Biomedical Informatics Commons^™

Mif/Nr3c2 Axis Regulates Glucose Metabolism Reprogramming In Pancreatic Cancer Through Mapk-Erk And Ap-1 Pathways, Shouhui Yang, Wei Tang, Azadeh Azizian, Jochen Gaedcke, Yuuki Ohara, Helen Cawley, Nader Hanna, Michael Ghadimi, Trisha Lal, Subrata Sen, Chad J Creighton, Jianjun Gao, Nagireddy Putluri, Stefan Ambs, Perwez Hussain

Faculty, Staff and Student Publications

Inflammation and aberrant cellular metabolism are widely recognized as hallmarks of cancer. In pancreatic ductal adenocarcinoma (PDAC), inflammatory signaling and metabolic reprogramming are tightly interwoven, playing pivotal roles in the pathogenesis and progression of the disease. However, the regulatory functions of inflammatory mediators in metabolic reprogramming in pancreatic cancer have not been fully explored. Earlier, we demonstrated that pro-inflammatory mediator macrophage migration inhibitory factor (MIF) enhances disease progression by inhibiting its downstream transcriptional factor nuclear receptor subfamily 3 group C member 2 (NR3C2). Here, we provide evidence that MIF and NR3C2 interactively regulate metabolic reprogramming, resulting in MIF-induced cancer growth …

Mitochondrial Permeability Transition Dictates Mitochondrial Maturation Upon Switch In Cellular Identity Of Hematopoietic Precursors, Sandeep P Dumbali, Paulina D Horton, Travis I Moore, Pamela L Wenzel

Faculty, Staff and Student Publications

The mitochondrial permeability transition pore (mPTP) is a supramolecular channel that regulates exchange of solutes across cristae membranes, with executive roles in mitochondrial function and cell death. The contribution of the mPTP to normal physiology remains debated, although evidence implicates the mPTP in mitochondrial inner membrane remodeling in differentiating progenitor cells. Here, we demonstrate that strict control over mPTP conductance shapes metabolic machinery as cells transit toward hematopoietic identity. Cells undergoing the endothelial-to-hematopoietic transition (EHT) tightly control chief regulatory elements of the mPTP. During EHT, maturing arterial endothelium restricts mPTP activity just prior to hematopoietic commitment. After transition in cellular …

Novel Il-4/Hb-Egf-Dependent Crosstalk Between Eosinophils And Macrophages Controls Liver Regeneration After Ischaemia And Reperfusion Injury, Yang Yang, Long Xu, Constance Atkins, Lily Kuhlman, Jie Zhao, Jong-Min Jeong, Yankai Wen, Nicolas Moreno, Kang Ho Kim, Yu A An, Fenfen Wang, Steve Bynon, Vincenzo Villani, Bin Gao, Frank Brombacher, Raymond Harris, Holger K Eltzschig, Elizabeth Jacobsen, Cynthia Ju

Faculty, Staff and Student Publications

OBJECTIVE: Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair.

DESIGN: Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding …

Pkd1 Mutant Clones Within Cirrhotic Livers Inhibit Steatohepatitis Without Promoting Cancer, Min Zhu, Yunguan Wang, Tianshi Lu, Jason Guo, Lin Li, Meng-Hsiung Hsieh, Purva Gopal, Yi Han, Naoto Fujiwara, Darren P Wallace, Alan S L Yu, Xiangyi Fang, Crystal Ransom, Sara Verschleisser, David Hsiehchen, Yujin Hoshida, Amit G Singal, Adam Yopp, Tao Wang, Hao Zhu

Faculty, Staff and Student Publications

Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness. However, it is uncertain whether these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency …

Women In Stem Becoming Independent: Our Shared Motivation And Enthusiasm Are Our Driving Force, Liudmila Andreeva, Lidia Bosurgi, Shu Zhen Chong, Coco Chu, Yejing Ge, Esther Hoste, Kellie A Jurado, Jette Lengefeld, Archita Mishra, Stefanie Wculek, Arabella Young

Faculty, Staff and Student Publications

This year at JEM, we are highlighting women in science by sharing their stories and amplifying their voices. In this Viewpoint, we hear from a cross section of women, across multiple research fields, discussing their science and the process of setting up a lab as an independent researcher.

