Digital Commons Network^™

Secretory Iga Dysfunction Underlies Poor Prognosis In Fusobacterium-Infected Colorectal Cancer, Ilseok Choi, Kyung-A Kim, Sang Cheol Kim, Donghwan Park, Ki Taek Nam, Jun Hyung Cha, Seungbyn Baek, Junha Cha, Hye-Yeong Jo, Minsun Jung, Melody Y Zeng, Irina Matei, Susan Bullman, Joong Bae Ahn, Yoon Dae Han, Han Sang Kim, Insuk Lee

Faculty, Staff and Student Publications

Fusobacterium nucleatum (Fn) is commonly enriched in colorectal cancer (CRC) and associated with poor outcomes, though its mechanisms remain unclear. Our study investigated how Fn affects the tumor microenvironment through single-cell transcriptomic analyses of 42 CRC patient tissues, comparing Fn-positive and Fn-negative tumors. We discovered that Fn impairs IgA plasma cell development and secretory IgA (sIgA) production by disrupting communication with tumor-associated macrophages. Additional experiments in germ-free mice, together with our re-analysis of a publicly available single-cell RNA-seq data set from a CRC mouse model with an intact gut microbiome–both models having been orally gavaged with Fn–jointly validated the causal …

Surgical Removal Of Implanted Microchips To Correct Mri Susceptibility Artifacts In Mice, Elizabeth Hipskind, Nicole Hernandez, Sydney Fox, Tina Manirambona, Rita Schack, Brian Gibson, Robia G Pautler

Center on Aging Staff Publications

Purpose: Implanted microchips are becoming increasingly common in research for animal identification and have been adopted by commercial vendors for some mouse strains. However, they often contain metal components, which generate magnetic susceptibility artifacts on MR images. Despite this, some microchips are marketed as MR-compatible, even though they are likely to affect image quality.

Methods: We assessed the impact of a radiofrequency identification microchip on MR images of the mouse brain and present a method for precise surgical removal. A handheld magnet was used to locate and stabilize the microchips during removal. Mice were imaged before and after microchip removal. …

Transcriptional Coregulator Zmiz1 Modulates Estrogen Responses That Are Essential For Healthy Endometrial Function, Sylvia C Hewitt, Frank Orellana, Ryan M Marquardt, Myeongjin Yi, Cynthia J Willson, Mark Y Chiang, Yong Song, Goutham Venkata Naga Davuluri, Christopher Day, Ramakrishna Kommagani, Joseph Rodriguez, Asgerally T Fazleabas, John P Lydon, Francesco J Demayo

Faculty, Staff and Students Publications

Estrogen is a critical regulator of endometrial health. Aberrant estrogen stimulation can result in infertility, endometrial cancer, and endometriosis. Here, we identified Zinc Finger MIZ-Type Containing 1 (Zmiz1) as a coregulator of uterine estrogen signaling. ZMIZ1 is colocalized with an estrogen receptor α–binding (ESR1-binding) super enhancer. ZMIZ1 mutations are found in endometrial cancer and its RNA levels trend toward reduction in endometrium of patients with endometriosis. ZMIZ1 is dynamically expressed in human endometrial tissues during the menstrual cycle. Disrupting ZMIZ1 in cultured human endometrial stromal cells resulted in impaired cell proliferation and decidual differentiation. Ablation of Zmiz1 using …

Gene Therapy Cm-Yapon Protects The Mouse Heart From Myocardial Infarction, Fansen Meng, Jeffrey D Steimle, Elizabeth Straight, Rich G Li, Yuka Morikawa, Zohaib Iqbal, Bing Xie, Jun Wang, Wyatt G Paltzer, Yi Zhao, Chang-Ru Tsai, Lin Liu, Maggie Lim, Rita A Schack, Daniel Ramirez, Katherine Carlson, Vaibhav Deshmukh, Jason M Karch, Robia G Pautler, Xiao Li, James F Martin

Faculty, Staff and Students Publications

Myocardial infarction (MI) affects millions of people worldwide, causing irreversible injury to the heart and impairing cardiac function1. In both mouse and pig MI models, activating YAP in cardiomyocytes (CMs) stimulates regenerative repair2,3. Here we developed an adeno-associated virus 9 (AAV9)-based therapy, termed CM-YAPon, which enables transient expression of an active YAP variant (YAP5SA) in CMs following exposure to the small molecule LMI070. A single LMI070 dose in mice triggers YAP5SA expression, CM cell cycle re-entry, and reprogramming of the cardiac microenvironment. YAP5SA induction after MI rapidly improves cardiac function while pre-MI induction confers …

