Medical Genetics Commons^™

Synaptic Transmission Promotes Brain Metastatic Outgrowth In Breast Cancer, Jayanta Mondal, Patrick Nylund, Prit Benny Malgulwar, William E Johnson, Jason T Huse

Faculty, Staff and Student Publications

This work demonstrates that normal neuron-to-neuron signaling machinery is hijacked by metastasizing cancer cells during their outgrowth in the central nervous system.

Quiescent Oxphos-High Triple-Negative Breast Cancer Cells That Persist After Chemotherapy Depend On Bcl-Xl For Survival, Slawomir Andrzejewski, Marie Winter, Leandro Encarnacao Garcia, Olusiji Akinrinmade, Francisco Madeira Marques, Emmanouil Zacharioudakis, Anna Skwarska, Julio Aguirre-Ghiso, Marina Konopleva, Guangrong Zheng, Susan A Fineberg, Daohong Zhou, Evripidis Gavathiotis, Tao Wang, Eugen Dhimolea

Faculty, Staff and Student Publications

The persistent residual tumor cells that survive after chemotherapy are a major cause of treatment failure, but their survival mechanisms remain largely elusive. These cancer cells are typically characterized by a quiescent state with suppressed activity of MYC and MTOR. We observed that the MYC-suppressed persistent triple-negative breast cancer (TNBC) cells are metabolically flexible and can upregulate mitochondrial oxidative phosphorylation (OXPHOS) genes and respiratory function ("OXPHOS-high" cell state) in response to DNA-damaging anthracyclines such as doxorubicin, but not to taxanes. The elevated biomass and respiratory function of mitochondria in OXPHOS-high persistent cancer cells were associated with mitochondrial elongation and remodeling, …

Biliverdin Reductase A Is A Major Determinant Of Protective Nrf2 Signaling, Chirag Vasavda, Ruchita Kothari, Navneet Ammal Kaidery, Suwarna Chakraborty, Sunil Jamuna Tripathi, Ryan S Dhindsa, Cristina Ricco, Shruthi Shanmukha, Samaneh Saberi, Julia E Lefler, Priyanka Kothari, Kalyani Chaubey, Adele M Snowman, Michael C Ostrowski, Eugenio Barone, Lakshminarayan M Iyer, L Aravind, Sudarshana M Sharma, Andrew A Pieper, Bobby Thomas, Solomon H Snyder, Bindu D Paul

Duncan NRI Faculty and Staff Publications

Biliverdin reductase A (BVRA), the terminal enzyme in heme catabolism, generates the neuroprotective and lipophilic antioxidant bilirubin. Here, we identify a nonenzymatic role for BVRA in redox regulation. Through phylogenetic, genetic, biochemical, and enzymatic assays, we found that BVRA exerts critical nonenzymatic antioxidant activity. Transcriptomic analyses further revealed that BVRA physically and genetically interacts with nuclear factor erythroid-derived factor-like 2 (NRF2), a major transcriptional regulator of cellular redox signaling. ChIP-seq and RNA-seq analyses reveal that BVRA and NRF2 coordinate the expression of antioxidant genes, many of which are typically dysregulated in neurodegenerative conditions such as Alzheimer's disease. Thus, this noncanonical …

Enhanced Piezo1 Function Contributes To The Pathogenesis Of Sickle Cell Disease, Luis O Romero, Manisha Bade, Laila Elsherif, Jada D Williams, Xiangmei Kong, Adebowale Adebiyi, Kenneth I Ataga, Shang Ma, Julio F Cordero-Morales, Valeria Vásquez

