Medical Cell Biology Commons^™

Routine Transfusion Of Rh(D)-Positive Rbcs To Rh(D)-Negative Patients Designated As Do Not Resuscitate Conserves Rh(D)-Negative Red Blood Cell Inventory, Julie Katz Karp, Jovanna Everetts, Juliana Guarente, Angelica Vivero, Tiffany Bohr, Mary Harach

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background: A minority of blood donors are Rh(D)-negative, and Rh(D)-negative red blood cell (RBC) products are often overutilized. As such, Rh(D)-negative RBCs may be difficult to maintain in blood bank inventory.

Study design and methods: We changed our blood bank laboratory policy to approve non-alloimmunized Rh(D)-negative patients to receive Rh(D)-positive RBCs for routine transfusion under defined criteria. Those criteria included Rh(D)-negative males (all ages) and females (aged >50 years) who were designated as do not resuscitate (DNR), either with or without intubation, in the electronic medical record.

Results: From August 15, 2024 through August 15, 2025, a total of 204 …

Anti-Csf-1r Therapy With Combined Immuno-Chemotherapy Coordinate An Adaptive Immune Response To Eliminate Macrophage Enriched Triple Negative Breast Cancers, Diego A Pedroza, Xueying Yuan, Fengshuo Liu, Hilda L Chan, Christina Zhang, William Bowie, Alex J Smith, Sebastian J Calderon, Nadia Lieu, Weiguo Wu, Paul Porter, Poonam Sarkar, Na Zhao, Constanze V Oehler, Ondrej Peller, M Waleed Gaber, Qian Zhu, Charles M Perou, Xiang H-F Zhang, Jeffrey M Rosen

Faculty, Staff and Students Publications

Women diagnosed with metastatic triple negative breast cancer (mTNBC) have limited treatment options, are more prone to develop resistance and are associated with high mortality. A cold tumor immune microenvironment (TIME) characterized by low T cells and high tumor associated macrophages (TAMs) in mTNBC is associated with the failure of standard-of-care chemotherapy and immune checkpoint blockade (ICB) treatment. We demonstrate that the combination of immunomodulatory low-dose Cyclophosphamide (CTX) coupled with anti-CSF-1R antibody targeted therapy (SNDX-ms6352) and anti-PD-1 (ICB), was highly effective against aggressive metastatic Trp53 null TNBC transplantable syngeneic models that present with high macrophage infiltration. Mechanistically, CSF-1R inhibition along …

The Microstructure Of Metastatic Bone Lesions Suggests Tumor Mediated Alterations In Bone Mineralization, Hanwen Fan, Zhan Xu, Carla Berrospe Rodriguez, Noah Dover, Andrei Demkov, Morgan Lilly, Guillermo Aguilar, Larry J Suva, Xiang H-F Zhang, Yuxiao Zhou

Faculty, Staff and Students Publications

Breast, prostate and lung cancer cells frequently metastasize to bone, leading to disruption of the bone microstructure. This study utilized mechanical testing coupled with micro-CT imaging, digital volume correlation (DVC), and atomic force microscopy (AFM) nanomechanical testing to examine the mechanical property variations in mouse long bones (tibia) with metastatic lung cancer cell involvement, spanning from the whole-bone scale to the microstructural level. In addition, we also investigated how metastatic invasion alters the morphology of hydroxyapatite nanocrystals in bone at the nanometer scale. The biochemical composition within metastatic lesions was assessed using Raman spectroscopy and correlated with AFM mechanical testing …

Lilrb4 Regulates Circadian Disruption-Induced Mammary Tumorigenesis Via Non-Canonical Wnt Signaling Pathway, Olajumoke Ogunlusi, Mrinmoy Sarkar, Kayla Carter, Arhit Chakrabarti, Devon J Boland, Tristan Nguyen, James Sampson, Christian Nguyen, Danielle Fails, Yava Jones-Hall, Loning Fu, Gus Wright, Da Mi Kim, James J Cai, Bani Mallick, Alex C Keene, Jeff R Jones, Tapasree Roy Sarkar

Faculty, Staff and Students Publications

Epidemiological studies have shown that circadian rhythm disruption (CRD) is associated with the risk of breast cancer. However, the role of CRD in mammary gland morphology and aggressive basal mammary tumorigenesis and the molecular mechanism underlying CRD-induced carcinogenesis remain unknown. To investigate the effect of CRD on aggressive tumorigenesis, a genetically engineered mouse model of aggressive breast cancer was used. The impact of CRD on the tumor microenvironment was investigated using the tumors from LD12:12 and CRD mice via scRNA-seq, flow cytometry, multiplexing immunostaining, and realtime PCR. The effect of LILRB4-immunotherapy on CRD-induced tumorigenesis was also investigated. Here we investigated …