Alternative Splicing Of The Snap23 Microexon Is Regulated By Mbnl, Qki, And Rbfox2 In A Tissue-Specific Manner And Is Altered In Striated Muscle Diseases, Gabrielle M Gentile, R Eric Blue, Grant A Goda, Bryan B Guzman, Rachel A Szymanski, Eunice Y Lee, Nichlas M Engels, Emma R Hinkle, Hannah J Wiedner, Aubriana N Bishop, Jonathan T Harrison, Hua Zhang, Xander H T Wehrens, Daniel Dominguez, Jimena Giudice

Faculty, Staff and Students Publications

The reprogramming of alternative splicing networks during development is a hallmark of tissue maturation and identity. Alternative splicing of microexons (small, genomic regions ≤ 51 nucleotides) functionally regulate protein-protein interactions in the brain and is altered in several neuronal diseases. However, little is known about the regulation and function of alternatively spliced microexons in striated muscle. Here, we investigated alternative splicing of a microexon in the synaptosome-associated protein 23 (Snap23) encoded gene. We found that inclusion of this microexon is developmentally regulated and tissue-specific, as it occurs exclusively in adult heart and skeletal muscle. The alternative region is …

Adrenomedullin Overexpression Protects Mice From Experimental Bronchopulmonary Dysplasia And Associated Pulmonary Hypertension, Shyam Thapa, Poonam Sarkar, M Waleed Gaber, Roberto Barrios, Madhulata Chauhan, Chandrasekhar Yallampalli, Binoy Shivanna

Faculty, Staff and Students Publications

Bronchopulmonary dysplasia (BPD) associated pulmonary hypertension (PH) or BPD-PH is a lung disease of infants with significant morbidity. Adrenomedullin (Adm) is an angiogenic peptide that signals through calcitonin receptor-like receptor (Calcrl) and receptor activity modifying protein 2 (RAMP2). Adm deficiency potentiates hyperoxia-induced experimental BPD-PH in mice; however, whether Adm overexpression can mitigate this lung disease is unclear. Thus, we tested the hypothesis that Adm overexpression attenuates hyperoxia (HO)-induced murine experimental BPD-PH by using a novel transgenic mouse that overexpresses Adm globally (Admhi/hi mice). One-day-old Admhi/hi mice or their wild-type littermates (Adm+/+ mice) were exposed to …

Cross-Species Standardised Cortico-Subcortical Tractography, Stephania Assimopoulos, Shaun Warrington, Davide Folloni, Katherine Bryant, Ali-Reza Mohammadi-Nejad, Wei Tang, Saad Jbabdi, Sarah R Heilbronner, Rogier B Mars, Stamatios N Sotiropoulos

Faculty, Staff and Students Publications

Despite their importance for brain function, cortico-subcortical white matter tracts are under-represented in diffusion magnetic resonance imaging tractography studies. Their non-invasive mapping is more challenging and less explored compared to other major cortico-cortical bundles. We introduce a set of standardised tractography protocols for delineating tracts between the cortex and various deep subcortical structures, including the caudate, putamen, amygdala, thalamus, and hippocampus. To enable comparative studies, our protocols are designed for both human and macaque brains. We demonstrate how tractography reconstructions follow topographical principles obtained from tracers in the macaque and how these translate to humans. We show that the proposed …

Bypassing Cisplatin Resistance In Nrf2 Hyperactivated Head And Neck Cancer Through Effective Pi3kinase Targeting, Pedram Yadollahi, Kelli A Mccord, Yang Li, Hussam Dayoub, Kalil Saab, Fonma Essien, Sean Hyslop, Emerald Kan, Kazi M Ahmed, Parker R Kirby, Vasanta Putluri, Chandra Shekar R Ambati, Karthik Reddy Kami Reddy, Patricia Castro, Heath D Skinner, Cristian Coarfa, William K Decker, Abdullah A Osman, Rutulkumar Patel, Jeffrey N Myers, Stephen Y Lai, Nagireddy Putluri, Faye M Johnson, Mitchell J Frederick, William H Hudson, Vlad C Sandulache

Faculty, Staff and Students Publications

Background: For patients with head and neck squamous cell carcinoma (HNSCC), failure of definitive radiation combined with cisplatin nearly universally results in death. Although hyperactivation of the Nrf2 pathway can drive radiation and cisplatin resistance along with suppressed anti-tumor immunity, treatment-refractory HNSCC tumors may retain sensitivity to targeted agents secondary to synergistic lethality with other oncogenic drivers (e.g., NOTCH1 mutations).

Methods: Using state of the science mechanistic, metabolomic and spatial transcriptomic approaches combined with preclinical models of HNSCC, we tested whether a novel PI3K inhibitor, gedatolisib, can bypass hyperactivation of the Nrf2 pathway.

Results: The PI3K pathway is activated in …

Method For Generation And Ex Vivo Expansion Of Genetically Edited Mouse Tregs, Yosef Gilad, Adam M Dean, Yan Xia, Sang Jun Han, David M Lonard, Bert W O'Malley

Faculty, Staff and Students Publications

Regulatory T cells (Tregs) play a crucial role in the immune system, and their dysfunction can lead to the development of autoimmune conditions. In cancer, tumors frequently hijack the immunosuppressive function of Tregs to evade immune responses. Due to their central role in key pathological processes, Tregs have gained increasing attention as promising targets for various clinical applications. However, their relative scarcity (∼5% to 10% of CD4+ T cells) and instability presents a technical challenge for research and therapeutic development. In congenic animal models used to investigate autologous cell transfer-based therapies, this challenge is even greater, as Treg donor animals …

Pan-Cancer Single Cell Transcriptomic Clustering Reveals Heterogeneous Cd8+ Exhausted T Cell Populations With Different Immune Checkpoint Inhibitor Responses, Rui Mu, Rasha Barakat, David H Gutmann

2020-Current year OA Pubs

In most cancers, T lymphocytes comprise an essential cellular component of the non-neoplastic microenvironment, where they have the capacity to both suppress and support tumor growth. One specialized T lymphocyte population is the CD8

Age-Dependent Zap70 Expression In Thymocytes Regulates Selection Of The Neonatal Regulatory T Cell Repertoire, Brian D Stadinski, Robert A Campbell, Et Al.

2020-Current year OA Pubs

The Foxp3⁺ regulatory T (T

Recombination Suppression Drives Expansion Of The Drosophila Dot Chromosome, Timothy J Stanek, Wilson Leung, Christopher D Shaffer, Ishtar Olaveja, Annabelle Laughlin, Jaquelyn Hester, Darwin Garrido, Emily K Oh, Maria Volski, Nistha Panda, Mia Mo, Ethan Cordes, Martin Dalling, Kacie Kershaw, Malcolm Arnott, Stephen Daly, Silvia Garcia Valenzuela, Paige Thompson, Kayla L Hastert, Destiny Sabb, Kathryn Karpinski, Meher Naaz Arora, Nicholas Rius, Larissa Lobello, Sebastian Jaramillo, Omkar Sonavane, Alice Herrmann, Laura K Reed, Sarah C R Elgin, Cindy Arrigo, Christopher E Ellison

Faculty, Staff and Student Publications

Genome size varies widely, even among closely related species, yet much less is known about chromosome size variation. Here we use the fourth chromosome of Drosophila, also known as the "Muller F element" or "dot chromosome", as a model to investigate chromosome-specific size expansion. The F element of most Drosophila species is small (∼1.3 Mb) and almost entirely heterochromatic, yet harbors approximately 80 protein-coding genes. Here, we study D. kikkawai, D. takahashii, D. ananassae, and D. bipectinata, whose F elements are 2- to 15-fold larger in size compared to D. melanogaster. Through manual gene curation and comparative genomic analysis, we …

Stra8 Links Neuronal Activity To Inhibitory Circuit Protection In The Adult Mouse Brain., Ming Huang, Shuwen Yue, Xiaoyu Zhang, Lan Wu, Jay L. Vivian, Zi-Jun Wang, Ning Wang

Manuscripts, Articles, Book Chapters and Other Papers

While neuronal activity is essential for brain function, it also poses threats to neuronal integrity. Here, we show that activity-induced expression of stimulated by retinoic acid gene 8 (Stra8) protects neurons from degeneration. Previously considered germline specific, Stra8 is expressed in the adult mouse brain and is induced by neuronal activity via calcium influx and N-methyl-D-aspartate (NMDA) receptor signaling. Neuron-specific Stra8 knockout mice display hallmark features of neurodegeneration, including DNA damage, impaired proteostasis, inflammation, nuclear envelope erosion, reduced dendritic plasticity, memory deficits, and heightened excitotoxic vulnerability. Electrophysiological studies reveal disrupted inhibitory circuit function. Mechanistically, Stra8 binds regulatory regions of neuromodulator …

Deep Learning Reveals How Cells Pull, Buckle, And Navigate Fibrous Environments, Abinash Padhi, Arka Daw, Atharva Agashe, Medha Sawhney, Maahi M Talukder, Mehran M H Pour, Mohammad Jafari, Guy M Genin, Farid Alisafaei, Sohan Kale, Anuj Karpatne, Amrinder S Nain

2020-Current year OA Pubs

Cells in tissues navigate fibrous environments fundamentally differently than they do on flat substrates, but the establishment of cell forces in physiological fibrous settings remains poorly understood. Although factors such as the stiffness of the extracellular matrix (ECM) are known to drive behaviors, including cell motility on flat nonfibrous substrates, the interplay between fiber architecture and stiffness in fibrous ECM is not known. Here, we find that in fibrous environments, the directionality of mechanical forces overrides ECM stiffness as the primary regulator of contractility in migrating cells. Using an approach combining phase microscopy with deep learning to map forces in …

Divergent Prefrontal Cortex Circuits Regulate Cued Food Seeking Under Distinct Metabolic Or Emotional States, Xu O Zhang, Guillermo Aquino-Miranda, Claire E Cho, Yongzhe Wang, Duy Hoang Ha, Nikita Elinson-Watson, Allen Dong, Caleb Kemere, Fabricio H Do-Monte

Faculty, Staff and Student Publications

Flexibly adjusting food-seeking behaviour in response to food-associated cues and internal states is crucial for animals' survival. However, the neural mechanisms that modulate cued food-seeking behaviour during varying metabolic (i.e., hungry vs. satiated) and emotional (i.e., safe vs. threatened) states remain elusive. Here, we show that the encoding of metabolic or threat states in projection-defined neurons in the prelimbic cortex (PL) mediates cued food-seeking responses in rats. Using microendoscopic imaging, we demonstrate that neural population dynamics in PL consistently represent food cues, task-relevant behaviours, and internal state changes by recruiting distinct subsets of cue-responsive neurons at each state. Single-unit recording …

Depth-Variant Deconvolution Applied To Widefield Microscopy For Rapid Large-Volume Tissue Imaging, Daniel D Lee, Kevin A Telfer, Mark A J Koenis, Yim K Lee, Kevin W Namink, Brian T Saunders, Heyun Lee, Hailey Kelley, Heather S Ruiz, Joseph P Gaut, Gwendalyn J Randolph, Bernd H Zinselmeyer

2020-Current year OA Pubs

Innovations in 3D tissue imaging have revolutionized research, but limitations stemming from lengthy protocols and equipment accessibility persist. Widefield microscopy is fast and accessible but often excluded from 3D imaging workflows due to its lack of optical sectioning. Here we combine tissue clearing with a commercial depth-variant deconvolution approach that we optimized for large-volume widefield imaging. By implementing prefiltering with z-brick splitting, we achieve subnuclear axial resolution in tissues to a depth of 500 µm in multi-tile scan images. We illustrate the utility of this method in a model of ileitis and to gain a 3D perspective in thick brain …

Generation And Characterization Of A Knockout Mouse Of An Enhancer Of Ebf3., Emily Cordova Hurtado, Janine M Wotton, Alexander Gulka, Crystal Burke, Jeffrey K Ng, Ibrahim Bah, Juana Manuel, Hillary Heins, Stephen A Murray, David U Gorkin, Jacqueline K White, Kevin A Peterson, Tychele N Turner

Faculty Research 2025

Genomic studies of neurodevelopmental disorders (NDDs) have identified several relevant genomic variants. EBF3 is a gene with an excess of protein-coding de novo variants and underlies Hypotonia, Ataxia, and Delayed Development Syndrome. We previously identified noncoding de novo variants in an enhancer of EBF3 and further found enrichment of deletions of this enhancer in NDDs. In this study, we generated a novel mouse line that deletes the highly conserved, orthologous mouse region within the Rr169617 regulatory region, and characterized the molecular and phenotypic aspects of this mouse model. We found a deviation from Mendelian expectation (P=0.02) with significant depletion of …

Characterizing The Metabolites Of The Tyrosine-Kinase Inhibitor Pexidartinib In Mouse Feces, Urine, Plasma, And Liver, Xuan Qin, Si Chen, John M Hakenjos, Jian Wang, Lei Guo, Ashish Dogra, Zhaoyong Hu, Kevin R Mackenzie, Feng Li

Faculty, Staff and Students Publications

Pexidartinib (PEX, TURALIO®), a tyrosine kinase inhibitor, is approved for treating tenosynovial giant cell tumor in adults. However, its potential to cause fatal liver injury has prompted the U.S. FDA to issue a black box warning, and the mechanisms underlying its hepatotoxicity remain largely unknown. As biotransformation may contribute to PEX-induced hepatotoxicity, understanding its metabolism is essential. Our previous research indicated that PEX forms reactive metabolites in human and mouse liver microsomes and in human hepatocytes. We investigated PEX metabolism and liver distribution in mice with a focus on metabolite characterization. Our data shows that PEX is mainly excreted into …

Generation And Characterization Of A Knockout Mouse Of An Enhancer Of Ebf3, Emily Cordova Hurtado, Janine M Wotton, Alexander Gulka, Crystal Burke, Jeffrey K Ng, Ibrahim Bah, Juana Manuel, Hillary Heins, Stephen A Murray, David U Gorkin, Jacqueline K White, Kevin A Peterson, Tychele N Turner

2020-Current year OA Pubs

Genomic studies of neurodevelopmental disorders (NDDs) have identified several relevant genomic variants. EBF3 is a gene with an excess of protein-coding de novo variants and underlies Hypotonia, Ataxia, and Delayed Development Syndrome. We previously identified noncoding de novo variants in an enhancer of EBF3 and further found enrichment of deletions of this enhancer in NDDs. In this study, we generated a novel mouse line that deletes the highly conserved, orthologous mouse region within the Rr169617 regulatory region, and characterized the molecular and phenotypic aspects of this mouse model. We found a deviation from Mendelian expectation (P=0.02) with significant depletion of …

Low Mutation Rate But High Male-Bias In The Germline Of A Short-Lived Opossum, Yadira Peña-García, Richard J Wang, Muthuswamy Raveendran, R Alan Harris, Paul B Samollow, Jeffrey Rogers, Matthew W Hahn

Faculty, Staff and Students Publications

Age and sex have been found to be important determinants of the mutation rate per generation in mammals, but the mechanisms underlying these factors are still unclear. One approach to distinguishing between alternative mechanisms is to study species that reproduce at very young ages, as competing hypotheses make different predictions about patterns of mutation in these organisms. Here, we study the germline mutation rate in the gray short-tailed opossum, Monodelphis domestica, a laboratory model species that becomes reproductively mature at less than 6 mo of age. Whole-genome sequencing of 22 trios reveals one of the lowest mutation rates per generation …

Slc35g3 Is A Udp-N-Acetylglucosamine Transporter For Sperm Glycoprotein Formation And Underpins Male Fertility In Mice, Daisuke Mashiko, Shingo Tonai, Haruhiko Miyata, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Despite the recognized importance of glycans in biological phenomena, their complex roles in spermatogenesis and sperm function remain unclear. SLC35G3, a 10-transmembrane protein specifically found in early round spermatids, belongs to the sugar-nucleotide transporter family, indicating its involvement in glycan formation. In this study, we found that Slc35g3 knockout male mice were sterile due to impaired sperm functions in uterotubal junction passage, zona pellucida binding, and oocyte fusion. Mouse SLC35G3 has UDP-GlcNAc transporter activity, and its ablation caused abnormal processing of the sperm plasma membrane and acrosome membrane proteins. Reported human SLC35G3 mutations (F267L and T179HfsTer27) diminished the UDP-GlcNAc transporter …

Cardiac Sr-Mitochondria Contacts-Impact On Cardiac Physiology And Mitochondrial Fitness, Celia Fernandez-Sanz, Shey-Shing Sheu, Sergio De La Fuente