Faculty, Staff and Student Publications

Sickle cell disease (SCD), an inherited blood disorder caused by a mutation in the β-globin gene, is characterized by sickle erythrocytes that are prone to hemolysis, leading to anemia and vaso-occlusion crises. In sickle erythrocytes, hemoglobin aggregation is followed by altered cation permeability and subsequent dehydration. Interventions that restore cation permeability can decrease hemolysis and ameliorate the symptoms associated with SCD. PIEZO1 is a nonselective mechanosensitive cation channel that regulates erythrocyte volume. Gain-of-function (GOF) mutations in PIEZO1 cause hemolytic anemia by increasing cation permeability, leading to erythrocyte dehydration in humans and mice. Although PIEZO1 plays a key role in erythrocyte …

Multicenter Stroke Preclinical Assessment Network Analysis Of Cardiovascular Risk Factor Subgroups Treated With The Poly(Adp-Ribose) Polymerase Inhibitor Veliparib, Raymond C Koehler, Karni Bedirian, Mu-Hsun Chen, Yanrong Shi, Suyi Cao, Brooklyn D Avery, Senthilkumar S Karuppagounder, Kazi Akhter, Adnan Bibic, Valina L Dawson, Ted M Dawson, Márcio A Diniz, Jessica Lamb, Karisma A Nagarkatti, Anjali Chauhan, Jaroslaw Aronowski, Louise D Mccullough, Andreia Lopes De Morais, Xuyan Jin, Cenk Ayata, Mariia Kumskova, Rakesh B Patel, Anil K Chauhan, Enrique C Leira, Pradip K Kamat, Mohammad B Khan, Krishnan M Dhandapani, David C Hess, Ligia S B Boisserand, Basavaraju G Sanganahalli, Lauren H Sansing, Patrick D Lyden

Faculty, Staff and Student Publications

Background: The Stroke Preclinical Assessment Network tested 6 therapeutic interventions initiated at the time of reperfusion after focal ischemic stroke in young mice, aging mice, obese mice, and spontaneously hypertensive rats. This randomized, controlled trial was conducted across 6 sites with concealed treatment and blinded neurobehavior assessments. The trial had an adaptive design with preset levels of efficacy and futility interrogated after each of 4 stages. The primary outcome was turning preference on the corner test at 1 month. The PARP (poly(ADP-ribose) polymerase) inhibitor, veliparib, was considered futile after the second stage when pooling all animal models (n=231 …

Atg16l1 Controls Mammalian Vacuolar Proton Atpase, Thabata L A Duque, Masroor Paddar, Einar Trosdal, Ruheena Javed, Lee Allers, Michal H Mudd, Prithvi Akepati, Soumya R Mishra, Michelle Salemi, Brett Phinney, Shawn B Bratton, Thomas Wileman, Vojo Deretic

Faculty, Staff and Student Publications

The mechanisms governing mammalian proton pump V-ATPase function are of fundamental and medical interest. The assembly and disassembly of cytoplasmic V1 domain with the membrane-embedded V0 domain of V-ATPase is a key aspect of V-ATPase localization and function. Here, we show that the mammalian protein ATG16L1, primarily appreciated for its role in canonical autophagy and in noncanonical membrane atg8ylation processes, controls V-ATPase. ATG16L1 knockout elevated V-ATPase activity, increased V1 presence on endomembranes, and increased the number of acidified intracellular compartments. ATG16L1's ability to efficiently bind V-ATPase was required for its inhibitory role in endolysosomal acidification and for control of Mycobacterium …

Atg Conjugation-Dependent/Independent Mechanisms Underlie Lysosomal Stress-Induced Tfeb Regulation, Shiori Akayama, Takayuki Shima, Tatsuya Kaminishi, Mengying Cui, Jlenia Monfregola, Kohei Nishino, Andrea Ballabio, Hidetaka Kosako, Tamotsu Yoshimori, Shuhei Nakamura