The Oncolytic Adenovirus Delta-24-Rgd In Combination With Onc201 Induces A Potent Antitumor Response In Pediatric High-Grade And Diffuse Midline Glioma Models, Daniel De La Nava, Iker Ausejo-Mauleon, Virginia Laspidea, Marisol Gonzalez-Huarriz, Andrea Lacalle, Noelia Casares, Marta Zalacain, Lucía Marrodan, Marc García-Moure, Maria C Ochoa, Antonio Carlos Tallon-Cobos, Reyes Hernandez-Osuna, Javier Marco-Sanz, Laasya Dhandapani, Irati Hervás-Corpión, Oren J Becher, Javad Nazarian, Sabine Mueller, Timothy N Phoenix, Jasper Van Der Lugt, Mikel Hernaez, Elizabeth Guruceaga, Carl Koschmann, Sriram Venneti, Joshua E Allen, Matthew D Dun, Juan Fueyo, Candelaria Gomez-Manzano, Jaime Gallego Perez-Larraya, Ana Patiño-García, Sara Labiano, Marta M Alonso

Faculty, Staff and Student Publications

BACKGROUND: Pediatric high-grade gliomas (pHGGs), including diffuse midline gliomas (DMGs), are aggressive pediatric tumors with one of the poorest prognoses. Delta-24-RGD and ONC201 have shown promising efficacy as single agents for these tumors. However, the combination of both agents has not been evaluated.

METHODS: The production of functional viruses was assessed by immunoblotting and replication assays. The antitumor effect was evaluated in a panel of human and murine pHGG and DMG cell lines. RNAseq, the seahorse stress test, mitochondrial DNA content, and γH2A.X immunofluorescence were used to perform mechanistic studies. Mouse models of both diseases were used to assess the …

Tumour-Intrinsic Endomembrane Trafficking By Arf6 Shapes An Immunosuppressive Microenvironment That Drives Melanomagenesis And Response To Checkpoint Blockade Therapy, Yinshen Wee, Junhua Wang, Emily C Wilson, Coulson P Rich, Aaron Rogers, Zongzhong Tong, Evelyn Degroot, Y N Vashisht Gopal, Michael A Davies, H Atakan Ekiz, Joshua K H Tay, Chris Stubben, Kenneth M Boucher, Juan M Oviedo, Keke C Fairfax, Matthew A Williams, Sheri L Holmen, Roger K Wolff, Allie H Grossmann

Faculty, Staff and Student Publications

Tumour-host immune interactions lead to complex changes in the tumour microenvironment (TME), impacting progression, metastasis and response to therapy. While it is clear that cancer cells can have the capacity to alter immune landscapes, our understanding of this process is incomplete. Herein we show that endocytic trafficking at the plasma membrane, mediated by the small GTPase ARF6, enables melanoma cells to impose an immunosuppressive TME that accelerates tumour development. This ARF6-dependent TME is vulnerable to immune checkpoint blockade therapy (ICB) but in murine melanoma, loss of Arf6 causes resistance to ICB. Likewise, downregulation of ARF6 in patient tumours correlates with …

Kinesin Facilitates Phenotypic Targeting Of Therapeutic Resistance In Advanced Prostate Cancer, Maddison Archer, Diane Begemann, Edgar Gonzalez-Kozlova, Prerna R Nepali, Estefania Labanca, Peter Shepherd, Navneet Dogra, Nora Navone, Natasha Kyprianou

Faculty, Staff and Student Publications

Understanding the mechanisms underlying resistance is critical to improving therapeutic outcomes in patients with metastatic castration-resistant prostate cancer. Previous work showed that dynamic interconversions between epithelial-mesenchymal transition to mesenchymal-epithelial transition defines the phenotypic landscape of prostate tumors, as a potential driver of the emergence of therapeutic resistance. In this study, we use in vitro and in vivo preclinical MDA PCa patient-derived xenograft models of resistant human prostate cancer to determine molecular mechanisms of cross-resistance between antiandrogen therapy and taxane chemotherapy, underlying the therapeutically resistant phenotype. Transcriptomic profiling revealed that resistant and sensitive prostate cancer C4-2B cells have a unique differential …

Brca1-Mediated Dual Regulation Of Ferroptosis Exposes A Vulnerability To Gpx4 And Parp Co-Inhibition In Brca1-Deficient Cancers, Guang Lei, Chao Mao, Amber D Horbath, Yuelong Yan, Shirong Cai, Jun Yao, Yan Jiang, Mingchuang Sun, Xiaoguang Liu, Jun Cheng, Zhihao Xu, Hyemin Lee, Qidong Li, Zhengze Lu, Li Zhuang, Mei-Kuang Chen, Anagha Alapati, Timothy A Yap, Mien-Chie Hung, Mingjian James You, Helen Piwnica-Worms, Boyi Gan

Faculty, Staff and Student Publications

Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) limits the therapeutic efficacy of PARP inhibition in treating breast cancer susceptibility gene 1 (BRCA1)-deficient cancers. Here we reveal that BRCA1 has a dual role in regulating ferroptosis. BRCA1 promotes the transcription of voltage-dependent anion channel 3 (VDAC3) and glutathione peroxidase 4 (GPX4); consequently, BRCA1 deficiency promotes cellular resistance to erastin-induced ferroptosis but sensitizes cancer cells to ferroptosis induced by GPX4 inhibitors (GPX4i). In addition, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and defective GPX4 induction unleash potent ferroptosis in BRCA1-deficient cancer cells upon PARPi and GPX4i …

Rosiglitazone And Trametinib Exhibit Potent Anti-Tumor Activity In A Mouse Model Of Muscle Invasive Bladder Cancer, Sakina A Plumber, Tiffany Tate, Hikmat Al-Ahmadie, Xiao Chen, Woonyoung Choi, Merve Basar, Chao Lu, Aaron Viny, Ekatherina Batourina, Jiaqi Li, Kristjan Gretarsson, Besmira Alija, Andrei Molotkov, Gregory Wiessner, Byron Hing Lung Lee, James Mckiernan, David J Mcconkey, Colin Dinney, Bogdan Czerniak, Cathy Lee Mendelsohn

Faculty, Staff and Student Publications

Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. …

Neoantigen-Specific Cytotoxic Tr1 Cd4 T Cells Suppress Cancer Immunotherapy, Hussein Sultan, Yoshiko Takeuchi, Jeffrey P Ward, Naveen Sharma, Tian-Tian Liu, Vladimir Sukhov, Maria Firulyova, Yuang Song, Samuel Ameh, Simone Brioschi, Darya Khantakova, Cora D Arthur, J Michael White, Heather Kohlmiller, Andres M Salazar, Robert Burns, Helio A Costa, Kelly D Moynihan, Yik Andy Yeung, Ivana Djuretic, Ton N Schumacher, Kathleen C F Sheehan, Marco Colonna, James P Allison, Kenneth M Murphy, Maxim N Artyomov, Robert D Schreiber

Faculty, Staff and Student Publications

CD4+ T cells can either enhance or inhibit tumour immunity. Although regulatory T cells have long been known to impede antitumour responses1-5, other CD4+ T cells have recently been implicated in inhibiting this response6,7. Yet, the nature and function of the latter remain unclear. Here, using vaccines containing MHC class I (MHC-I) neoantigens (neoAgs) and different doses of tumour-derived MHC-II neoAgs, we discovered that whereas the inclusion of vaccines with low doses of MHC-II-restricted peptides (LDVax) promoted tumour rejection, vaccines containing high doses of the same MHC-II neoAgs (HDVax) inhibited rejection. Characterization of the inhibitory cells induced by HDVax identified …

Poly(Adp-Ribose) Polymerase-1 Regulates Pyroptosis Independent Function Of Nlrp3 Inflammasome In Neutrophil Extracellular Trap Formation, Louis J Delinois, Atul Sharma, Ashwin K Ramesh, Laurel D Boatright, Qun Li, Rong Xu, Hongbo R Luo, Bibhuti B Mishra, Jyotika Sharma

Faculty, Staff and Student Publications

Neutrophil extracellular traps (NETs) function to control infectious agents as well as to propagate inflammatory response in a variety of disease conditions. DNA damage associated with chromatin decondensation and NACHT domain-leucine-rich repeat-and pyrin domain-containing protein 3 (NLRP3) inflammasome activation have emerged as crucial events in NET formation, but the link between the two processes is unknown. In this study, we demonstrate that poly(ADP-ribose) polymerase-1 (PARP-1), a key DNA repair enzyme, regulates NET formation triggered by NLRP3 inflammasome activation in neutrophils. Activation of mouse neutrophils with canonical NLRP3 stimulants LPS and nigericin induced NET formation, which was significantly abrogated by pharmacological …

Mechanism And Rational Combinations With Gp-2250, A Novel Oxathiazine Derivative, In Ovarian Cancer, Mark S Kim, Deanna Glassman, Katelyn F Handley, Adrian Lankenau Ahumada, Nicholas B Jennings, Emine Bayraktar, Katherine Foster, Robiya Joseph, Sanghoon Lee, Robert L Coleman, Anil K Sood

Faculty, Staff and Student Publications

BACKGROUND: GP-2250, a novel analog of taurultam (TRLT), has emerged as a potent anti-neoplastic drug; however, the mechanisms underlying its effects are not well understood. Here, we investigated the mechanism of action and the biological effects of GP-2250 using in vitro and in vivo models.

METHODS: We carried out a series of in vitro (MTT assay, Annexin V/PI assay, colony formation assay, reverse-phase protein array [RPPA], and HRLC/IC analysis) to determine the biological activity of GP-2250 and investigate the mechanism of action. In vivo experiments were carried out to determine the therapeutic efficacy of GP-2250 alone and in combination with …

Autophagic Signaling Promotes Systems-Wide Remodeling In Skeletal Muscle Upon Oncometabolic Stress By D2-Hg, Yaqi Gao, Kyoungmin Kim, Heidi Vitrac, Rebecca L Salazar, Benjamin D Gould, Daniel Soedkamp, Weston Spivia, Koen Raedschelders, An Q Dinh, Anna G Guzman, Lin Tan, Stavros Azinas, David J R Taylor, Walter Schiffer, Daniel Mcnavish, Helen B Burks, Roberta A Gottlieb, Philip L Lorenzi, Blake M Hanson, Jennifer E Van Eyk, Heinrich Taegtmeyer, Anja Karlstaedt

Faculty, Staff and Student Publications

OBJECTIVES: Cachexia is a metabolic disorder and comorbidity with cancer and heart failure. The syndrome impacts more than thirty million people worldwide, accounting for 20% of all cancer deaths. In acute myeloid leukemia, somatic mutations of the metabolic enzyme isocitrate dehydrogenase 1 and 2 cause the production of the oncometabolite D2-hydroxyglutarate (D2-HG). Increased production of D2-HG is associated with heart and skeletal muscle atrophy, but the mechanistic links between metabolic and proteomic remodeling remain poorly understood. Therefore, we assessed how oncometabolic stress by D2-HG activates autophagy and drives skeletal muscle loss.

METHODS: We quantified genomic, metabolomic, and proteomic changes in …

Nf1 Mutation Disrupts Activity-Dependent Oligodendroglial Plasticity And Motor Learning In Mice, Yuan Pan, Jared D Hysinger, Belgin Yalçın, James J Lennon, Youkyeong Gloria Byun, Preethi Raghavan, Nicole F Schindler, Corina Anastasaki, Jit Chatterjee, Lijun Ni, Haojun Xu, Karen Malacon, Samin M Jahan, Alexis E Ivec, Benjamin E Aghoghovwia, Christopher W Mount, Surya Nagaraja, Suzanne Scheaffer, Laura D Attardi, David H Gutmann, Michelle Monje

Faculty, Staff and Student Publications

Neurogenetic disorders, such as neurofibromatosis type 1 (NF1), can cause cognitive and motor impairments, traditionally attributed to intrinsic neuronal defects such as disruption of synaptic function. Activity-regulated oligodendroglial plasticity also contributes to cognitive and motor functions by tuning neural circuit dynamics. However, the relevance of oligodendroglial plasticity to neurological dysfunction in NF1 is unclear. Here we explore the contribution of oligodendrocyte progenitor cells (OPCs) to pathological features of the NF1 syndrome in mice. Both male and female littermates (4-24 weeks of age) were used equally in this study. We demonstrate that mice with global or OPC-specific Nf1 heterozygosity exhibit defects …

Enolase Inhibitors As Therapeutic Leads For Naegleria Fowleri Infection, Jillian E Milanes, Victoria C Yan, Cong-Dat Pham, Florian Muller, Samuel Kwain, Kerrick C Rees, Brian N Dominy, Daniel C Whitehead, Steven W Millward, Madison Bolejack, Roger Shek, Logan Tillery, Isabelle Q Phan, Bart Staker, E Ashley Moseman, Xiang Zhang, Xipeng Ma, Audriy Jebet, Xinmin Yin, James C Morris