Nivolumab Plus Ipilimumab Induce Hyper-Progression In Renal Medullary Carcinoma: Results Of A Phase Ii Trial And Preclinical Evidence, Melinda Soeung, Xinmiao Yan, Ciro Zanca, Jing Qian, Menuka Karki, Fei Duan, Hania Khan, Li Zhang, David H Peng, Mariah Williams, Rong He, Ziheng Chen, Luigi Perelli, Jianfeng Chen, Rebecca S Tidwell, Pankaj K Chauhan, Courtney N Le, Truong N A Lam, Nirjar Bhattacharya, Rutvi Shah, I-Lin Ho, Jason P Gay, Caroline C Carrillo, Ningping Feng, Kang Le, Guang Gao, Teresa L Perry, Faika Mseeh, Yongying Jiang, Quanyun A Xu, Niki Marie Zacharias, Rahul A Sheth, Tharakeswara K Bathala, Priya Rao, Najat C Daw, Durga N Tripathi, Cheryl L Walker, Mohammad M Mohammad, Jianhua Zhang, Guangchun Han, Yanshuo Chu, Ruiping Wang, Minghao Dang, Enyu Dai, Fuduan Peng, Yunhe Liu, Akshaya Jadhav, Wenhua Lang, Claudio A Arrechedera, Leticia Campos Clemente, Edwin R Parra, Hsinyi Lu, Cara L Haymaker, Ignacio I Wistuba, Andrew Futreal, Andrea Viale, Michael J Soth, Philip Jones, Joseph R Marszalek, Timothy Heffernan, Giulio F Draetta, Nizar M Tannir, Jianjun Gao, Linghua Wang, Giannicola Genovese, Pavlos Msaouel

Faculty, Staff and Students Publications

Therapeutic options for patients with renal medullary carcinoma (RMC) are limited. Here we report the results of a phase II clinical trial (NCT03274258) of anti-PD1 nivolumab plus anti-CTLA4 ipilimumab in patients with RMC, with objective response rate as primary outcome. Enrollment was halted for futility at a prespecified interim analysis as all 10 treated patients experienced rapid disease progression. 5/10 met radiological criteria for hyperprogression and median progression-free survival (secondary outcome) was 1.38 months (95% confidence interval: 1.28, 1.60). In a post-hoc single-cell RNA sequencing analysis, data from patients with RMC before and after nivolumab plus ipilimumab treatment indicated that …

Preclinical Efficacy Of Tasquinimod-Based Combinations In Advanced Myeloproliferative Neoplasms In Blastic Phase, Warren Fiskus, Lucia Masarova, Christopher P Mill, Christine E Birdwell, Kaberi Das, Hanxi Hou, John A Davis, Antrix Jain, Anna Malovannaya, Taghi Manshouri, Andrew Dunbar, Surbhi Sharma, Tapan M Kadia, Courtney D Dinardo, Prithviraj Bose, Naveen Pemmaraju, Sanam Loghavi, Xiaoping Su, Raajit K Rampal, Marie Törngren, Kapil N Bhalla

Faculty, Staff and Students Publications

The alarmins, S100A8 (A8) and S100A9 (A9), are low molecular weight proteins belonging to the S100 protein family. A8 and A9 are secreted into the extracellular space and plasma, in which they interact with Toll-like receptor 4, receptor for advanced glycation end products, and CD33. In these studies, we determined the preclinical efficacy of tasquinimod (TQ) against advanced myeloproliferative neoplasm (MPN) cell lines and patient-derived (PD) CD34+ blastic phase (BP; >5% blasts in the peripheral blood) MPN cells. TQ induced loss of viability in cell lines and PD MPN-BP cells, but not in normal CD34+ progenitor cells. In TQ-treated PD …

Serum Response Factor Is Essential For Endometrial Function And Prevention Of Inflammatory Fibrosis, Ryan M Marquardt, Sara A Grimm, San-Pin Wu, Peter F Lais, Shu-Yun Li, Xin Xu, Erin Smithberger, David Cunefare, Charan Ganta, David Olson, Eunhee M Jeong, Jae-Wook Jeong, Bruce A Lessey, John P Lydon, Francesco J Demayo

Faculty, Staff and Students Publications

Pregnancy requires a supportive uterine environment facilitated by steroid hormone–regulated differentiation of endometrial stromal fibroblasts into decidual cells and tight control of inflammation. Serum response factor (SRF) is a widely expressed transcription factor essential for mesenchymal cell growth and differentiation with noted roles in hormonal regulation of muscle tissues but little characterization in reproductive organs. Here, we reveal that endometrial SRF is dysregulated in human endometriosis and is critical for female reproductive success in mice through regulation of endometrial stromal and epithelial cells. Immunohistochemical analysis identified decreased endometrial SRF expression in infertile endometriosis patient tissues. RNAi-based SRF knockdown in human …

Orphan Nuclear Receptor 4a1 (Nr4a1) And Nr4a2 Are Endogenous Regulators Of Cd71 And Their Ligands Induce Ferroptosis In Breast Cancer, Arafat Rahman Oany, Srijana Upadhyay, Wai Ning Tiffany Tsui, Amanuel Hailemariam, Sarah Latka, John D Landua, Sandra D Scherer, Alana L Welm, Hugo Villanueva, Michael T Lewis, Stephen Safe

Faculty, Staff and Students Publications

Ferroptosis is an iron-dependent cell death pathway that involves multiple genes, including the transferrin receptor (TFRC/CD71), glutathione peroxidase 4 (GPX4) and cystine-glutamate antiporter (SLC7A11). This study is based on the hypothesis that orphan nuclear receptor 4A1 (NR4A1) and NR4A2 maintain low levels of ferroptosis in triple negative breast cancer (TNBC) cells and bis-indole derived (CDIM) compounds act as NR4A1/2 ligands that induce ferroptosis by enhancing CD71 expression. 1,1-Bis(3'-indolyl)-1-(3,5-disubstitutedphenyl)methane (DIM-3,5) analogs were investigated for their cytotoxicity and effects on NR4A1 and NR4A2 regulated genes and induction of ferroptosis. Several assays also determined enhanced lipoperoxidation, reactive oxygen species and malondialdehyde formation in …

Integrative Proteogenomics And Forward Genetics Reveal A Novel Mitotic Vulnerability In Triple-Negative Breast Cancer, Nicholas J Neill, Shankha Satpathy, Karsten Krug, Jitendra K Meena, Nivetha Ramesh Babu, Cheyenne Calderon, Desmon Reed, Marcus J Weber, Lacey E Dobrolecki, Alaina Lewis, Christina Sallas, Meenakshi Anurag, Kimberly R Holloway, Chen Huang, Suhas Vasaikar, Maria F Cardenas, Beom-Jun Kim, Doug W Chan, Shayan C Avanessian, Siddhartha Tyagi, Mayra Orellana, Sufeng Mao, Heyuan Li, Fade Gong, Sarah J Kurley, Kristen L Meerbrey, Calla M Olson, Amritha Nair, Tingting Sun, Hsiang-Ching Chung, Elizabeth A Bowling, Jarey H Wang, Pengju Zhang, Peng Xiao, Duxiao Yang, Fabio Stossi, Mei-Yin C Polley, Alexander B Saltzman, Filip Mundt, D R Mani, Michael A Gillette, Susan G Hilsenbeck, George Miles, Carolina Gutierrez, C Kent Osborne, Charles Y Lin, Nathanael S Gray, Jinpeng Sun, David A Wheeler, Charles M Perou, Anna Malovannaya, Michael T Lewis, Bing Zhang, Matthew J Ellis, Steven A Carr, Thomas F Westbrook

Faculty, Staff and Students Publications

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with few effective targeted therapies. Taxanes and other microtubule-targeting agents (MTAs) are frontline chemotherapies for TNBC; however, the molecular pathways that cause TNBC taxane sensitivity are largely unknown, preventing selection of taxane-responsive patients and development of more selective therapeutic strategies. In this study, we identified tumor-selective vulnerabilities in TNBC harboring inactivation of the tumor suppressor PTPN12 by integrating proteogenomic characterization and synthetic lethality screening. We discovered that PTPN12 inactivation drives mitotic defects through aberrant hyperactivation of the ubiquitin ligase complex APCFZR1, a critical regulator of the cell cycle. Consistent …

Molecular Mechanisms In Masld/Mash-Related Hcc, Xiaobo Wang, Liang Zhang, Bingning Dong

Faculty, Staff and Students Publications

Liver cancer is the third leading cause of cancer-related deaths and ranks as the sixth most prevalent cancer type globally. NAFLD or metabolic dysfunction-associated steatotic liver disease, and its more severe manifestation, NASH or metabolic dysfunction-associated steatohepatitis (MASH), pose a significant global health concern, affecting approximately 20%-25% of the population. The increased prevalence of metabolic dysfunction-associated steatotic liver disease and MASH is parallel to the increasing rates of obesity-associated metabolic diseases, including type 2 diabetes, insulin resistance, and fatty liver diseases. MASH can progress to MASH-related HCC (MASH-HCC) in about 2% of cases each year, influenced by various factors such …

Dysregulated Mitochondrial Energy Metabolism Drives The Progression Of Mucosal Field Effects To Invasive Bladder Cancer, Sangkyou Lee, Sung Yun Jung, Pawel Kuś, Jolanta Bondaruk, June Goo Lee, Roman Jaksik, Nagireddy Putluri, Khanh N Dinh, David Cogdell, Huiqin Chen, Yishan Wang, Jiansong Chen, Neema Navai, Colin Dinney, Cathy Mendelsohn, David Mcconkey, Richard R Behringer, Charles C Guo, Peng Wei, Marek Kimmel, Bogdan Czerniak

Faculty, Staff and Students Publications

Multiplatform mutational and gene expression profiling complemented with proteomic and metabolomic spatial mapping were used on the whole-organ scale to identify the molecular profile of bladder cancer evolution from field effects. Analysis of the mutational landscape identified three types of mutations, referred to as α, β, and γ. Time modeling of the mutations revealed that carcinogenesis may span 30 years and can be divided into dormant and progressive phases. The α mutations developed in the dormant phase. The progressive phase lasted 5 years and was signified by expanding β mutations, but it was driven to invasive cancer by γ mutations. …

Pathogenic Xpo1 Variants Cause A Dominant Neurodevelopmental Disorder, Amber S E Van Oirsouw, Pavla Nedbalova, Miroslava Hancarova, Jan Prchal, Darina Prchalova, Marketa Vlckova, Sarka Bendova, Kristin G Monaghan, Lisa M Dyer, Yanmin Chen, Deanna Alexis Carere, Emma A M Te Bogt, Heather Fisher, Angela E Scheuerle, Stephanie Riley, Mahim Jain, Weiyi Mu, Joann N Bodurtha, Albertien M Van Eerde, Marijn F Stokman, Nicola Longo, Meena Balasubramanian, Michael Spiller, Gregory Costain, Charlotte Von Der Lippe, Kristian Tveten, Marianne Jortveit, Øystein L Holla, Bertrand Isidor, Benjamin Cogné, Kevin E Glinton, Blake Vuocolo, Roberta Ann Sierra, Brad Angle, Kelly Bontempo, Klaas Koop, Rachel Rabin, John Pappas, David A Staffenberg, Pascal Joset, Peter Miny, Isabel Filges, Abdulrazak Alali, Kara Vitalone, Jill A Rosenfeld, Weimin Bi, Samuel Bradbrook, Renee Perrier, Subhadra Ramanathan, June-Anne Gold, María Palomares Bralo, María Ángeles Gómez-Cano, Ann Haskins Olney, Shelly Nielsen, Alban Ziegler, Dominique Bonneau, Clément Prouteau, Ange-Line Bruel, Charlotte Caille-Benigni, Laëtitia Lambert, Andrea C Yu, Nathaniel H Robin, Dana Goodloe, Jan Fischer, Joseph Porrmann, Yvonne D Hennig, Rami Abou Jamra, Isabella Herman, Ivy R Johnson, Lucas Hérissant, Guillaume Jouret, Koen L I Van Gassen, Ellen Van Binsbergen, Bert Van Der Zwaag, Alwin Kamermans, Renske Oegema, Zdenek Sedlacek, Michaela Fenckova, Richard H Van Jaarsveld

Faculty, Staff and Students Publications

Purpose: XPO1 functions in key cellular processes, including nucleo-cytoplasmic export and mitosis. The gene is deleted in a subset of patients with the 2p15p16.1 microdeletion syndrome; however, no monogenic XPO1-related disorder has been described to date.

Methods: We collected clinical data of individuals with de novo XPO1 variants through online matchmaking. We used Drosophila to study XPO1 function in development and habituation learning.

Results: A total of 22 individuals met the criteria to be included in the main study cohort. Of these, half have putative loss-of-function variants, and half have coding variants (10 missense and 1 in-frame deletion variant). We …

Glycerol-3-Phosphate Activates Chrebp, Fgf21 Transcription And Lipogenesis In Citrin Deficiency, Vinod Tiwari, Byungchang Jin, Olivia Sun, Edwin D J Lopez Gonzalez, Min-Hsuan Chen, Xiwei Wu, Hardik Shah, Andrew Zhang, Mark A Herman, Cassandra N Spracklen, Russell P Goodman, Charles Brenner

Faculty, Staff and Students Publications

Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. Here we show that SLC25A13 loss causes the accumulation of glycerol-3-phosphate (G3P), which activates the carbohydrate response element-binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol and to transcribe key genes driving lipogenesis. Mouse and human data suggest that G3P-ChREBP is a mechanistic component of the Randle Cycle that contributes to metabolic-dysfunction-associated steatotic liver disease and forms …

Cdk4/6 Inhibitors In Breast Cancer-Who Should Receive Them?, Anran Chen, Ze-Yi Zheng, Meenakshi Anurag, Ahmed Elkhanany, Natalie C Chen, Eric C Chang

Faculty, Staff and Students Publications

More than 70% of breast cancers are estrogen receptor-positive (ER+). Endocrine therapy that blocks estrogen signaling remains the cornerstone of treatment, yet relapses continue to affect many patients. Cyclin-dependent kinases 4 and 6 (CDK4/6) regulate the G1-S phase transition in the cell cycle, and pharmacological inhibition of this pathway has been successfully leveraged to reduce recurrence. CDK4/6 inhibitors combined with endocrine therapy are now the standard of care, although determining the optimal patient population for treatment remains a key challenge. A newly published study provides important insight, showing that loss of the NF1/neurofibromin tumor suppressor confers greater sensitivity to CDK4/6 …

Stereoelectroencephalography Reveals Neural Signatures Of Multisensory Integration In The Human Superior Temporal Sulcus During Audiovisual Speech Perception, Yue Zhang, John F Magnotti, Xiang Zhang, Zhengjia Wang, Yingjia Yu, Kathryn A Davis, Sameer A Sheth, H Isaac Chen, Daniel Yoshor, Michael S Beauchamp

Faculty, Staff and Students Publications

Human speech perception is multisensory, integrating auditory information from the talker's voice with visual information from the talker's face. BOLD fMRI studies have implicated the superior temporal gyrus (STG) in processing auditory speech and the superior temporal sulcus (STS) in integrating auditory and visual speech, but as an indirect hemodynamic measure, fMRI is limited in its ability to track the rapid neural computations underlying speech perception. Using stereoelectroencephalography (sEEG) electrodes, we directly recorded from the STG and STS in 42 epilepsy patients (25F, 17M). Participants identified single words presented in auditory, visual, and audiovisual formats with and without added auditory …

Resilience And Vulnerabilities Of Tumor Cells Under Purine Shortage Stress, Jianpeng Yu, Chen Jin, Cheng Su, David Moon, Michael A Sun, Hong Zhang, Xue Jiang, Fan Zhang, Nomi Tserentsoodol, Michelle L Bowie, Christopher J Pirozzi, Daniel J George, Robert Wild, Xia Gao, David M Ashley, Yiping He, Jiaoti Huang

Faculty, Staff and Students Publications

Purpose: Purine metabolism is a promising therapeutic target in cancer; however, how cancer cells respond to purine shortage, particularly their adaptation and vulnerabilities, remains unclear.

Experimental design: Using the recently developed purine shortage-inducing prodrug DRP-104 and genetic approaches, we investigated the responses in prostate, lung, and glioma cancer models.

Results: We demonstrate that when de novo purine biosynthesis is compromised, cancer cells employ microtubules to assemble purinosomes, multiprotein complexes of de novo purine biosynthesis enzymes that enhance purine biosynthesis efficiency. Although this process enables tumor cells to adapt to purine shortage stress, it also renders them more susceptible to the …

Polychlorinated Biphenyls Alter Estrogen Receptor Β-Mediated Epigenetic Regulation, Promoting Endometriosis, Yuri Park, Nuri Sung, Eunsu Kim, Jaeyeong Jeong, Juhee Sim, Mi Jin Park, John P Lydon, Xiaoming Guan, Sang Jun Han

Faculty, Staff and Students Publications

Endometriosis is a pathological condition characterized by the ectopic growth of endometrial cells, leading to chronic pelvic pain and infertility. Epidemiological studies have associated exposure to dioxin-like polychlorinated biphenyls, particularly PCB126, with an increased risk of endometriosis. However, the underlying mechanisms of this association remain poorly understood. We utilized a surgically induced endometriosis mouse model and human endometrial cell lines to assess the impact of PCB126 on endometriosis progression. Mice were exposed to environmentally relevant doses of PCB126. Endometriotic lesion growth, estrogen receptor signaling, receptor tyrosine kinase activity, and gene expression changes induced by PCB126-mediated elevation of DNA methyltransferase 3A …

Dual Targeting Of Orphan Nuclear Receptors Nr4a1 And Nr4a2 For Nonhormonal Endometriosis Therapy, Wai Ning Tiffany Tsui, Yuri Park, Srijana Upadhyay, Da Mi Kim, Lei Zhang, Gus Wright, Amanuel Hailemariam, Arafat Rahman Oany, Sang Jun Han, Stephen Safe

Faculty, Staff and Students Publications

Previous studies show that orphan nuclear receptor 4A1 (NR4A1) regulates endometriotic cell growth, survival, estrogen receptor β (ERβ), mechanistic target of rapamycin signaling and fibrosis. NR4A2 is also expressed in epithelial and stromal derived endometriotic cells, and in this study the effects of 1,1-bis(3'-indolyl)-(3,5-disubstitutedphenyl)methane (DIM-3,5) dual NR4A1/nuclear receptor 4A2 (NR4A2) ligands and knockdown of NR4A1 and NR4A2 were investigated. The dual NR4A1/2 DIM-3,5 analogs inhibited previously identified proendometriotic pathways and gene products, and they also inhibited TWIST1 and multiple markers associated with epithelial-to-mesenchymal transition (EMT). The results show that both NR4A1 and NR4A2 regulate the same pathways, including endometriotic cell …

Plasma Proteome Correlations With Liver Stiffness In Pediatric Cholestasis Implicate Epithelial To Mesenchymal Transition, Benjamin L Shneider, Rupa S Kanchi, Sandra L Grimm, Sridevi Devaraj, Juliet Emamaullee, Jeremy Schraw, Philip J Lupo, Jorge A Bezerra, Kathleen M Loomes, John C Magee, Ronald J Sokol, Kasper S Wang, Alyssa Kriegmeier, Evelyn Hsu, Jean P Molleston, Philip Rosenthal, Rohit Kohli, Saul J Karpen, Simon P Horslen, M Kyle Jensen, Arianna Barbetta, Cristian Coarfa

Faculty, Staff and Students Publications

Background: Pediatric cholestatic liver diseases can be characterized by rapidly progressive fibrosis. A multicenter cross-sectional analysis of vibration-controlled elastography in biliary atresia (BA), alpha-1 antitrypsin deficiency (A1AT), and Alagille syndrome (ALGS) was leveraged to interrogate the plasma proteome relative to liver stiffness measurements (LSM).

Methods: Slow off-rate modified aptamer scanning profiling of >7000 proteins in plasma from 187 children with BA (n=93), A1AT (n=31), ALGS (n=46), and healthy pediatric controls (n=17) was performed, and correlations with LSM were undertaken.

Results: There was an abundance of LSM correlated proteins (BA n=2720, A1AT n=694, ALGS n=5968). Interestingly, a distinct plasma proteome was …

Nrf2 Hyperactivation As A Driver Of Radiotherapy Resistance And Suppressed Antitumor Immunity In Head And Neck Squamous Cell Carcinoma, Rutulkumar Patel, Kalil Saab, Lixia Luo, Yan Ma, Rashid Abdullah Osman, Nerissa T Williams, Jeffrey Everitt, Maciej J Zelazowski, Patricia Castro, William K Decker, William H Hudson, Jeffrey N Myers, Vlad C Sandulache, Mitchell J Frederick, Yvonne M Mowery, David G Kirsch

Faculty, Staff and Students Publications

Purpose: Alterations in the KEAP1/NFE2L2 (NRF2)/CUL3 pathway occur in ∼20% of human head and neck squamous cell carcinomas (HNSCC) and are associated with resistance to standard-of-care therapy. However, this pathway's role in radiotherapy resistance in HNSCC has not been well studied.

Experimental design: We generated genetically engineered mouse models and developed primary murine cancer cell lines harboring mutations commonly observed in human HNSCC, including inducible activation of PIK3CA and deletion of Trp53, with or without Keap1 loss. Primary tumors were initiated via 4-hydroxytamoxifen injection ± the tobacco carcinogen benzo[a]pyrene (BAP) into the oral buccal mucosa. Tumors were analyzed by Western …

Examining The Relationship Between Dysphagia, Eating-Related Symptoms, And Diet Quality Among Oropharyngeal Cancer Patients During Critical Stages Of Cancer Survivorship: The U-Dine Study, Beatrice Manduchi, Vlad C Sandulache, Ji Yun Tark, Shreela Sharma, Ruosha Li, Emily Roller, Andrew Bevelhimer, Katherine A Hutcheson, Marcia C De Oliveira Otto

Faculty, Staff and Students Publications

Background: Diet quality is a modifiable factor impacting treatment outcomes in oropharyngeal cancer (OPC), yet the effect of dysphagia and self-reported eating-related symptoms remains unclear. This study examined their associations with diet quality in OPC patients.

Methods: A cross-sectional analysis was conducted with two parallel cohorts from MD Anderson Cancer Center and Michael E. DeBakey Veterans Affairs Medical Center as part of the Uncovering the Long-Term Impact of OPC and Dysphagia on Dietary Quality and Nutrition Among Cancer Survivors (U-DINE) Study. Participants at varying survivorship stages (prediagnosis, 3-6 and 18+ months posttreatment) were assessed for dysphagia (DIGEST scale) and six …

Cathartocytosis: Jettisoning Of Cellular Material During Reprogramming Of Differentiated Cells, Jeffrey W Brown, Xiaobo Lin, Gabriel Anthony Nicolazzi, Xuemei Liu, Thanh Nguyen, Megan D Radyk, Joseph Burclaff, Jason C Mills

Faculty, Staff and Students Publications

Injury causes differentiated cells to undergo massive reprogramming to become proliferative and repair tissue via paligenosis. Gastric chief cells use paligenosis to reprogram into progenitor-like spasmolytic-polypeptide-expressing metaplasia (SPEM) cells. Stage 1 of paligenosis is the downscaling of mature cell architecture via a process involving lysosomes. Here, we notice that sulfated glycoproteins are not only digested during paligenosis but also excreted into the gland. Various genetic and pharmacological approaches show that endoplasmic reticulum membranes and secretory granule cargo are also excreted and that the process proceeds in parallel with but is mechanistically independent of autophagy. Three-dimensional light and electron microscopy demonstrated …

Placental Polycyclic Aromatic Hydrocarbon (Pah) Levels Are Associated With Spontaneous Preterm Birth, Gwendolynn Hummel, Sohini Banerjee, Vasanta Putluri, Inaara Malick, Grace Johnson, Abu Hena Mostafa Kamal, Chandra Shekar R Ambati, Nagireddy Putluri, Lori Showalter, Cynthia D Shope, Joseph Hagan, Kjersti M Aagaard, Bhagavatula Moorthy, Melissa A Suter

Faculty, Staff and Students Publications

While the cause of preterm birth (PTB) (i.e., delivery before 37 weeks of gestation) is likely multifactorial, ambient exposure to environmental chemicals has been postulated to play a role in its etiology. Our prior studies of exposure to polycyclic aromatic hydrocarbons (PAHs) in pregnancy have shown an increased level of placental PAH-induced bulky DNA adducts with increasing levels of PAH exposures. In this investigation, we hypothesized that higher levels of placental PAHs would be associated with an increased risk of PTB. Using gas chromatography and mass spectrometry (GC-MS/MS), we measured levels of benzo(a)pyrene (BaP), benzo(b)fluoranthene (BbF) and dibenz(a,h)anthracene (DBA) from …

Proteogenomic Characterization Unveils Biomarkers Associated With Chemoresistance In Muscle-Invasive Bladder Cancer, Matthew V Holt, Yongchao Dou, Meggie N Young, Alexander B Saltzman, Meenakshi Anurag, Jonathan T Lei, Antrix Jain, Mei Leng, Beom-Jun Kim, Lacey E Dobrolecki, Stefanie F Faucher, Sara Savage, Chenwei Wang, Zhiao Shi, Hugo Villanueva, Karoline Kremers, Kyle D Drinnon, Patricia D Castro, Michael M Ittmann, Mehak Mehboob Khatani, Sung Han Kim, Matthew J Ellis, Bing Zhang, Anna Malovannaya, Seth P Lerner

Faculty, Staff and Students Publications

To explore potential chemoresistance mechanisms and identify therapeutic opportunities in muscle-invasive bladder cancer (MIBC), we conduct comprehensive proteogenomic characterization of 46 pre- and 14 post-treatment MIBC tumors incorporating genomics, transcriptomics, proteomics, and phosphoproteomics. Multi-omics clustering not only recapitulated established molecular subtypes but also revealed subtypes associated with chemotherapy sensitivity. Protein isoform level analysis identifies protein abundance of a short isoform of ATAD1 and RAF family proteins as biomarkers of chemosensitivity. Integration of proteomic and phosphoproteomic data reveals Wnt signaling via GSK3B-S9 phosphorylation and the JAK/STAT pathway as potential targets to overcome chemoresistance. Correlations between PD-L1 and TROP-2/NECTIN-4 indicate an additive …

Sox2 Regulates Foregut Squamous Epithelial Homeostasis And Is Lost During Barrett’S Esophagus Development, Ramon U Jin, Yuanwei Xu, T Mamie Lih, Yang-Zhe Huang, Toni M Nittolo, Blake E Sells, Olivia M Dres, Jean S Wang, Qing K Li, Hui Zhang, Jason C Mills

Faculty, Staff and Students Publications

Esophageal adenocarcinoma is increasingly prevalent and is thought to arise from Barrett's esophagus (BE), a metaplastic condition in which chronic acid and bile reflux transforms the esophageal squamous epithelium into a gastric-intestinal glandular mucosa. The molecular determinants driving this metaplasia are poorly understood. We developed a human BE organoid biobank that recapitulates BE's molecular heterogeneity. Bulk and single-cell transcriptomics, supported by patient tissue analysis, revealed that BE differentiation reflects a balance between SOX2 (foregut/esophageal) and CDX2 (hindgut/intestinal) transcription factors. Using squamous-specific inducible Sox2-KO (Krt5CreER/+ Sox2Δ/Δ ROSA26tdTomato/+) mice, we observed increased basal proliferation, reduced squamous differentiation, and expanded metaplastic glands at …

Nerve-To-Cancer Transfer Of Mitochondria During Cancer Metastasis, Gregory Hoover, Shila Gilbert, Olivia Curley, Clémence Obellianne, Mike T Lin, William Hixson, Terry W Pierce, Joel F Andrews, Mikhail F Alexeyev, Yi Ding, Ping Bu, Fariba Behbod, Daniel Medina, Jeffrey T Chang, Gustavo Ayala, Simon Grelet

Faculty, Staff and Students Publications

The nervous system has a pivotal role in cancer biology, and pathological investigations have linked intratumoural nerve density to metastasis1. However, the precise impact of cancer-associated neurons and the communication channels at the nerve–cancer interface remain poorly understood. Previous cancer denervation models in rodents and humans have highlighted robust cancer dependency on nerves, but the underlying mechanisms that drive nerve-mediated cancer aggressivity remain unknown2,3. Here we show that cancer-associated neurons enhance cancer metabolic plasticity by transferring mitochondria to cancer cells. Breast cancer denervation and nerve–cancer coculture models confirmed that neurons significantly improve tumour energetics. …

Effects Of Maackia Amurensis Seed Lectin (Masl) On Oscc Cell Morphology, Pdpn Expression, Growth, And Motility In A Phase 1 Clinical Trial, Ariel C Yin, Cayla J Holdcraft, Tyler J Hellmig, Eamonn J Brace, David I Suster, Alan J Shienbaum, Dylan Roden, Evelyne Kalyoussef, Ghayoour Mir, Eugenio Capitle, Soly Baredes, Rabie M Shanti, Mika K Kaneko, Yukinari Kato, Hisataka Kobayashi, Aki Furusawa, Mahnaz Fatahzadeh, Gary S Goldberg

Rowan-Virtua School of Osteopathic Medicine Departmental Research

BACKGROUND: Podoplanin (PDPN) has emerged as a functionally relevant biomarker and chemotherapeutic target expressed by OSCC cells. PDPN signaling can directly increase tumor cell invasion and metastasis, and also inhibit host lymphocyte activation and immune response. Accordingly, antibodies and Maackia amurensis seed lectin (MASL) can target the PDPN receptor to inhibit OSCC cell migration and viability. However, the effects of MASL on OSCC cells in oral cancer patients has not yet been reported.

METHODS: We conducted a Phase 1 human clinical trial to examine the effects of a single 100 mg oral dose of MASL on OSCC cell morphology, PDPN …

Single-Cell Profiling Of Bone Metastasis Ecosystems From Multiple Cancer Types Reveals Convergent And Divergent Mechanisms Of Bone Colonization, Fengshuo Liu, Yunfeng Ding, Zhan Xu, Xiaoxin Hao, Tianhong Pan, George Miles, Siyue Wang, Yi-Hsuan Wu, Jun Liu, Igor L Bado, Weijie Zhang, Ling Wu, Yang Gao, Liqun Yu, David G Edwards, Hilda L Chan, Sergio Aguirre, Michael Warren Dieffenbach, Elina Chen, Yichao Shen, Dane Hoffman, Luis Becerra Dominguez, Charlotte Helena Rivas, Xiang Chen, Hai Wang, Zbigniew Gugala, Robert L Satcher, Xiang H-F Zhang

Faculty, Staff and Students Publications

Bone is a common site for metastasis of solid cancers. The diversity of histological and molecular characteristics of bone metastases (BMs) remains poorly studied. Here, we performed single-cell RNA sequencing on 42 BMs from eight cancer types, identifying three distinct ecosystem archetypes, each characterized by an enrichment of specific immune cells: macrophages/osteoclasts, regulatory/exhausted T cells, or monocytes. We validated these archetypes by immunostaining on tissue sections and bioinformatic analysis of bulk RNA sequencing/microarray data from 158 BMs across more than 10 cancer types. Interestingly, we found only a modest correlation between the BM archetypes and the tissues of origin; BMs …

Decoding Metastatic Microenvironments Through Single-Cell Omics Reveals New Insights Into Niche Dynamics And Tumor Evolution, Fengshuo Liu, Xiang H-F Zhang

Faculty, Staff and Students Publications

Metastasis is the predominant cause of cancer mortality, primarily driven by complex tumor-host interactions within specialized metastatic niches. Recent advances in single-cell technologies have provided unprecedented insights into metastatic niche formation, evolution and function, including how primary tumors precondition distant organs for metastases and how disseminated tumor cells dynamically interact with host cells to modulate their environments. Integrated single-cell studies across multiple cancer types have also revealed divergent and convergent metastatic adaptation strategies. These findings collectively highlight metastasis as a dynamic, cooperative process shaped by intricate tumor-host interactions, and provide a foundation for novel therapeutic strategies targeting components of the …

Association Of Statin Use On Survival Outcomes Of Patients With Early-Stage Her2-Positive Breast Cancer In The Aphinity Trial, Christian Maurer, Elisa Agostinetto, Lieveke Ameye, Matteo Lambertini, Samuel Martel, Noam Ponde, Mariana Brandão, Francesca Poggio, Arlindo Ferreira, Rachel Schiff, Carmine De Angelis, Richard D Gelber, Susan Dent, Christoph Thomssen, Martine Piccart, Evandro De Azambuja

Faculty, Staff and Students Publications

Purpose: There is evidence that statins might improve the outcome of patients with breast cancer. The role of statins in patients with early HER2-positive breast cancer is unknown. Therefore, we explored the association between statin use and survival outcomes in early HER2-positive breast cancer patients in the phase III APHINITY trial (adjuvant pertuzumab/trastuzumab).

Methods: All patients (intent-to-treat population, n = 4804) were included (6.2 years median follow-up database). The primary objective was to investigate the association of statin use on invasive disease-free survival (IDFS), distant relapse-free interval (DRFI), and overall survival (OS). Patients who received statins at baseline, or started …