja, Irene S Molina, Jason Shoush, Hesham Mohei, Li Zhai, Md Naushad Akhtar, Veena Kochat, Emre Arslan, Alexander J Lazar, Khalida Wani, William P Israel, Zhan Zhang, Venkata S Chaluvadi, Robert J Norgard, Ying Liu, Ashley M Fuller, Mai T Dang, Robert E Roses, Giorgos C Karakousis, John T Miura, Douglas L Fraker, T S Karin Eisinger-Mathason, M Celeste Simon, Kristy Weber, Kai Tan, Yi Fan, Kunal Rai, Malay Haldar

Faculty, Staff and Student Publications

We define a subset of macrophages in the tumor microenvironment characterized by high intracellular iron and enrichment of heme and iron metabolism genes. These iron-rich tumor-associated macrophages (iTAMs) supported angiogenesis and immunosuppression in the tumor microenvironment and were conserved between mice and humans. iTAMs comprise two additional subsets based on gene expression profile and location-perivascular (pviTAM) and stromal (stiTAM). We identified the endothelin receptor type B (Ednrb) as a specific marker of iTAMs and found myeloid-specific deletion of Ednrb to reduce tumor growth and vascular density. Further studies identified the transcription factor Bach1 as a repressor of the iTAM transcriptional …