Faculty, Staff and Student Publications

Infections with the pathogenic free-living amoebae Naegleria fowleri can lead to life-threatening illnesses including catastrophic primary amoebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and the mortality rate remains >95% in the US. Glycolysis is very important for the infectious trophozoite lifecycle stage and inhibitors of glucose metabolism have been found to be toxic to the pathogen. Recently, human enolase 2 (ENO2) phosphonate inhibitors have been developed as lead agents to treat glioblastoma multiforme (GBM). These compounds, which cure GBM in a rodent model, are well-tolerated in mammals because enolase 1 (ENO1) is the predominant isoform used …

Smyd5 Methylation Of Rpl40 Links Ribosomal Output To Gastric Cancer, Juhyung Park, Jibo Wu, Krzysztof J Szkop, Jinho Jeong, Predrag Jovanovic, Dylan Husmann, Natasha M Flores, Joel W Francis, Ying-Jiun C Chen, Ana Morales Benitez, Emily Zahn, Shumei Song, Jaffer A Ajani, Linghua Wang, Kamini Singh, Ola Larsson, Benjamin A Garcia, Ivan Topisirovic, Or Gozani, Pawel K Mazur

Faculty, Staff and Student Publications

Dysregulated transcription due to disruption in histone lysine methylation dynamics is an established contributor to tumorigenesis1,2. However, whether analogous pathologic epigenetic mechanisms act directly on the ribosome to advance oncogenesis is unclear. Here we find that trimethylation of the core ribosomal protein L40 (rpL40) at lysine 22 (rpL40K22me3) by the lysine methyltransferase SMYD5 regulates mRNA translation output to promote malignant progression of gastric adenocarcinoma (GAC) with lethal peritoneal ascites. A biochemical-proteomics strategy identifies the monoubiquitin fusion protein partner rpL40 (ref. 3) as the principal physiological substrate of SMYD5 across diverse samples. Inhibiting the SMYD5-rpL40K22me3 axis in GAC cell lines reprogrammes …

Antitumor Activity Of A Novel Lair1 Antagonist In Combination With Anti-Pd1 To Treat Collagen-Rich Solid Tumors, Bertha L Rodriguez, Jiawei Huang, Laura Gibson, Jared J Fradette, Hung-I H Chen, Kikuye Koyano, Czrina Cortez, Betty Li, Carmence Ho, Amir M Ashique, Vicky Y Lin, Suzanne Crawley, Julie M Roda, Peirong Chen, Bin Fan, Jeong Kim, James Sissons, Jonathan Sitrin, Daniel D Kaplan, Don L Gibbons, Lee B Rivera

Faculty, Staff and Student Publications

We recently reported that resistance to PD-1 blockade in a refractory lung cancer-derived model involved increased collagen deposition and the collagen-binding inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1). Thus, we hypothesized that LAIR1 and collagen cooperated to suppress therapeutic response. In this study, we report that LAIR1 is associated with tumor stroma and is highly expressed by intratumoral myeloid cells in both human tumors and mouse models of cancer. Stroma-associated myeloid cells exhibit a suppressive phenotype and correlate with LAIR1 expression in human cancer. NGM438, a novel humanized LAIR1 antagonist mAb, elicits myeloid inflammation and allogeneic T-cell responses by binding …

Ephb2 Receptor Promotes Dermal Fibrosis In Systemic Sclerosis, Erika S A Egal, Severin Donald Kamdem, Masaaki Yoshigi, Ching-Chu Yang, Sarah Pellizzari, Ernest M Kameni, My N Helms, Shervin Assassi, Mark Henkemeyer, Tracy M Frech, Patrice N Mimche

Faculty, Staff and Student Publications

Objective: Erythropoietin-producing hepatocellular (Eph)/Ephrin cell-cell signaling is emerging as a key player in tissue fibrogenesis. The aim of this study was to test the hypothesis that the receptor tyrosine kinase EphB2 mediates dermal fibrosis in systemic sclerosis (SSc).

Methods: We assessed normal and SSc human skin biopsies for EphB2 expression. The in vivo role of EphB2 in skin fibrosis was investigated by subjecting EphB2-knockout mice to both bleomycin-induced and tight skin (Tsk1/+) genetic mouse models of skin fibrosis. EphB2 kinase-dead and overactive point mutant mice were used to evaluate the role of EphB2 forward signaling in bleomycin-induced dermal fibrosis. In …

Electrical Stimulation Of The Dorsal Motor Nucleus Of The Vagus In Male Mice Can Regulate Inflammation Without Affecting The Heart Rate, Aidan Falvey, Santhoshi P Palandira, Sangeeta S Chavan, Michael Brines, Robert Dantzer, Kevin J Tracey, Valentin A Pavlov

Faculty, Staff and Student Publications

Background: The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute to the regulation of inflammation is the brainstem dorsal motor nucleus of the vagus (DMN), as recently shown using optogenetics. In contrast to optogenetics, electrical neuromodulation has broad therapeutic implications. However, the anti-inflammatory effectiveness of electrical stimulation of the DMN (eDMNS) and the possible heart rate (HR) alterations associated with this approach have not been investigated. Here, we examined the effects of eDMNS on HR and cytokine levels in mice administered with lipopolysaccharide …

Targeting Adenosine A2b Receptor Promotes Penile Rehabilitation Of Refractory Erectile Dysfunction, Yang Xiong, Feng Qin, Shanzun Wei, Xingliang Yang, Jun Li, Changjing Wu, Fuxun Zhang, Jiuhong Yuan

Faculty, Staff and Student Publications

The mechanisms of adenosine and specific adenosine receptor subtypes in promoting penile rehabilitation remain unclear. Single‐cell RNA sequencing of human corpus cavernosum,  adenosine deaminase (ADA) and adenosine receptors knock‐out mice (ADA−/−, A1−/−, A2a−/−, A2b−/−, and A3−/−), and primary corpus cavernosum smooth muscle cells are used to determine receptor subtypes responsible for adenosine‐induced erection. Three rat models are established to characterize refractory erectile dysfunction (ED): age‐related ED, bilateral cavernous nerve crush related ED (BCNC), and diabetes mellitus‐induced ED. In single‐cell RNA sequencing data, the corpus cavernosum of ED patients show a decrease in adenosine A1, A2a and A2b receptors. In vivo, …

Pbi-05204, A Supercritical Co2 Extract Of Nerium Oleander, Suppresses Glioblastoma Stem Cells By Inhibiting Grp78 And Inducing Programmed Necroptotic Cell, Sharmistha Chakraborty, Daoyan Wei, Megan Tran, Frederick F Lang, Robert A Newman, Peiying Yang

Faculty, Staff and Student Publications

Successful treatment of glioblastoma multiforme (GBM), an aggressive form of primary brain neoplasm, mandates the need to develop new therapeutic strategies. In this study, we investigated the potential of PBI-05204 in targeting GBM stem cells (GSCs) and the underlying mechanisms. Treatment with PBI-05204 significantly reduced both the number and size of tumor spheres derived from patient-derived GSCs (GBM9, GSC28 and TS543), and suppressed the tumorigenesis of GBM9 xenografts. Moreover, PBI-05204 treatment led to a significant decrease in the expression of CD44 and NANOG, crucial markers of progenitor stem cells, in GBM9 and GSC28 GSCs. This treatment also down-regulated GRP78 expression …

Pb-05204, A Supercritical Co2 Extract Of Nerium Oleander, Suppresses Glioblastoma Stem Cells By Inhibiting Grp78 And Inducing Programmed Necroptotic Cell Death, Sharmistha Chakraborty, Daoyan Wei, Megan Tran, Frederick F Lang, Robert A Newman, Peiying Yang

Faculty, Staff and Student Publications

Successful treatment of glioblastoma multiforme (GBM), an aggressive form of primary brain neoplasm, mandates the need to develop new therapeutic strategies. In this study, we investigated the potential of PBI-05204 in targeting GBM stem cells (GSCs) and the underlying mechanisms. Treatment with PBI-05204 significantly reduced both the number and size of tumor spheres derived from patient-derived GSCs (GBM9, GSC28 and TS543), and suppressed the tumorigenesis of GBM9 xenografts. Moreover, PBI-05204 treatment led to a significant decrease in the expression of CD44 and NANOG, crucial markers of progenitor stem cells, in GBM9 and GSC28 GSCs. This treatment also down-regulated GRP78 expression …

A First-In-Class Selective Inhibitor Of Egfr And Pi3k Offers A Single-Molecule Approach To Targeting Adaptive Resistance, Christopher E Whitehead, Elizabeth K Ziemke, Christy L Frankowski-Mcgregor, Rachel A Mumby, June Chung, Jinju Li, Nathaniel Osher, Oluwadara Coker, Veerabhadran Baladandayuthapani, Scott Kopetz, Judith S Sebolt-Leopold

Faculty, Staff and Student Publications

Despite tremendous progress in precision oncology, adaptive resistance mechanisms limit the long-term effectiveness of molecularly targeted agents. Here we evaluated the pharmacological profile of MTX-531 that was computationally designed to selectively target two key resistance drivers, epidermal growth factor receptor and phosphatidylinositol 3-OH kinase (PI3K). MTX-531 exhibits low-nanomolar potency against both targets with a high degree of specificity predicted by cocrystal structural analyses. MTX-531 monotherapy uniformly resulted in tumor regressions of squamous head and neck patient-derived xenograft (PDX) models. The combination of MTX-531 with mitogen-activated protein kinase kinase or KRAS-G12C inhibitors led to durable regressions of BRAF-mutant or KRAS-mutant colorectal …

Central Irf4/5 Signaling Are Critical For Microglial Activation And Impact On Stroke Outcomes, Conelius Ngwa, Abdullah Al Mamun, Shaohua Qi, Romana Sharmeen, Maria P Blasco Conesa, Bhanu P Ganesh, Bharti Manwani, Fudong Liu

Faculty, Staff and Student Publications

Microglia and monocytes play a critical role in immune responses to cerebral ischemia. Previous studies have demonstrated that interferon regulatory factor 4 (IRF4) and IRF5 direct microglial polarization after stroke and impact outcomes. However, IRF4/5 are expressed by both microglia and monocytes, and it is not clear if it is the microglial (central) or monocytic (peripheral) IRF4-IRF5 regulatory axis that functions in stroke. In this work, young (8-12 weeks) male pep boy (PB), IRF4 or IRF5 flox, and IRF4 or IRF5 conditional knockout (CKO) mice were used to generate 8 types of bone marrow chimeras, to differentiate the role of …

P53r172h And P53r245w Hotspot Mutations Drive Distinct Transcriptomes In Mouse Mammary Tumors Through A Convergent Transcriptional Mediator, Joy M Mcdaniel, Rhiannon L Morrissey, Denada Dibra, Lalit R Patel, Shunbin Xiong, Yun Zhang, Gilda P Chau, Xiaoping Su, Yuan Qi, Adel K El-Naggar, Guillermina Lozano

Faculty, Staff and Student Publications

Aggressive breast cancers harbor TP53 missense mutations. Tumor cells with TP53 missense mutations exhibit enhanced growth and survival through transcriptional rewiring. To delineate how TP53 mutations in breast cancer contribute to tumorigenesis and progression in vivo, we created a somatic mouse model driven by mammary epithelial cell-specific expression of Trp53 mutations. Mice developed primary mammary tumors reflecting the human molecular subtypes of luminal A, luminal B, HER2-enriched, and triple-negative breast cancer with metastases. Transcriptomic analyses comparing MaPR172H/− or MaPR245W/− mammary tumors to MaP−/− tumors revealed (1) differences in cancer-associated pathways activated in both p53 …

A Cell Cycle-Aware Network For Data Integration And Label Transferring Of Single-Cell Rna-Seq And Atac-Seq, Jiajia Liu, Jian Ma, Jianguo Wen, Xiaobo Zhou

Faculty, Staff and Student Publications

In recent years, the integration of single-cell multi-omics data has provided a more comprehensive understanding of cell functions and internal regulatory mechanisms from a non-single omics perspective, but it still suffers many challenges, such as omics-variance, sparsity, cell heterogeneity, and confounding factors. As it is known, the cell cycle is regarded as a confounder when analyzing other factors in single-cell RNA-seq data, but it is not clear how it will work on the integrated single-cell multi-omics data. Here, a cell cycle-aware network (CCAN) is developed to remove cell cycle effects from the integrated single-cell multi-omics data while keeping the cell …

T-Bet Suppresses Proliferation Of Malignant B Cells In Chronic Lymphocytic Leukemia, Philipp M Roessner, Isabelle Seufert, Vicente Chapaprieta, Ruparoshni Jayabalan, Hannah Briesch, Ramon Massoni-Badosa, Pavle Boskovic, Julian Benckendorff, Tobias Roider, Lavinia Arseni, Mariana Coelho, Supriya Chakraborty, Alicia M Vaca, Mariela Sivina, Markus Muckenhuber, Sonia Rodriguez-Rodriguez, Alice Bonato, Sophie A Herbst, Marc Zapatka, Clare Sun, Helene Kretzmer, Thomas Naake, Peter-Martin Bruch, Felix Czernilofsky, Elisa Ten Hacken, Martin Schneider, Dominic Helm, Deyan Y Yosifov, Joseph Kauer, Alexey V Danilov, Moritz Bewarder, Kristina Heyne, Christof Schneider, Stephan Stilgenbauer, Adrian Wiestner, Jan-Philipp Mallm, Jan A Burger, Dimitar G Efremov, Peter Lichter, Sascha Dietrich, José I Martin-Subero, Karsten Rippe, Martina Seiffert

Faculty, Staff and Student Publications

The T-box transcription factor T-bet is known as a master regulator of the T-cell response but its role in malignant B cells has not been sufficiently explored. Here, we conducted single-cell resolved multi-omics analyses of malignant B cells from patients with chronic lymphocytic leukemia (CLL) and studied a CLL mouse model with a genetic knockout of Tbx21. We found that T-bet acts as a tumor suppressor in malignant B cells by decreasing their proliferation rate. NF-κB activity, induced by inflammatory signals provided by the microenvironment, triggered T-bet expression, which affected promoter-proximal and distal chromatin coaccessibility and controlled a specific gene …

Tumoral Interferon Beta Induces An Immune-Stimulatory Phenotype In Tumor-Associated Macrophages In Melanoma Brain Metastases, Julia Gellert, Dennis A Agardy, Swaminathan Kumar, Alexandros Kourtesakis, Tamara Boschert, Kristine Jähne, Michael O Breckwoldt, Lukas Bunse, Wolfgang Wick, Michael A Davies, Michael Platten, Theresa Bunse

Faculty, Staff and Student Publications

Type I interferons (IFN) are immune-stimulatory cytokines involved in antiviral and antitumor immune responses. They enhance the efficacy of immunogenic anticancer therapies such as radiotherapy by activating both innate and adaptive immune cells. Macrophages are one of the most abundant innate immune cells in the immune microenvironment of melanoma brain metastases (MBM) and can exert potent immune-suppressive functions. Here, we investigate the potential of tumoral type I IFNs to repolarize tumor-associated macrophages (TAM) in two murine MBM models and assess the effects of radiotherapy-induced type I IFN on TAMs in a transcriptomic MBM patient dataset. In mice, we describe a …

Systematic Transcriptome Profiling Of Hpsc-Derived Osteoblasts Unveils Corin’S Mastery In Governing Osteogenesis Through Cebpd Modulation, Dandan Zhu, Mo-Fan Huang, An Xu, Xueqin Gao, Yu-Wen Huang, Trinh T T Phan, Linchao Lu, Ting-Yen Chi, Yulin Dai, Lon Kai Pang, Julian A Gingold, Jian Tu, Zijun Huo, Danielle A Bazer, Rachel Shoemaker, Jun Wang, Catherine G Ambrose, Jingnan Shen, Jun Kameoka, Zhongming Zhao, Lisa L Wang, Yang Zhang, Ruiying Zhao, Dung-Fang Lee

Faculty, Staff and Student Publications

The commitment of stem cells to differentiate into osteoblasts is a highly regulated and complex process that involves the coordination of extrinsic signals and intrinsic transcriptional machinery. While rodent osteoblastic differentiation has been extensively studied, research on human osteogenesis has been limited by cell sources and existing models. Here, we systematically dissect human pluripotent stem cell-derived osteoblasts to identify functional membrane proteins and their downstream transcriptional networks involved in human osteogenesis. Our results reveal an enrichment of type II transmembrane serine protease CORIN in humans but not rodent osteoblasts. Functional analyses demonstrated that CORIN depletion significantly impairs osteogenesis. Genome-wide chromatin …