Center for Translational Medicine Faculty Papers

In adult cardiomyocytes, within the Mitochondrial Associated Membranes (MAMs), the sarcoplasmic reticulum (SR) and mitochondria juxtapose each other, forming a unique and highly repetitive functional structure throughout the cells. These SR-mitochondria contact sites have emerged as critical structures that regulate various physiological processes, including lipid exchange, calcium (Ca²⁺) communication, control of excitation-contraction bioenergetics coupling, and reactive oxygen species (ROS) production. Over the years, several scientific studies have reported the accumulation of diverse proteins within these SR-mitochondria close contacts. Some proteins strategically accumulate in these areas to enhance their function, such as the mitochondrial Ca²⁺ uniporter, while others …

Reprogramming Tumor Microenvironment Via Systemic Delivery Of Tlr3 Agonist And Manganese Nanoparticle, Young Seok Cho, Xingwu Zhou, Xiaoqi Sun, Ziye Wan, Julia Crowther, Mariko Takahashi, Swetha Kodamasimham, Qi Wu, May Thazin Phoo, Youngseo Na, Kai Han, Zaiye Li, Anna Schwendeman, Steven P Schwendeman, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Toll-like receptor (TLR) agonists, as potent immunostimulatory adjuvants, play a critical role in linking the innate and adaptive immune responses. However, their antitumor effects as cancer immunotherapeutic agents have been limited. Here, we report our finding that manganese ion (Mn2+) potentiates various TLR agonists, leading to robust activation of the TLR pathway and the stimulator of interferon genes (STING) pathway among innate immune cells. In particular, we have observed robust antitumor efficacy after intratumoral administration of a TLR3 agonist and Mn2+. To achieve systemic codelivery of TLR3 agonist and Mn2+, we have developed a low-molecular-weight poly(inosinic:cytidylic acid)-Mn2+ coordination lipid nanoparticle …

Cgas-Agonistic Spherical Nucleic Acids Reprogram The Glioblastoma Immune Microenvironment And Promote Antitumor Immunity, Akanksha S Mahajan, Corey Dussold, Seunghyun Kim, Rachel Jarvis, Lisa A Hurley, Serena Tommasini-Ghelfi, Jungsoo Park, Connor M Forsyth, Bin Zhang, Jason Miska, Amy B Heimberger, Chad A Mirkin, Alexander H Stegh

2020-Current year OA Pubs

The cyclic GMP-AMP synthase-Stimulator of Interferon Genes (cGAS-STING) pathway is an important DNA-sensing mechanism that increases T cell trafficking and activation in tumors and reverses the immunosuppressive phenotype of myeloid cells. Therefore, direct STING targeting using synthetic cyclic dinucleotides (CDNs) is an attractive strategy for treating lymphocyte-depleted and myeloid cell-enriched tumors, such as glioblastoma (GBM). However, inadequate bioavailability and poor cellular accumulation limit the clinical development of CDNs, particularly for noninvasive administration strategies. Spherical nucleic acids (SNAs) have emerged as promising modular constructs for creating therapeutic lead compounds for many diseases, including different forms of cancer. Here, we report the …

Lrp8 Is An Entry Receptor For Tick-Borne Encephalitis Viruses, Pengfei Li, Sean Hui, Zhenlu Chong, Michael N Nguyen, Stefanie P Muraro, Hana Janova, Hongming Ma, Shiqi Cao, Tomasz Kaszuba, Brian Imbiakha, Sathvik Palakurty, David A Price, Gaya K Amarasinghe, Daisy W Leung, Daved H Fremont, Michael S Diamond, Et Al.

2020-Current year OA Pubs

Orthoflaviviruses are a genus of arthropod-transmitted RNA viruses that infect humans and other vertebrate animals on a global scale, resulting in extensive morbidity and mortality. Among the orthoflaviviruses, tick-borne encephalitis viruses (TBEV) are an antigenic group that causes severe neurological disease in humans. However, the entry receptors for TBEV, which contribute to cell and tissue tropism, remain largely unknown. Because recent studies identified members of the low-density lipoprotein receptor (LDLR) family as possible receptors for some orthoflaviviruses and distantly related alphaviruses, we performed a targeted screen in transgenic cells expressing different LDLR members and identified LRP8 (also called ApoER2) as …

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

Kimmel Cancer Center Faculty Papers

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

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

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 …

Therapeutic Radiation Drives Leptomeningeal Dissemination Of Medulloblastoma Through An Innate Immune Process, Carolina Nör, Kaitlin Kharas, Alex Rasnitsyn, Maria C Vladoiu, Nam Woo Cho, Jacob S Young, Felipe Nör, Ncedile Mankahla, Joonas Haapasalo, Kristiina Nordfors, Sara Rapic, Patryk Skowron, Raúl A Suárez, Alexander T Bahcheli, Oliver Ocsenas, Xin Chen, Shahrzad Bahrampour, Ali Momin, Lakshmikirupa Sundaresan, Winnie Ong, Liam D Hendrikse, Namal Abeysundara, Kyle Juraschka, Michelle Ly, Jonelle G Pallota, Tajana Douglas, Ning Huang, Hao Wang, Esta Mak, Lei Qin, Jessica Liu, Lily Shen, Betty Luu, Alex Manno, Sachin A Kumar, Laura K Donovan, Vernon Fong, Cory Richman, Craig Daniels, Livia Garzia, Jeremy N Rich, Cynthia Hawkins, Xiaochong Wu, Ralph Dacosta, Jüri Reimand, Xi Huang, Vijay Ramaswamy, David R Raleigh, Michael D Taylor

Faculty, Staff and Students Publications

Leptomeningeal metastases are the most important source of morbidity and mortality for medulloblastoma patients. Radiation of the entire brain is highly effective in the treatment and/or prevention of medulloblastoma leptomeningeal metastases. Infants treated on clinical trials with focal tumor radiation recur metastatically, whereas infants treated with only chemotherapy relapse locally. In murine medulloblastoma model systems, provision of a single dose of radiation to the tumor drives leptomeningeal dissemination. An inflammatory response after radiation-induced tumor cell death recruits a variety of immune cells. Inflammation opens the local blood-brain barrier, allowing intravasation of medulloblastoma cells. Experimental induction of inflammation with lipopolysaccharide drives …

An Annotated Biobank Of Triple-Negative Breast Cancer Patient-Derived Xenografts Features Treatment-Naïve And Longitudinal Samples During Neoadjuvant Chemotherapy, Amanda L Rinkenbaugh, Yuan Qi, Shirong Cai, Jiansu Shao, Faiza Baameur Hancock, Sabrina L Jeter-Jones, Xiaomei Zhang, Emily Powell, Lei Huo, Rosanna Lau, Chunxiao Fu, Rebekah Gould, Petra Den Hollander, Elizabeth E Ravenberg, Jason B White, Gaiane M Rauch, Banu Arun, Clinton Yam, Alastair M Thompson, Gloria V Echeverria, Stacy L Moulder, W Fraser Symmans, Jeffrey T Chang, Helen Piwnica-Worms

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) that fails to respond to neoadjuvant chemotherapy (NACT) can be lethal. Developing effective strategies to eradicate chemoresistant disease requires experimental models that recapitulate the heterogeneity characteristic of TNBC. To that end, we established a biobank of 92 orthotopic patient-derived xenograft (PDX) models of TNBC from the tumors of 75 patients enrolled in the ARTEMIS clinical trial (NCT02276443), including 12 longitudinal sets generated from serial patient biopsies collected throughout NACT treatment and from metastatic disease. Models were established from both chemosensitive and chemoresistant tumors, and nearly 30% of the PDX models were capable of metastasizing …

Muscle Fatigue Arising Intrinsically From Sur2- But Not Kir6.1-Dependent Gain-Of-Function In Cantu Syndrome Mice, Rosa Scala, Maya Mukadam, Yuezhou Chen, Courtney Frazier, Nathaniel W York, Robert C Tryon, Gretchen A Meyer, Colin G Nichols

2020-Current year OA Pubs

Cantu syndrome (CS) is a rare disease caused by gain-of-function (GOF) mutations of Kir6.1 or SUR2 subunits of ATP-sensitive potassium (KATP) channels. CS patients with SUR2 and Kir6.1 variants display a similar constellation of symptoms, including muscle weakness and fatigue. The effects of CS mutations on skeletal muscle KATP channels, and any consequent direct effects on contractility, are currently unclear. Here, we used two knock-in mouse models of CS, respectively, carrying GOF mutations Kir6.1[V65M] or SUR2[A478V], to assess KATP channel properties and contractility in isolated fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus (SOL) muscles. Electrophysiological recordings in isolated myofibers …