Duncan NRI Faculty and Staff Publications

TFEB, a master regulator of autophagy and lysosomal biogenesis, is activated by several cellular stresses including lysosomal damage, but its underlying mechanism is unclear. TFEB activation during lysosomal damage depends on the ATG conjugation system, which mediates lipidation of ATG8 proteins. Here, we newly identify ATG conjugation-independent TFEB regulation that precedes ATG conjugation-dependent regulation, designated Modes I and II, respectively. We reveal unique regulators of TFEB in each mode: APEX1 in Mode I and CCT7 and/or TRIP6 in Mode II. APEX1 interacts with TFEB independently of the ATG conjugation system, and is required for TFEB stability, while both CCT7 and …

A Mast Cell Receptor Mediates Post-Stroke Brain Inflammation Via A Dural-Brain Axis, Ruchita Kothari, Mostafa W Abdulrahim, Hyun Jong Oh, Daniel H Capuzzi, Collin B Kilgore, Sumil K Nair, Yaowu Zhang, Nathachit Limjunyawong, Sarbjit S Saini, Jennifer E Kim, Justin M Caplan, Fernanado L Gonzalez, Christopher M Jackson, Chetan Bettegowda, Judy Huang, Bhanu P Ganesh, Chunfeng Tan, Raymond C Koehler, Rafael J Tamargo, Louise D Mccullough, Risheng Xu, Xinzhong Dong

Faculty, Staff and Student Publications

The immune environment surrounding the brain plays a fundamental role in monitoring signs of injury. Insults, including ischemic stroke, can disrupt this balance and incite an exaggerated inflammatory response, yet the underlying mechanism remains unclear. Here, we show that the mast-cell-specific receptor Mrgprb2 regulates post-stroke brain inflammation from the meninges. Mrgprb2 causes meningeal mast cell degranulation after stroke, releasing immune mediators. This process recruits skull bone marrow neutrophils into the dura and further promotes neutrophil migration from the dura into the brain by cleaving the chemorepellent semaphorin 3a. We demonstrate that the human ortholog, MRGPRX2, is expressed in human meningeal …

Preclinical Models Of Melanoma Leptomeningeal Disease To Assess Intrathecal Checkpoint Blockade, Renato A Guerrieri, Grant M Fischer, Jacob R Cortez, Barbara G Knighton, Debora A Ledesma, Courtney W Hudgens, Yimmy F Delcid, Qianghua Hu, Christian Y B Onana, Fernando C L Carapeto, Michael T Tezlaff, Jason T Huse, Patrick Hwu, Elizabeth M Burton, Isabella C Glitza Oliva, Michael A Davies, Sherise D Ferguson

Faculty, Staff and Student Publications

Leptomeningeal disease (LMD) is a subtype of central nervous system metastatic disease that is associated with poor patient outcomes and limited treatment options. There is an unmet need to develop preclinical models of LMD to expedite and improve the development of new therapeutics. Here, we describe the development of multiple orthotopic immunocompetent murine models of melanoma LMD, including their use to assess the efficacy of systemic and/or intrathecal immunotherapy. LMD was established by direct intrathecal injection of murine cell lines (B16-F10, BP, D4M, D4M-UV2, MC38-gp100, RMS, YUMM3.1, and YUMMER1.7) into the cisterna magna of C57BL/6 mice. Tumor take rate, distribution, …

Adeno-Associated Virus-Mediated Silencing Of Sox4 Leads To Long-Term Amelioration Of Liver Phenotypes In Mouse Models Of Alagille Syndrome, Duncan Fox, Jun Xie, Jennifer L Burwinkel, Josh M Adams, Kashish Chetal, Marzieh Keivandarian, Yaniv Faingelernt, Sanjay Subramanian, Mario F Lopez, Anna L Peters, Nathan Salomonis, Neda Zarrin-Khameh, Guangping Gao, Stacey S Huppert, Hamed Jafar-Nejad

Faculty, Staff and Students Publications

Background & aims: In patients with Alagille syndrome (ALGS), bile duct paucity often leads to severe cholestatic phenotypes for which liver transplantation remains the only definitive treatment. No Food and Drug Administration-approved mechanism-based strategies exist to enhance biliary development in ALGS or other diseases with bile duct paucity. We aimed to identify a therapeutic target to address this unmet need.

Methods: Preclinical ALGS mouse models lacking 1 copy of Jag1 with or without conditional deletion of 1 or both copies of Sox9 were used. Sox4 levels were reduced genetically or with adeno-associated virus 8 (AAV8) vectors driving a Sox4-silencing sequence. …

Site-Specific Drug Release Of Monomethyl Fumarate To Treat Oxidative Stress Disorders, Thomas D Avery, Jiahe Li, Dion J L Turner, Mohd S U Rasheed, Fisher R Cherry, Damian L Stachura, Fátima Rivera-Escalera, David M Ruiz, Michael J Lacagnina, Caitlyn M Gaffney, Clarissa Aguilar, Jingxian Yu, Yang Wang, Huan Xie, Dong Liang, Andrew J Shepherd, Andrew D Abell, Peter M Grace

Faculty, Staff and Student Publications

Treatment of diseases of oxidative stress through activation of the antioxidant nuclear factor E2-related factor 2 (NRF2) is limited by systemic side effects. We chemically functionalize the NRF2 activator monomethyl fumarate to require Baeyer-Villiger oxidation for release of the active drug at sites of oxidative stress. This prodrug reverses chronic pain in mice with reduced side effects and could be applied to other disorders of oxidative stress.

Pka-Driven Spp1 Activation As A Novel Mechanism Connecting The Bone Microenvironment To Prostate Cancer Progression, Pablo Sanchis, Agustina Sabater, Julia Lechuga, Jimena Rada, Rocio Seniuk, Gaston Pascual, Mora Gatti, Juan Bizzotto, Peter D A Shepherd, Jun Yang, Javier Cotignola, Elba Vazquez, Joaquin Mateo, Pia Valacco, Estefania Labanca, Christopher Logothetis, Geraldine Gueron, Nicolas Anselmino

Faculty, Staff and Student Publications

Prostate cancer (PCa) bone metastasis (BM) poses a significant clinical challenge due to the heterogeneity of treatment responses and patient outcomes. In this study, we examined the role of Protein Kinase A (PKA) signaling in modulating the expression of osteopontin (SPP1/OPN), a protein associated with poor prognosis, within a subset of PCa BM patients. By integrating multi-omics results we identified a novel mechanism in which bone-derived type-I collagen (Col1a1) and fibronectin (Fn1) stimulate SPP1 expression in PCa cells through the activation of PKA signaling. This bone-induced regulation of SPP1 was confirmed both in vitro, using PCa-bone co-culture systems (PC3 or …

Cancer-Induced Nerve Injury Promotes Resistance To Anti-Pd-1 Therapy, Erez N Baruch, Frederico O Gleber-Netto, Priyadharsini Nagarajan, Xiayu Rao, Shamima Akhter, Tuany Eichwald, Tongxin Xie, Mohammad Balood, Adebayo Adewale, Shorook Naara, Hinduja N Sathishkumar, Shajedul Islam, William Mccarthy, Brandi J Mattson, Renata Ferrarotto, Michael K Wong, Michael A Davies, Sonali Jindal, Sreyashi Basu, Karine Roversi, Amin Reza Nikpoor, Maryam Ahmadi, Ali Ahmadi, Catherine Harwood, Irene Leigh, Dennis Gong, Paulino Tallón De Lara, Derrick L Tao, Tara M Davidson, Nadim J Ajami, Andrew Futreal, Kunal Rai, Veena Kochat, Micah Castillo, Preethi Gunaratne, Ryan P Goepfert, Sharia D Hernandez, Nikhil I Khushalani, Jing Wang, Stephanie S Watowich, George A Calin, Michael R Migden, Mona Yuan, Naijiang Liu, Yi Ye, William L Hwang, Paola D Vermeer, Nisha J D'Silva, Yuri L Bunimovich, Dan Yaniv, Jared K Burks, Javier Gomez, Patrick M Dougherty, Kenneth Y Tsai, James P Allison, Padmanee Sharma, Jennifer A Wargo, Jeffrey N Myers, Sebastien Talbot, Neil D Gross, Moran Amit

Faculty, Staff and Student Publications

Perineural invasion (PNI) is a well-established factor of poor prognosis in multiple cancer types1, yet its mechanism remains unclear. Here we provide clinical and mechanistic insights into the role of PNI and cancer-induced nerve injury (CINI) in resistance to anti-PD-1 therapy. Our study demonstrates that PNI and CINI of tumour-associated nerves are associated with poor response to anti-PD-1 therapy among patients with cutaneous squamous cell carcinoma, melanoma and gastric cancer. Electron microscopy and electrical conduction analyses reveal that cancer cells degrade the nerve fibre myelin sheets. The injured neurons respond by autonomously initiating IL-6- and type I interferon-mediated …

Inhibition Of Ros1 Activity With Lorlatinib Reversibly Suppresses Fertility In Male Mice, Yuki Oyama, Kentaro Shimada, Haruhiko Miyata, Rie Iida-Norita, Chihiro Emori, Maki Kamoshita, Seiya Oura, Ryohei Katayama, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Background: Inhibition of sperm maturation in the epididymis is a promising post-testicular strategy for short-acting male contraceptives. It has been shown that ROS1, a receptor tyrosine kinase expressed in the epididymis, is essential for epididymal differentiation, sperm maturation, and male fertility in mice. However, it is unknown if inhibition of ROS1 suppresses male fertility reversibly.

Objectives: Our study aimed to investigate the effects of ROS1 inhibitor administration in male mice on sperm function and fertility.

Materials and methods: We used lorlatinib, an anti-cancer drug that inhibits ROS1. We treated 10-week-old sexually mature male mice with lorlatinib for 3 weeks and …

Normal Urinary Oxalate Excretion In 4-Hydroxy-2-Oxo-Glutarate Aldolase 1 (Hoga1) Deficient Mice With Agt Expression In Peroxisomes And Not In Mitochondria, Iolanda Boffa, Rosa Ferriero, Mariarosaria Cancelliere, Edoardo Nusco, Leonardo Gatticchi, Donna Palmer, Philip Ng, Pasquale Piccolo, Barbara Cellini, Kyle Wood, John Knight, Nicola Brunetti-Pierri

Faculty, Staff and Students Publications

Primary hyperoxaluria type 3 (PH3) is caused by mutations in Hoga1 gene. PH3 individuals develop nephrolithiasis, but the mechanism underlying hyperoxaluria is unclear and a mouse model recapitulating the human disease can provide insights into the pathogenesis of PH3. Hoga1−/− mice do not have increased urinary oxalate excretion, probably due to the murine mitochondrial alanine-glioxylate-aminotransferase (AGT) activity, which in humans is only expressed in peroxisomes. However, Hoga1−/−/Agxt−/− mice with AGT installed on peroxisome and not on mitochondria did not show increased urinary oxalate, suggesting that AGT expression in both cellular compartments is not an explanation for …

Aging In Mice Alters Regionally Enriched Striatal Astrocytes, Kay E Linker, Violeta Duran-Laforet, Matthias Ollivier, Xinzhu Yu, Dorothy P Schafer, Baljit S Khakh

Faculty, Staff and Student Publications

Aging affects multiple organs and within the brain drives distinct molecular changes across different cell types. The striatum encodes motor behaviors that decline with age, but our understanding of how cells within the striatum change remains incomplete. Using single-cell RNA sequencing from young and aged mice we identify molecularly distinct astrocyte subtypes. We show that astrocytes change significantly with age, exhibiting downregulation of genes, reduced diversity, and a shift to more homogenous inflammatory transcriptomic profiles. By exploring where striatal astrocyte subtypes are located with single-cell resolution, we map astrocytes enriched in dorsal, medial, and ventral striatum. Age increases inflammatory marker …

Distinct Intrinsic And Extrinsic Factors Differentially Regulate Skeletal Stem Cells In Calvaria Versus Long Bones During Bone Regeneration, Jea Solidum, Kohei Yamasaki, Youngjae Jeong, Laura Ortinau, Francisco Heralde, Dongsu Park

Faculty, Staff and Students Publications

Calvarial suture skeletal stem cells (Su-SSCs) are a distinct stem cell population for craniofacial bone formation by intramembranous ossification, compared to long bone periosteal SSCs (LB-PSSCs) with endochondral (osteochondrogenic) ossification. However, whether SSC intrinsic or extrinsic factors affect their differentiation process has not been well elucidated. Here, using an inducible Prx1-CreER-EGFP+/−;Rosa26-tdTomato mouse model, we observed that endogenous Prx1+ Su-SSCs and their orthotopic transplantation into calvarial injury do not form cartilage intermediates at the injury sites, while the transplantation of Prx1+ LB-PSSCs into LB injury induces osteochondrogenic differentiation, respectively. However, the heterotopic transplantation of Prx1+ Su-SSCs (Su-SSCs …

Kmt2d Temporally Activates Neuronal Transcriptional Factor Genes To Mediate Cerebellar Granule Cell Differentiation, Shilpa S Dhar, Kyung-Pil Ko, Jinho Jang, Calena Brown-Abel, Tao Lin, Sharad Awasthi, Kaifu Chen, Roy V Sillitoe, Jae-Il Park, Min Gyu Lee

Duncan NRI Faculty and Staff Publications

Spatiotemporal gene expression is the fundamental feature of cellular differentiation, including neuron differentiation. The epigenetic mechanism underlying spatiotemporal gene regulation during in vivo neuron differentiation remains largely unknown. Granule cells (GCs) constitute the vast majority of neurons in the cerebellum, which contains most of neurons in the brain. Here, we show that

Adsl Deficiency Is A Secondary Mitochondrial Disease Affecting Organelle Homeostasis And Erk2/Akt Signaling In A Linear Genotype-Phenotype Relation, Matteo Bordi, Beatrice Testa, Claudia Compagnucci, Fiorella Colasuonno, Francesca Cipressa, Elisabetta Betterini, Andrea Mancini, Claudia Carsetti, Illari Salvatori, Caterina Ferraina, Ming Yang, Rossella De Cegli, Eugenio Del Prete, Chiara Veroni, Salvatore Rizza, Sofia Mauri, Elena Ziviani, Marina Macchiaiolo, Davide Vecchio, Filippo Maria Panfili, Teresa Rizza, Gerrit Weber, Rosalba Carrozzo, Alberto Ferri, Silvia Campello, Andrea Ballabio, Christian Frezza, Gianluca Cestra, Marco Tartaglia, Andrea Bartuli, Francesco Cecconi

Duncan NRI Faculty and Staff Publications

Adenylosuccinate lyase deficiency (ADSLd) is a rare autosomal recessive purine metabolism disorder with several clinical manifestations. While toxic substrate accumulation is a known hallmark, no additional molecular mechanisms have been established. Here, we show that ADSLd is associated with mitochondrial dysfunction, including increased fragmentation, impaired respiration, and reduced ATP production. The severity of mitochondrial impairment correlates with ADSLd pathology, especially in mitochondria-dependent tissues. We also identify defects in mitochondrial dynamics and transport linked to ERK2 and AKT suppression. Notably, overexpressing constitutively active ERK2 or supplementing purine intermediates partially rescues the mitochondrial phenotype. These findings suggest an alternative disease mechanism and …

Next-Gen Tools In Cancer Neuroscience, Vera Thiel, Debpali Sur, Caroline C Picoli, Tamara Mcerlain, Katalina Couto, David J Simon, Yuan Pan, Karen Olivia Dixon, Rajan P Kulkarni, Sebastien Talbot, Alexander Birbrair

Faculty, Staff and Student Publications

The emerging field of cancer neuroscience is rapidly evolving, driven by novel technologies and tools. These include advances in single-cell and spatial transcriptomics; genetic mouse models paired with automated high-throughput; and innovative optical electrophysiological approaches, optogenetics, chemogenetics, engineered viruses, and new methods for visualizing neuronal activity. Collectively, these technologies are revolutionizing how we investigate, manipulate, and characterize distinct components that contribute to the nervous system-cancer interface. In the present review, we discuss the key technologies that are closing the gap between oncology and neuroscience, highlighting the innovations that are propelling the cancer neuroscience field forward.

Rna/Dna-Binding Protein Tdp43 Regulates Dna Mismatch Repair Genes With Implications For Genome Stability, Vincent E Provasek, Albino Bacolla, Suganya Rangaswamy, Manohar Kodavati, Joy Mitra, Issa O Yusuf, Vikas H Malojirao, Velmarini Vasquez, Gavin W Britz, Guo-Min Li, Zuoshang Xu, Sankar Mitra, Ralph M Garruto, John A Tainer, Muralidhar L Hegde

Faculty, Staff and Student Publications

TDP43 is an RNA/DNA-binding protein increasingly recognized for its role in neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to detrimental cytosolic aggregates and a reduction in nuclear functionality in neurons. Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expression. Here, we show that TDP43 depletion or overexpression …

Blue-Shifted Ancyromonad Channelrhodopsins For Multiplex Optogenetics, Elena G Govorunova, Oleg A Sineshchekov, Hai Li, Yueyang Gou, Hongmei Chen, Shuyuan Yang, Yumei Wang, Stephen Mitchell, Alyssa Palmateer, Leonid S Brown, François St-Pierre, Mingshan Xue, John L Spudich

Duncan NRI Faculty and Staff Publications

Light-gated ion channels from protists (channelrhodopsins or ChRs) are optogenetic tools widely used for controlling neurons and cardiomyocytes. Multiplex optogenetic applications require spectrally separated molecules, which are difficult to engineer without disrupting channel function. Scanning numerous sequence databases, we identified three naturally blue-shifted ChRs from ancyromonads. They form a separate branch on the phylogenetic tree and contain residue motifs characteristic of anion ChRs (ACRs). However, only two conduct chloride, whereas the closely related Nutomonas longa homolog generates inward cation currents in mammalian cells under physiological conditions, significantly exceeding those by previously known tools with similar spectral maxima (peak absorption at …

Galntl5 Binds Galnac And Is Required For Migration Through The Uterotubal Junction And Sperm-Zona Pellucida Binding, Taichi Noda, Reika Uriu, Daisuke Mashiko, Hina Shinohara, Yongcun Qu, Ayumu Taira, Ryan M Matzuk, Duri Tahala, Motochika Nakano, Kimi Araki, Zhifeng Yu, Ying Zhang, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Objective: To review the global impact of the COVID-19 pandemic on stroke care-metrics and report data from a health system in Houston.

Methods: We performed a meta-analysis of the published literature reporting stroke admissions, intracerebral hemorrhage (ICH) cases, number of thrombolysis (tPA) and thrombectomy (MT) cases, and time metrics (door to needle, DTN; and door to groin time, DTG) during the pandemic compared to prepandemic period. Within our hospital system, between January-June 2019 and January-June 2020, we compared the proportion of stroke admissions and door to tPA and MT times.

Results: A total of 32,640 stroke admissions from 29 studies …

Elevated Nr2f1 Underlies The Persistence Of Invasive Disease After Treatment Of Braf-Mutant Melanoma, Manoela Tiago, Timothy J Purwin, Casey D Stefanski, Renaira Oliveira Da Silva, