Digital Commons Network^™

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 …

Mta-Cooperative Prmt5 Inhibitors Are Efficacious In Mtap-Deleted Malignant Peripheral Nerve Sheath Tumor Models, Xiaochun Zhang, Dana C Borcherding, Yang Lyu, Guangfeng Wang, Kevin He, Gorkem Oztosun, Ishita Sachdeva, Liuzhan Yang, Kuangying Yang, Angela C Hirbe, Et Al.

2020-Current year OA Pubs

PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with poor prognosis. The enzyme methylthioadenosine phosphorylase (MTAP) is lost in ∼25% to 50% of MPNSTs, which is associated with loss of the tumor suppressor gene CDKN2A. Inhibition of PRMT5 was found to be synthetically lethal in cells with MTAP loss due to accumulation of the substrate methylthioadenosine (MTA), an endogenous PRMT5 inhibitor. TNG908 and TNG462 are clinical-stage MTA-cooperative PRMT5 inhibitors that demonstrate selectivity for MTAP-deleted (null) cells over MTAP-proficient [wild-type (WT)] cells. Both compounds drive durable tumor regressions in various cancer xenograft models with MTAP loss.

EXPERIMENTAL DESIGN: …

Oligomeric Cystatin C Supports The Immunosuppressive Activity Of Myeloid Cells Through Interaction With Inhibitory Receptors, Chengcheng Zhang, Yubo He, Xiaoye Liu, Jingjing Xie, Meng Fang, Xing Yang, Ryan Huang, Qi Lou, Bufan Li, Ankit Gupta, Cheryl Lewis, Marc I Diamond, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang

Faculty, Staff and Student Publications

Amyloid proteins are linked to various diseases; however, their functional roles in immunity and cancer remain unclear. Here, we establish a direct link between oligomeric cystatin C-a cysteine cathepsin inhibitor and a well-characterized amyloidogenic protein-within the tumor microenvironment and the immune inhibitory receptors LILRB2 and LILRB5 on myeloid cells. We demonstrated that human LILRB2 and LILRB5, along with their murine counterpart PIRB, serve as functional receptors for cystatin C oligomers. Engagement of these inhibitory receptors by oligomeric cystatin C enhances the immunosuppressive activity of myeloid cells, leading to T-cell suppression and tumor progression. Deletion of the CST3 gene, which encodes …

A Role For Gut Mycobiome And Altered Fungal-Bacterial Interactions In Women With Endometriosis†, Chandni Talwar, Ashirbad Guria, Kristi Hoffman, Scott Biest, Patricia Jimenez, Ramakrishna Kommagani

Faculty, Staff and Students Publications

Endometriosis is a gynecological pathology prevalent in reproductive age women in which the inner uterine wall (endometrium) grows outside as ectopic lesions. The inflammation resulting from these growing implants closely associates with disease severity, causing chronic pain and infertility. Emerging studies have found altered bacterial communities in endometriosis and a causal role for gut bacteria in endometriosis. However, the role of the gut mycobiome, i.e., the fungal component of the microbiome in endometriosis is a current knowledge gap that needs to be addressed. In this study, utilizing the stool samples from women with endometriosis, we found that the gut fungal …

Targeting Tomm40 And Tomm22 To Rescue Statin-Impaired Mitochondrial Function, Dynamics, And Mitophagy In Skeletal Myotubes, Neil V Yang, Sean Rogers, Rachel Guerra, Justin Y Chao, David J Pagliarini, Elizabeth Theusch, Ronald M Krauss

2020-Current year OA Pubs

Statins are the drugs most commonly used for lowering plasma low-density lipoprotein (LDL) cholesterol levels and reducing cardiovascular disease risk. Although generally well-tolerated, statins can induce myopathy, a major cause of non-adherence to treatment. Impaired mitochondrial function has been implicated in the development of statin-induced myopathy, but the underlying mechanism remains unclear. We have shown that simvastatin downregulates the transcription of

Developing A General Ai Model For Integrating Diverse Genomic Modalities And Comprehensive Genomic Knowledge, Zhenhao Zhang, Xinyu Bao, Linghua Jiang, Xin Luo, Zheyu Zhang, Jing Yin, Meiqi Zhao, Yichun Wang, Annelise Comai, Joerg Waldhaus, Anders S Hansen, Wenbo Li, Jie Liu

Faculty, Staff and Student Publications

Advances in next-generation sequencing technologies have vastly expanded the availability of diverse genomic, epigenomic, and transcriptomic data, presenting the opportunity to develop a general AI model that integrates comprehensive genomic knowledge into a unified model. Unlike previous predictive models, which are typically specialized to certain tasks, our general AI model unifies a wide range of genomic modalities, such as nascent RNA and ultra-high-resolution chromatin organization, within a multi-task architecture. Using ATAC-seq and DNA sequences as inputs, we incorporated diverse genomic modalities as output, and the model exhibits strong generalizability across different cell types and tissues in all tasks we trained. …

Design, Optimization, And Development Of Ripk1 Degraders With Improved Pharmacokinetic And Pharmacodynamic Properties, Dong Lu, Xin Yu, Hanfeng Lin, Ran Cheng, Bin Yang, Min Zhang, Jingjing Chen, Feng Li, Xiaoli Qi, Jin Wang

Faculty, Staff and Students Publications

Pharmacological degradation of receptor-interacting protein kinase 1 (RIPK1) offers a compelling therapeutic strategy to overcome its scaffolding role in tumor resistance and to enhance the efficacy of immune checkpoint blockade (ICB) therapies. In this study, we report the discovery of a novel RIPK1 degrader, LD5097(24b), developed through systematic optimization of its precursor compound, LD4172—specifically refining the linker, RIPK1 warhead exit vector, and VHL ligand components. LD5097(24b) exhibits potent and selective RIPK1 degradation, triggering rapid and efficient downregulation of RIPK1 and significantly enhancing TNFα-mediated apoptosis in Jurkat cells. Compared to LD4172, LD5097(24b) demonstrates markedly improved metabolic stability and pharmacokinetic properties. In …

Host Cysteine Proteases Promote The Severity Of Catheter-Associated Urinary Tract Infection And Kidney Fibrosis, Wei Xu, Jian Chen, Lisa K Mclellan, Ana L Flores-Mireles, David A Hunstad, Michael G Caparon

2020-Current year OA Pubs

UNLABELLED: The bacterium

IMPORTANCE: Catheter-associated urinary tract infections (CAUTIs) are the most prevalent healthcare-associated infection globally, with

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 …

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 …

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 …

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 …

Genome-Wide Crispr Screens Identify Critical Targets To Enhance Car-Nk Cell Antitumor Potency, Alexander Biederstädt, Rafet Basar, Jeong-Min Park, Nadima Uprety, Rejeena Shrestha, Francia Reyes Silva, Merve Dede, John Watts, Sunil Acharya, Donghai Xiong, Bin Liu, May Daher, Hind Rafei, Pinaki Banerjee, Ping Li, Sanjida Islam, Huihui Fan, Mayra Shanley, Jingling Jin, Bijender Kumar, Vernikka Woods, Paul Lin, Silvia Tiberti, Ana Karen Nunez Cortes, Xin Ru Jiang, Inci Biederstädt, Patrick Zhang, Ye Li, Seema Rawal, Enli Liu, Luis Muniz-Feliciano, Gary M Deyter, Elizabeth J Shpall, Natalie Wall Fowlkes, Ken Chen, Katayoun Rezvani

Faculty, Staff and Student Publications

Adoptive cell therapy using engineered natural killer (NK) cells is a promising approach for cancer treatment, with targeted gene editing offering the potential to further enhance their therapeutic efficacy. However, the spectrum of actionable genetic targets to overcome tumor and microenvironment-mediated immunosuppression remains largely unexplored. We performed multiple genome-wide CRISPR screens in primary human NK cells and identified critical checkpoints regulating resistance to immunosuppressive pressures. Ablation of MED12, ARIH2, and CCNC significantly improved NK cell antitumor activity against multiple treatment-refractory human cancers in vitro and in vivo. CRISPR editing augmented both innate and CAR-mediated NK cell function, associated with enhanced …

Development Of A Targeted Bioprotac Degrader Selective For Misfolded Sod1, Christen G Chisholm, Rachael Bartlett, Mikayla L Brown, Emma-Jayne Proctor, Natalie E Farrawell, Jody Gorman, Fabien Delerue, Lars M Ittner, Kara L Vine-Perrow, Heath Ecroyd, Neil R Cashman, Darren N Saunders, Luke Mcalary, Jeremy S Lum, Justin J Yerbury

Faculty, Staff and Student Publications

The accumulation of misfolded proteins underlies a broad range of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Due to their dynamic nature, these misfolded proteins have proven challenging to target therapeutically. Here, we specifically target misfolded disease variants of the ALS-associated protein superoxide dismutase 1 (SOD1), using a biological proteolysis targeting chimera (BioPROTAC) composed of a SOD1-specific intrabody and an E3 ubiquitin ligase. Screening of intrabodies and E3 ligases for optimal BioPROTAC construction reveals a candidate capable of degrading multiple disease variants of SOD1, preventing their aggregation in cells. Using CRISPR/Cas9 technology to develop a BioPROTAC transgenic mouse line, we …

Cofilin Inhibition Ameliorates Piezo2 And Ampa Dysfunction In A Mouse Model Of Angelman Syndrome, Luis O Romero, Manisha Bade, Elisa Carrillo, Sonia Paz-López, Syed A M Hasan, William James Antonisamy, Vasanthi Jayaraman, Zahoor A Shah, Valeria Vásquez, Julio F Cordero-Morales

Faculty, Staff and Student Publications

Angelman syndrome (AS) is a neurogenetic disorder characterized by motor coordination and cognitive deficits. In AS, hippocampal neurons show reduced filamentous (F-)actin, a decrease we also reported in dorsal root ganglia (DRG) neurons, along with impaired mechanosensitive ion channel activity. Currently, there are no pharmacological targets to prevent the decrease of F-actin in AS. Here, we utilize a first-in-class selective cofilin inhibitor (SZ-3) to restore PIEZO2 function in DRG neurons and glutamate-evoked currents in hippocampal neurons from AS mice. Using atomic force microscopy, we demonstrate that inhibiting cofilin, an actin-severing protein, with SZ-3 increases cellular stiffness by stabilizing the actin …

Mutant P53 Variants Differentially Impact Replication Initiation And Activate Cgas-Sting To Affect Immune Checkpoint Inhibition, Kang Liu, Lidija A Wilhelms Garan, Fang-Tsyr Lin, Weei-Chin Lin

Faculty, Staff and Students Publications

Prior research shows that Akt-dependent phosphorylation of TopBP1 in S phase results in the switch of TopBP1/Treslin binding to TopBP1/E2F1 binding, which is important to prevent replication re-initiation in late S and G2 phases. Here, we demonstrate that contact, but not conformational, mutant p53 can override this switch by binding to both TopBP1 and Treslin, thereby facilitating persistent TopBP1/Treslin interaction in late S and G2 phases, which ultimately leads to over-firing of replication initiation. This increases micronuclei formation, which is further enhanced by genotoxic stressors such as doxorubicin, PARP inhibitors, or ATR inhibitors. Consequently, contact mutant p53 increases the sensitivity …

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 …

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 …

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 …

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 …

Overexpression Of The Signaling Coordinator Gab2 Can Play An Important Role In Acute Myeloid Leukemia Progression, Michael H. Kramer, Stephanie N. Richardson, Yang Li, Tiankai Yin, Nichole M. Helton, Daniel R. George, Michelle Cai, Sai Mukund Ramakrishnan, Casey Ds Katerndahl, Christopher A. Miller, Timothy J. Ley

2020-Current year OA Pubs

Mutations that initiate acute myeloid leukemia (AML) can cause clonal expansion without transformation (clonal hematopoiesis). Cooperating mutations, usually in signaling genes, are needed to cause overt disease, but these may require a specific fitness state to be tolerated. Here, we show that nearly all AMLs arising in a mouse model expressing 2 common AML-initiating mutations (Dnmt3aR878H and Npm1cA) acquired a single copy amplification of chromosome 7 (chr7), followed by activating mutations in signaling genes. We show that overexpression of a single gene on chr7 (Gab2, which coordinates signaling pathways) was tolerated in the presence of the Npm1cA mutation, could accelerate …

Preclinical Fluorescence-Guided Imaging Leveraging Surrounding Sentinel Tumor Microenvironment Identifies High-Risk Premalignant Pancreatic Lesions, Shilpa Sharma, Xiaoxia Wen, Jianbo Wang, Beibei Huang, Denise A Hernandez, Cong-Dat Pham, Zhiwen Liu, Susanne Je-Han Lin, Aiko Yamaguchi, Dimitra K Georgiou, Ryan P Coll, H Charles Manning

Faculty, Staff and Student Publications

Purpose: Because surgery is the only potential cure for pancreatic cancer, high-risk premalignant pancreatic lesions often evade detection by palpation or white-light visualization, increasing the risk of recurrence. We asked whether near-infrared fluorescence imaging of tumor-associated inflammation could identify high-risk premalignant lesions, leveraging the tumor microenvironment as a sentinel of local disease and, thus, enhance surgery outcomes.

Experimental design: Fluorescence-guided surgery was performed on genetically engineered mice [Ptf1a-Cre; LSL-KrasG12D/+; Smad4flox/flox (KSC)] at discrete stages of disease progression, histologically confirmed high-risk, premalignant lesions in postnatal mice to locally advanced pancreatic tumors in adults, using the imaging agent V-1520, a translocator protein …

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 …

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 …

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 …

The Potential Effect Of Ginger As An Adjuvant Treatment In Mice With Induced Multiple Sclerosis: Histological And Physiological Studies, Abdulkader M. A. Shaikh Omar, Salim M. El-Hamidy, Dalia Mohammed Kenani, Safa Hassan Qahl, Ghadah Alshahrani

The Journal of King Abdulaziz University: Science

Objectives: Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system that affect liver and kidneys. Newer treatments for MS were developed such as drug Ibudilast (IBD) and natural plants such as 6-Shogaols (Ginger components). The current study investigates the protective effects of IBD, 6-Shogaols, and their combination on the liver and kidneys of MS mice model.

Methods: Thirty-five mice were used. The study duration was 9 weeks; 5 weeks for demyelination induction by Cuprizone (CPZ) followed by 4 weeks for remyelination. At demyelination, mice were assigned into; Control group (n = 10) and CPZ group (n = …

Direct-In-Nod Genetic Ablation Of Bcl3 Leads To Complete Type 1 Diabetes Protection., Jeremy Racine, Jennifer R Dwyer, Harold D Chapman, Amy Bell, Raymond F. Robledo, David V. Serreze

Faculty Research 2025

It was previously reported that genetic ablation of the NF-κB atypical inhibitor Bcl3 through congenic introduction of a 129P2-embryo derived knockout allele (Bcl3tm1Ver) accelerated autoimmune diabetes in the NOD mouse model. Conversely, we found that direct CRISPR-mediated ablation of this gene in the NOD/ShiLtDvs substrain completely inhibited diabetes development. Our CRISPR approach excised exons 3-7 within the NOD Bcl3 gene. These new NOD-Bcl3-/- mice had very low levels of insulitis, indicating protective mechanisms elicited early in the disease process. Dissimilar to reports of Bcl3 ablation in nonautoimmune C57BL/6-background mice, we found that splenic and lymph node B cells were not …

From Human To Mouse And Back Again: Genetic And Genomic Ta(I)Les Of Islet Dysfunction In Type 2 Diabetes., Romy Kursawe, Khushdeep Bandesh, Sai Nivedita Krishnan, Kevin S Liu, Redwan M Bhuiyan, Michael L. Stitzel

Faculty Research 2025

Type 2 diabetes (T2D) is a complex genetic disease with substantial environmental inputs leading to glucose homeostasis defects. Insulin production is central to proper glucose control, and islet cell dysfunction and death lie at the nexus of T2D genetics and pathophysiology. Comprehensive identification of genes and pathways contributing to these processes is essential for mechanistic understanding and therapeutic targeting. Here, we summarize the latest human and mouse T2D genetic and genomic studies and assess how these parallel variant-to-function efforts and associated data contribute convergent or complementary insights and new opportunities to dissect T2D islet (dys)function. We distill mechanistic and phenotypic …

Rapid Changes In Cholinergic Signaling, Myelination, And Thyroid Signaling Pathway Gene Expression In Amygdala Subnuclei In Response To Social Status Maintenance And Reorganization., Tyler M Milewski, Won Lee, Köll R Rada, James P Curley

Faculty Research 2025

Male CD-1 mice form linear social hierarchies and can rapidly reform them following social reorganization. Through tag-based sequencing in the medial amygdala (MeA), we identified several genes regulating cholinergic signaling, myelination, and thyroid signaling that rapidly shift expression 70 min after animals change social status. Here, we further characterize the expression patterns of individual genes within these pathways in both stable and reorganized hierarchies. We find that genes related to cholinergic signaling show higher expression in the MeA of dominant males in stable hierarchies as well as when reestablishing dominance in reorganized hierarchies. Dominant males also show higher levels of …

Complete Genome Assemblies Of Two Mouse Subspecies Reveal Structural Diversity Of Telomeres And Centromeres., Bailey A Francis, Landen Gozashti, Kevin Costello, Takaoki Kasahara, Olivia S Harringmeyer, Jingtao Lilue, Tianzhen Wu, Katarzyna Zoltowska, Mohab Helmy, Tadafumi Kato, Anne M Czechanski, Iraad F Bronner, Emma Dawson, Michael A Quail, Anne Ferguson-Smith, Laura G Reinholdt, David J Adams, Thomas M Keane

Faculty Research 2025

It has been more than 20 years since the publication of the C57BL/6J mouse reference genome, which has been a key catalyst for understanding the biology of mammalian diseases. However, the mouse reference genome still lacks telomeres and centromeres, contains 281 chromosomal sequence gaps and only partially represents many biomedically relevant loci. Here we present the first telomere-to-telomere (T2T) mouse genomes for two key inbred strains, C57BL/6J and CAST/EiJ. These T2T genomes reveal substantial variability in telomere and centromere sizes and structural organization. We thus add an additional 213 Mb of new sequence to the reference genome, which contains 517 …