Genetic Phenomena Commons^™

Microarray Analysis Of Human Abdominal Aortic Aneurysm With Emphasis On Cardiovascular Genes Revealed Differentially Expressed Genes, Song Lu, Li Ping Li, John V. White, Xiaoying Zhang, Ifeyinwa Nwaneshiudu, Adaobi Nwaneshiudu, Nectaria Ntaoula, John Gaughan, Dimitri S. Monos, Wan-Lu Lin, Charalambos C. Solomides, Emilia L. Oleszak, Chris D. Platsoucas

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND/AIM: We examined gene expression profiles in abdominal aortic aneurysm (AAA) lesions vs. normal aortas by cDNA microarray and real-time quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR).

MATERIALS AND METHODS: Phosphorus (³²P)-labeled cDNA from AAA specimens (mean AAA size 6.65 cm) and normal aortas were hybridized with a 588-gene microarray primarily of the cardiovascular system. The results were validated by qRT-PCR.

RESULTS: A total of 35 out of the 588 genes were differentially expressed, with either log₂ ratio of AAAs/controls ≥1 (upregulated; 20 genes) or ≤-1 (downregulated; 15 genes) in AAA lesions vs. normal aorta, and …

Concordance Analysis Of Dna And Rna Profiling: The Md Anderson Impact2 Study In Precision Oncology, Stephanie T Schmidt, Mehmet A Baysal, Siqing Fu, David S Hong, Sarina A Piha-Paul, Aung Naing, Jordi Rodon Ahnert, Timothy A Yap, Ecaterina Elena Dumbrava, Jennifer Beck, Funda Meric-Bernstam, Apostolia Maria Tsimberidou

Faculty, Staff and Student Publications

DNA profiling is an established method for cancer treatment selection, while RNA profiling remains investigational. We explored associations between DNA and RNA alterations and between the number of genes with altered expression and overall survival (OS) using patient data from IMPACT2 (NCT02152254), a randomized study evaluating molecular profiling for guiding cancer therapy across tumor types. Molecular profiling, including DNA next-generation sequencing, was performed on all 829 patients in the IMPACT2 study. RNA profiling was performed by Tempus for 253 of 829 patients. We evaluated the concordance between DNA and RNA profiling, analyzed OS in 217 treated patients with …

Tumor Microenvironment Transcriptional Activity Enables Robust Stratification Of Chemotherapy Response In Triple-Negative Breast Cancer, Yaoyi Dai, Xiaoxi Pan, Shuai Guo, Shuangxi Ji, Shaolong Cao, Matthew D Montierth, Yujie Jiang, Jeffrey T Chang, Leming Shi, Shabnam Shalapour, Gloria V Echeverria, Lucy Yates, Johan Staaf, Bora Lim, Yinyin Yuan, Wenyi Wang

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) exhibits heterogeneous treatment responses, yet molecular subtypes based on predefined biological pathways show limited prognostic value. We introduce tumor-specific total mRNA expression (TmS), a pathway-agnostic deconvolution metric derived from matched RNA/DNA sequencing, as a robust stratification tool. Analyzing 575 TNBC patients across Western and East Asian populations, TmS outperforms established subtypes in predicting chemotherapy outcomes, stratifying patients into high TmS with favorable prognosis and low TmS with poor prognosis. Stromal enrichment with immune exclusion emerges as a universal feature of chemotherapy-resistant low-TmS tumors across all cohorts. Population-specific features distinguish Asian cohorts: high-TmS tumors exhibit cell cycle-driven …

Identification Of Raptor And Gli1 As Usp37 Substrates Highlight Its Context-Specific Function In Medulloblastoma Cells, Ashutosh Singh, Donghang Cheng, Amanda R Haltom, Yanwen Yang, Tara Dobson, Rashieda Hatcher, Veena Rajaram, Vidya Gopalakrishnan

Faculty, Staff and Student Publications

The USP37 gene encodes a deubiquitylase (DUB), which catalyzes the proteolytic removal of ubiquitin moieties from proteins to modulate their stability, cellular localization or activity. Its expression is downregulated in a subgroup of medulloblastomas driven by constitutive activation of sonic hedgehog (SHH) signaling. Patients with SHH-driven medulloblastomas with elevated expression of the RE1 silencing transcription factor (REST) and reduced expression of USP37 have poor outcomes. In previous studies, we showed sustained proliferation of SHH-medulloblastoma cells due to blockade of terminal cell cycle exit and neuronal differentiation stemming from a failure in USP37-dependent stabilization of its target, the cyclin-dependent kinase inhibitor …

A Guide To Transcriptomic Deconvolution In Cancer, Yaoyi Dai, Shuai Guo, Yidan Pan, Carla Castignani, Matthew D Montierth, Peter Van Loo, Wenyi Wang

Faculty, Staff and Student Publications

Cancer tissues are heterogeneous mixtures of tumour, stromal and immune cells, where each component comprises multiple distinct cell types and/or states. Mapping this heterogeneity and understanding the unique contributions of each cell type to the tumour transcriptome is crucial for advancing cancer biology, yet high-throughput expression profiles from tumour tissues only represent combined signals from all cellular sources. Computational deconvolution of these mixed signals has emerged as a powerful approach to dissect both cellular composition and cell-type-specific expression patterns. Here, we provide a comprehensive guide to transcriptomic deconvolution, specifically tailored for cancer researchers, presenting a systematic framework for selecting and …

Tbr2-Dependent Parallel Pathways Regulate The Development Of Distinct Iprgc Subtypes, Takae Kiyama, Ching-Kang Chen, Halit Y Altay, Yu-Jiun Chen, Leviette Sigala, Dan Su, Steven Eliason, Brad A Amendt, Chai-An Mao

Faculty, Staff and Student Publications

The intrinsically photosensitive retinal ganglion cells (ipRGC) are the conduit between the retina and brain regions responsible for non-image-forming and image-forming vision. In mice, six ipRGC subtypes have been discovered based on morphological characteristics, functions, and molecular profiles. All ipRGCs arise from Tbr2-expressing RGCs during developmental stages and subsequently diverge and differentiate into the six mature, distinct subtypes in adult retinas. However, the cellular and molecular mechanisms controlling the formation and maturation of the six ipRGC subtypes remain elusive. Here, we demonstrate that two Tbr2-dependent transcription factors, Iroquois‑related homeobox 1 (Irx1) and T-box containing factor 20 (Tbx20), are key downstream …

High Levels Of Circulating Mir-19a-3p In Patients With Metastatic Her2 + Breast Cancer Are Associated With A Favorable Prognosis And Anti-Tumor Immune Responses, Evan N Cohen, Hui Gao, Sanda Tin, Qiong Wu, Cristina Ivan, Naoto T Ueno, Wendy A Woodward, James M Reuben, Simone Anfossi

Faculty, Staff and Student Publications

Background: Trastuzumab, combined with chemotherapy, is the current standard treatment for both metastatic and early-stage HER2-positive (HER2 +) breast cancer. One of the mechanisms of action of trastuzumab is antibody-dependent cellular cytotoxicity (ADCC), which involves engaging FcγRIIIA (CD16) on natural killer (NK) cells. A competent immune system and properly functioning NK cells are crucial for effective ADCC, as they can influence favorable clinical outcomes. Resistance to trastuzumab often develops after about one year. We previously reported that elevated levels of miR-19a-3p in the serum of patients with metastatic HER2 + breast cancer treated with trastuzumab were associated with a favorable …

The Gene Encoding Ornithine Decarboxylase For Putrescine Biosynthesis Is Essential For The Viability Of Fusobacterium Nucleatum, Shiqi Xu, Bibek G C, Alex Phan, Chenggang Wu

Faculty, Staff and Student Publications

Fusobacterium nucleatum is a Gram-negative anaerobe associated with periodontitis and colorectal cancer. It secretes putrescine, a polyamine that promotes biofilm formation by oral co-colonizers and enhances the proliferation of cancer cells. However, the physiological importance of putrescine for F. nucleatum itself remains unexplored. Here, we show that putrescine biosynthesis, mediated by the ornithine decarboxylase gene oda, is essential for F. nucleatum viability. Deletion of oda was only possible when a functional copy was provided in trans, and CRISPR interference of oda expression resulted in complete growth defects. The essentiality of oda was conserved across multiple subspecies. Supplementation with …

Foxo1 Inhibition And Fadd Knockdown Have Opposing Effects On Anticancer Drug-Induced Cytotoxicity And P21 Expression In Osteosarcoma Cells, Danielle Walker, Antanay Hall, Alexis Bonwell, Nancy Gordon, Danielle Robinson, Mario G Hollomon

Faculty, Staff and Student Publications

Forkhead box class O1 (FOXO1) and fas-associated death domain (FADD) regulate cell death pathways and homeostatic processes such as cell cycle progression and apoptosis. FADD phosphorylation promotes nuclear localization of FOXO1, and FOXO1 regulates FADD expression. Therefore, it is plausible that FOXO1 and FADD have synergistic or antagonistic effects on cell cycle regulation and the response to anticancer drug treatment in cancer cells. In the present study, we report that AS1842856-mediated inhibition of FOXO1 reverses anticancer drug-induced cytotoxicity, while FADD knockdown increases anticancer drug-induced cytotoxicity in osteosarcoma (OS). Reversed anticancer drug-induced cytotoxicity was accompanied by G2/M cell cycle arrest and …

A Prognostic Matrix Gene Expression Signature Defines Functional Glioblastoma Phenotypes And Niches, Monika Vishnoi, Zeynep Dereli, Zheng Yin, Elisabeth K Kong, Meric Kinali, Kisan Thapa, Ozgun Babur, Kyuson Yun, Nourhan Abdelfattah, Xubin Li, Behnaz Bozorgui, Mary C Farach-Carson, Robert C Rostomily, Anil Korkut

Faculty, Staff and Student Publications

Interactions among tumor, immune, and vascular niches play major roles in glioblastoma (GBM) malignancy and treatment responses. The composition and heterogeneity of extracellular core matrix proteins (CMPs) that mediate such interactions are not well understood. Here, we present an analysis of the clinical relevance of CMP expression in GBM at bulk, single-cell, and spatial anatomical resolution. We show that CMP enrichment is associated with worse patient survival, specific driver oncogenic alterations, mesenchymal state, pro-tumor immune infiltration, and immune checkpoint expression. Matrisome expression is enriched in vascular and leading edge/infiltrative niches that are known to harbor glioma stem cells. Finally, we …

Functional, Pharmacogenomic, And Immune Landscapes Of Long Non-Coding Rnas In Cancer, Runhao Wang, Mei Luo, Yuan Liu, Jingwen Yang, Yamei Chen, Chengxuan Chen, Lifei Ma, Stephanie Ding, James Wengler, Yong Zang, Bora Lim, Wenbo Li, Liuqing Yang, Chunru Lin, Lixia Diao, Leng Han

Faculty, Staff and Student Publications

Long non-coding RNAs (lncRNAs) are emerging as key regulators in cancer, with significant potential as diagnostic, prognostic, and therapeutic targets. Here, this work systematically analyzes lncRNA associations with targeted therapies and immunotherapies across 33 cancer types using The Cancer Genome Atlas (TCGA) and real-world datasets. This work identifies 53,173 lncRNA-pathway associations, millions of lncRNA-drug response associations (via CancerRxTissue and VAEN), and extensive correlations with immune checkpoints and infiltration. This work further identifies 69 lncRNAs associated with immunotherapy response and 2,611 differentially expressed lncRNAs between low and high objective response rate (ORR) groups. Additionally, two lncRNAs are correlated with immune-related adverse …

Nsd2 Inhibitors Rewire Chromatin To Treat Lung And Pancreatic Cancers, Jinho Jeong, Simone Hausmann, Hanyang Dong, Kacper Szczepski, Natasha M Flores, Andy Garcia Gonzalez, Liyang Shi, Xiaoyin Lu, Joanna Lempiäinen, Moritz Jakab, Liyong Zeng, Tourkian Chasan, Eric Bareke, Rui Dong, Emma Carlson, Reinnier Padilla, Dylan Husmann, Julia Thompson, Gerry A Shipman, Emily Zahn, Courtney A Barnes, Laiba F Khan, Liz Marie Albertorio-Sáez, Eva Brill, Vishnu Udayakumar Sunita Kumary, Matthew R Marunde, Danielle N Maryanski, Cheryl C Szany, Bryan J Venters, Carolina Lin Windham, Michal Eligiusz Nowakowski, Iwona Czaban, Mariusz Jaremko, Michael-Christopher Keogh, Kang Le, Michael J Soth, Benjamin A Garcia, Łukasz Jaremko, Jacek Majewski, Pawel K Mazur, Or Gozani

Faculty, Staff and Student Publications

NSD2 catalyses the epigenetic modification H3K36me2 (refs. 1,2) and is a candidate convergent downstream effector of oncogenic signalling in diverse malignancies3–5. However, it remains unclear whether the enzymatic activity of NSD2 is therapeutically targetable. Here we characterize a series of clinical-grade small-molecule catalytic NSD2 inhibitors (NSD2i) and show that the pharmacological targeting of NSD2 constitutes an epigenetic dependency with broad therapeutic efficacy in KRAS-driven preclinical cancer models. NSD2i inhibits NSD2 with single-digit nanomolar half-maximal inhibitory concentration potency and high selectivity over related methyltransferases. Structural analyses reveal that the specificity of NSD2i for NSD2 …

Key Regulatory Roles Of Prdm1 In Human Nk-Cell Differentiation And Activation, Xuxiang Liu, Yunfei Shi, Jibin Zhang, Kunal Shetty, Krystie Chew, Can Küçük, Qiang Gong, Esra Esmeray, Haiqing Li, Ru Chen, Sheng Pan, Katarzyna Dąbrowska, Roger E Moore, Krystine Garcia-Mansfield, Patrick Pirrotte, Jinhui Wang, Yuping Li, Gehong Dong, Logan Lee, Timothy W Mckeithan, Javeed Iqbal, Wing C Chan

Faculty, Staff and Student Publications

PRDM1, encoding a transcription factor (TF), regulates plasma cell and CD8+ T-cell terminal differentiation and Th2 lineage specification, while its role in human NK-cell differentiation and homeostasis is largely unknown. Here, we employed a multi-omics approach to dissect the transcriptional control of PRDM1 on human NK-cells. PRDM1 is important in NK-cell terminal differentiation based on gene expression profiling and its targeting of key regulators in the process. PRDM1-deleted NK-cells displayed a less mature phenotype simulating the CD56bright NK-cell population accompanied by upregulation of stem-like gene signatures. PRDM1-bound genes were enriched in T/NK-cell receptor signaling, activation, and NK-cell effector …

The Lysine Demethylase Kdm4c Is An Oncogenic Driver And Regulates Erk Activity In Kras-Mutant Pancreatic Ductal Adenocarcinoma, Menna-T-Allah Shaheen, Sarah Dhebat, Kimal I Rajapakshe, Bidyut Ghosh, Benson Chellakkan Selvanesan, Shariq S Ansari, Cara L Haymaker, Dorsay Sadeghian, Huamin Wang, Ching-Fei Li, Haoqiang Ying, Anirban Maitra

Faculty, Staff and Student Publications

Deregulation of proteins involved in chromatin regulation is common in pancreatic ductal adenocarcinoma (PDAC). Lysine demethylase 4C (KDM4C) is one of the chromatin-modifying proteins frequently overexpressed across multiple solid cancers and is linked to chromatin instability, increased cell proliferation, and enhanced stem cell–like behavior. We observed upregulation of KDM4C protein in a panel of human PDAC cell lines and patient samples compared with nonneoplastic controls. CRISPR/Cas9-mediated deletion of KDM4C in human and murine PDAC cells reduced proliferation, clonogenicity, and increased survival of orthotopically implanted murine PDAC allografts. Transcriptomic and proteomic analyses revealed that loss of KDM4C in both human and …

Batf2 Is A Glutamine-Responsive Tumour Suppressor Required For Type-I Interferon-Dependent Anti-Tumour Immunity, Wang Gong, Hülya F Taner, Yuesong Wu, Yumin He, Xingwu Zhou, Zaiye Li, Xin Hu, Charisse Ursin, Kala Chand Debnath, Kohei Okuyama, Qiang Hu, Christopher R Donnelly, Felipe Nör, Chamila D Perera, Emily Bellile, Arash Yunesi, Zhiqian Zhai, Mei Zhao, Wanqing Cheng, Zackary R Fitzsimonds, Luke Broses, Jiaqian Li, Shadmehr Demehri, Deepak Nagrath, Gregory T Wolf, Andrew G Sikora, Yanbao Yu, Haitao Wen, Lei Wei, Steven B Chinn, Jeffrey N Myers, Shizuo Akira, Yuying Xie, James J Moon, Yu Leo Lei

Faculty, Staff and Student Publications

Recent evidence highlights the significance of a new type of tumour suppressors, which are not frequently mutated but inhibited by metabolic cues in cancers. Here, we identify BATF2 as a tumour suppressor whose expression is epigenetically silenced by glutamine in Head and Neck Squamous Cell Carcinomas (HNSCC). BATF2 correlates with type-I interferon and Th1 signatures in human HNSCC, with correlation coefficients even stronger than those of the positive control, STING. The phosphorylation of BATF2 at serine 227 promotes the oligomerization of STING. BATF2 deficiency or high glutamine levels result in higher oxygen consumption rates and metabolic profiles unfavorable for …

Lung Adenocarcinoma Surfaceome Remodeling With Egfr Inhibitors Uncovers Placental Alkaline Phosphatase As A Target For Combination Therapy, Yihui Chen, Rongzhang Dou, Monica J Hong, Hanwen Xu, Jody Vykoukal, Ricardo A León-Letelier, Yining Cai, Soyoung Park, Ehsan Irajizad, Fu Chung Hsiao, Jennifer B Dennison, Edwin J Ostrin, Johannes F Fahrmann, Hiroyuki Katayama, Samir M Hanash

Faculty, Staff and Student Publications

Treatment of lung adenocarcinomas (LUADs) that exhibit activated epidermal growth factor receptor (EGFR) with EGFR tyrosine kinase inhibitors (TKIs) has limited efficacy. Assessment of the impact of EGFR TKI on the LUAD surfaceome remodeling reveals potential therapeutic targets. We identify placental type alkaline phosphatase (ALPP), which has restricted expression in normal tissues, among upregulated surface proteins following EGFR TKI treatment of both TKI sensitive as well as resistant cells. EGF treatment represses ALPP expression, whereas EGFR TKIs upregulate its expression through dephosphorylation and activation of FoxO3a, a transcriptional regulator that binds to the promoter region of ALPP. The combination of …

Single Cell Spatial Profiling Of The Matrisome Identifies Region-Specific Adhesion And Signaling Networks In Glioblastoma, Arpan De, Santiago A Forero, Ali Pirani, John E Morales, Marisol De La Fuente-Granada, Sumod Sebastian, Jason T Huse, Leomar Y Ballester, Jeffrey S Weinberg, Frederick F Lang, Kadir C Akdemir, Joseph H Mccarty

Faculty, Staff and Student Publications

The human brain contains a milieu of extracellular matrix (ECM) components that promote normal development and physiology. ECM signaling pathways are often dysregulated in brain pathologies including the malignant cancer glioblastoma (GBM). Here, we used single-cell spatial transcriptomic platforms to map the expression of nearly 400 ECM genes in matching non-cancerous brain and GBM samples. At least four different GBM cell populations have been identified that show unique ECM expression profiles and spatial enrichment in distinct intratumor regions. Spatial mapping demonstrates largely non-overlapping expression signatures of ECM components in GBM stromal cell types, particularly in vascular endothelial cells and microglia/macrophages. …

Actin Dysregulation Induces Neuroendocrine Plasticity And Immune Evasion: A Vulnerability Of Small Cell Lung Cancer, Yoojeong Seo, Shengzhe Zhang, Jinho Jang, Kyung-Pil Ko, Kee-Beom Kim, Yuanjian Huang, Dong-Wook Kim, Bongjun Kim, Gengyi Zou, Jie Zhang, Sohee Jun, Wonhong Chu, Nicole A Kirk, Ye Eun Hwang, Young Ho Ban, Shilpa S Dhar, Joseph M Chan, Min Gyu Lee, Charles M Rudin, Kwon-Sik Park, Jae-Il Park

Faculty, Staff and Student Publications

Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. Capping protein inhibiting regulator of actin dynamics (CRACD) that promotes actin polymerization, is frequently inactivated in SCLC. However, the role of CRACD loss in SCLC is unknown. Here we show that CRACD depletion drives neuroendocrine (NE) cell plasticity and immune evasion in SCLC. Mechanistically, CRACD inactivation disrupts actin organization, leading to suppression of Yap1-NOTCH signaling and subsequent NE gene upregulation. Simultaneously, CRACD loss drives EZH2-mediated histone methylation via nuclear actin disruption, leading to repression of MHC-I genes and depletion of CD8⁺ T cells. Consequently, CRACD-downregulated tumors exhibit …

Multi-Omic Profiling Provides Insights Into The Heterogeneity, Microenvironmental Features, And Biomarker Landscape Of Small-Cell Lung Cancer, Mingchao Xie, Miljenka Vuko, Shashank Saran, Siyu Liu, Andrew G Chambers, Hana Baakza, Helen K Angell, Felicia Ng, Carl M Gay, Robert J Cardnell, Felix J Segerer, Alma Andoni, Jaime Rodriguez-Canales, Paul M Waring, Markus Schick, J Carl Barrett, Lauren A Byers, Giulia Fabbri

Faculty, Staff and Student Publications

Background: Greater understanding of differential therapeutic sensitivity, specifically to immunotherapy, in small-cell lung cancer (SCLC) is required.

Methods: We explored SCLC heterogeneity through integrated molecular characterization of tumor tissue samples from 159 treatment-naive patients, utilizing genetic, epigenetic, transcriptional, and proteomic profiling, immunohistochemistry staining for multiple biologically relevant markers including transcriptional subtype-defining proteins, and spatial immune profiling using multiplex immunofluorescence.

Results: Multi-omics analysis confirmed high heterogeneity across/within neuroendocrine and non-neuroendocrine subtypes. Methylomics analysis identified four methylome clusters that may enhance subtype prediction, prognosis, and longitudinal monitoring of subtype evolution. Immunohistochemistry analysis showed high MHC-I expression in non-neuroendocrine subtypes, which have greatest …

Hif-2-Dependent Regulation Of Pthrp And Paraneoplastic Hypercalcemia In Aggressive Clear-Cell Renal Cell Carcinoma, Arijit Mal, Bingqing Xie, Zane Gray, Charlotte Small, Susmita G Ramanand, Yunpeng Gao, Vanina Toffessi Tcheuyap, Sashi Debnath, Alana Christie, Jeffrey Miyata, Brooklyn Jackson, Hua Zhong, Boning Gao, Jay Lohrey, Naim M Maalouf, Sangeetha M Reddy, John D Minna, Ivan Pedrosa, Xiankai Sun, Ram S Mani, Payal Kapur, James Brugarolas

Faculty, Staff and Student Publications

Renal cell carcinoma (RCC) patients with hypercalcemia (HC) have worse outcomes. HC often involves PTHrP, and the role of HIF-2 is incompletely understood. Leveraging RCC tumorgraft (TG) models of HC, which were characterized by tumor cell autonomous inflamatory/immune signatures, we show that HIF-2 inhibition with PT2399 frequently normalized calcium, downregulated circulating PTHrP and reduced HIF-2 binding to the PTHLH (PTHrP) promoter. Likely contributing to the selective induction of PTHrP in a subset of HIF-2-dependent tumors, the PTHLH locus was generally more accessible in TG(HC). However, PTHLH chromatin accessibility was grossly unaffected by PT2399, unlike elsewhere (including EPO locus in a …

Tumor Intrinsic Mettl5 Modulates Atf4 Translation To Prevent T Cell-Induced Ferroptosis In Ovarian Cancer, Jiakai Hou, Cheng-Wei Ju, Nicholas A Egan, Yanjun Wei, Yunfei Wang, Minghao Dang, Tianyi Zhou, Leilei Shi, Ningbo Zheng, Si Chen, Ashley M Guerrero, Xiaofang Liang, Wanfu Wu, Areej Akhtar, Chitra Dhiman, Debanwita Roy Burman, Andro E Gerges, Mason D Flores, Han Li, Li-Sheng Zhang, Marleen Kok, Xiaobo Mao, Linghua Wang, Qin Feng, Yiwen Chen, Sanghoon Lee, Daniel J Mcgrail, Nidhi Sahni, Chuan He, Amir A Jazaeri, Weiyi Peng

Faculty, Staff and Student Publications

Poor clinical responses to immune checkpoint blockade (ICB) observed in ovarian cancer (OC) highlight an unmet need to understand the mechanisms driving immune evasion in this disease. To address this, an integrative analysis is conducted by combining in vitro genome‐wide immune screens, in vivo ICB screens, and clinical data mining, and METTL5 is identified as a crucial OC‐intrinsic factor that promotes immune resistance. Immunologically “cold” OC tumors and poor responders to ICB exhibit elevated METTL5 expression. Mechanistically, knocking out (KO) METTL5 in OC disrupts ATF4 translation by altering 18S rRNA m6A levels, leading to the downregulation of SLC7A11 and SLC3A2 …

Periostin Promotes Sarcoma Growth By Promoting Tumor-Associated Macrophage Migration And Differentiation, Jin-Fen Xiao, Kristin Ishaya, Emily Y Ko, Annaliese Fowler, Marina T Broz, Jlenia Guarnerio

Faculty, Staff and Student Publications

Soft-tissue sarcomas (STS) are characterized by abundant extracellular matrix (ECM) deposition, yet the functional contribution of specific ECM components remains poorly understood. In this study, we identify periostin (POSTN), a matricellular protein, as a regulator of sarcoma progression and the tumor immune microenvironment. Analysis of human sarcoma datasets revealed that high POSTN expression correlates with poor prognosis and elevated expression of ECM-related and myeloid cell–associated genes. In murine genetic models of sarcoma, tumors expressing high levels of Postn displayed enhanced expression of ECM genes and monocyte-recruiting cytokines. Functional silencing of Postnin vivo reduced tumor growth without altering tumor cell …

Developmental Stage-Dependent Transcriptomic Responses To Neonatal Intraventricular Hemorrhage, Elizabeth Wallace-Anthony, Miriam Zamorano, Hemendra J Vekaria, Braden B Oldham, Kiara P Umpornpun, Scott D Olson, Stefano Berto, Brandon A Miller

Faculty, Staff and Student Publications

Neonatal intraventricular hemorrhage (IVH) is a major complication of preterm birth, yet how developmental stage influences the brain's response to injury remains unclear. We performed single-nucleus RNA sequencing on rat brains 24 h after IVH at postnatal day 2 (PND2) or day 5 (PND5) to define transcriptional responses across cell types. We identified 42 distinct cell populations and found that PND5 brains exhibited a markedly stronger immune and inflammatory response to IVH, with a threefold increase in differentially expressed genes compared to PND2. Microglia were the most perturbed cell type at both stages, showing increased oxidative stress and polarization toward …

Mecp2 Interacts With The Super Elongation Complex To Regulate Transcription, Jun Young Sonn, Wonho Kim, Marta Iwanaszko, Yuki Aoi, Yan Li, Guantong Qi, Luke Parkitny, Janice L Brissette, Lorin Weiner, Juan Botas, Ismael Al-Ramahi, Ali Shilatifard, Huda Y Zoghbi

Faculty, Staff and Students Publications

Loss-of-function mutations in methyl-CpG binding protein 2 (MECP2) cause Rett syndrome. While we know that MeCP2 binds to methylated cytosines on DNA, the full breadth of the molecular mechanisms by which MeCP2 regulates gene expression remains incompletely understood. Here, using a genetic modifier screen, we identify the super elongation complex, a P-TEFb–containing elongation factor that releases promoter-proximally paused RNA polymerase II, as a genetic interactor of MECP2. MeCP2 physically interacts with SEC subunits and directly binds AFF4, the scaffold of the SEC, via the transcriptional repression domain. Furthermore, MeCP2 facilitates the binding of AFF4 on a subset …

Identification Of Therapeutic Targets For Renal Medullary Carcinoma Via Integrated Genomic And Transcriptomic Profiling, Pavlos Msaouel, Nizar M Tannir, Funda Meric-Bernstam, Jennifer M King, Martin H Voss, Jessica P Cheng, Susan S Thomas, Zita D Lim, Menuka Karki, Rong He, Giannicola Genovese, Rahul A Sheth, Davis R Ingram, Diana Shamsutdinova, Khalida M Wani, Wei-Lien Wang, Alexander J Lazar, Dominique Knipper-Davis, Amber Berlinski, Tayla Soares, Danil Stupichev, Kirill Kryukov, Suren Davitavyan, Anna Novokreshchenova, Dmitry Lebedev, Stanislav Kurpe, Andrey Kravets, Dmitrii Belousov, Michael Hensley, Alexander Bagaev, Francesca Paradiso, Vladimir Kushnarev

Faculty, Staff and Student Publications

Renal medullary carcinoma (RMC) is a rare but highly aggressive kidney cancer that resists conventional therapies. To identify therapeutic targets, this study employs histopathologic, genomic, and transcriptomic profiling of 25 RMC samples. TROP2, EPCAM, CLDN6, and CDH6 are significantly overexpressed compared with other renal and solid tumors. Pathway analyses indicate Hippo pathway upregulation and a tumor microenvironment rich in fibroblasts and neutrophils. We subsequently explore treatment of four heavily pretreated patients, all with high TROP2 expression, using sacituzumab govitecan, a TROP2-targeted antibody-drug conjugate. Of these four patients, one patient achieves a partial response with symptom improvement, two patients maintain stable …

Distinct Tumor-Associated Macrophage Signatures Shape The Immune Microenvironment And Patient Prognosis In Renal Cell Carcinoma, Youngsoo Han, Aidan Shen, Cheng-Chi Chao, Lucas Yeung, Aliesha Garrett, Jianming Zeng, Satoru Kawakita, Jesse Wang, Zhaohui Wang, Alireza Hassani, Xiling Shen, Chongming Jiang

Faculty, Staff and Student Publications

Renal cell carcinoma (RCC) accounts for 90% of adult renal cancer cases and is characterized by significant heterogeneity within its tumor microenvironment. This study tests the hypothesis that tumor-associated macrophages (TAMs) influence RCC progression and patient response to treatment by investigating the prognostic implications of TAM signatures. Utilizing independent single-cell RNA sequencing data from RCC patients, we developed eight distinct TAM signatures reflective of TAM presence. A LASSO Cox regression model was constructed to predict survival outcomes, evaluated using the TCGA dataset, and validated across independent RCC cohorts. Model performance was assessed through Kaplan-Meier survival plots, receiver operating characteristic (ROC) …

Therapeutic Potential Of Prmt1 As A Critical Survival Dependency Target In Multiple Myeloma, Tabish Hussain, Sharad Awasthi, Farid Shahid, S Stephen Yi, Nidhi Sahni, C Marcelo Aldaz

Faculty, Staff and Student Publications

Multiple myeloma (MM) is a neoplasm of antibody-producing plasma cells and is the second most prevalent hematological malignancy worldwide. Development of drug resistance and disease relapse significantly impede the success of MM treatment, highlighting the critical need to discover novel therapeutic targets. In a custom CRISPR/Cas9 screen targeting 197 DNA damage response-related genes, Protein Arginine N-Methyltransferase 1 (PRMT1) emerged as a top hit, revealing it as a potential therapeutic vulnerability and survival dependency in MM cells. PRMT1, a major Type I PRMT enzyme, catalyzes the asymmetric transfer of methyl groups to arginine residues, influencing gene transcription and protein function through …

Restricting Metabolic Plasticity Enhances Stress Adaptation Through The Modulation Of Pdh And Hif1a In Trap1-Depleted Colon Cancer, Hong-Yuan Tsai, Miao-Hsueh Chen, Jihye Yun, Lisa A Lai, John F Valentine, Mary P Bronner, Teresa A Brentnall, Sheng Pan, Ru Chen

Faculty, Staff and Student Publications

Metabolic plasticity allows cancer cells to survive under adverse conditions. To investigate the role of mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) in this process, we used CRISPR/Cas9 mediated genetic deletion to knock out (KO) TRAP1 in colon cancer cells. Depletion of TRAP1 triggered a series of events: induced metabolic reprogramming, increased glycolytic flux, downregulation of mitochondrial complex I, and elevated ROS generation. TRAP1-deficient cells showed tolerance to Oxidative Phosphorylation (OXPHOS) inhibitors and exhibited a higher extracellular acidification rate (ECAR). Additionally, TRAP1 depletion activated hypoxia response elements (HREs) and upregulated HIF1A target genes such as GLUT1 and MCT1. …

Multi-Modal Spatial Characterization Of Tumor Immune Microenvironments Identifies Targetable Inflammatory Niches In Diffuse Large B Cell Lymphoma, Yibo Dai, Atish Kizhakeyil, Dai Chihara, Xubin Li, Yunhe Liu, Tania Patricia Sainz Zuniga, Ashley Wilson, Jared Henderson, Daniil Vibe, Arman Petrosyants, Connor Jacobson, Alexander Sarachakov, Krystle Nomie, Kirill Kryukov, Aleksander Bagaev, Ayushi Chauhan, Jason R Westin, Christopher R Flowers, Francisco Vega, Linghua Wang, Michael R Green

Faculty, Staff and Student Publications

Diffuse large B cell lymphomas (DLBCLs) are a heterogeneous group of malignancies that can arise in lymph nodes or extranodal locations, including immune-privileged sites. Here, we applied highly multiplexed spatial transcriptomics and proteomics together with genomic profiling to characterize the immune microenvironment architecture of 78 DLBCL tumors. We define seven distinct cellular niches, each characterized by unique cellular compositions, spatial organizations and patterns of intercellular communication associated with niche-specific phenotypes of both T cells and tumor B cells. Among these, DLBCLs from immune-privileged sites showed abundant T cell infiltration into diffuse niches, where immune cells were intermixed with tumor B …

Sexually Dimorphic Sail Feathers In The Mandarin Duck As A Model For Lifelong Developmental Modulation, Pin-Chi Tang, Hsu-Chen Cheng, Gee-Way Lin, Yung-Chih Lai, Ya-Chen Liang, Ping Wu, Tzu-Chiao Lin, Chen Siang Ng, Isheng Jason Tsai, Ang Li, Wen Hsiung Li, Chih-Feng Chen, Cheng-Ming Chuong, Randall Widelitz

Faculty, Staff and Student Publications

Developmental processes extend beyond embryogenesis to support lifelong tissue adaptations. Avian feather follicles, with their resident stem cells and capacity for cyclic regeneration, provide a dynamic model for postnatal tissue remodeling. Here, we propose the Mandarin duck (Aix galericulata) as an ideal model to study lifelong developmental modulation, focusing on the sexually dimorphic "sail feather"-a secondary flight feather in males that undergoes seasonal transformation into a strikingly asymmetric, ornamented phenotype during the breeding season. We identified asymmetric morphogen expression in regenerating male sail feathers and used transcriptome and H3K27ac ChIP-seq to uncover male and female signaling pathways and regulatory elements. …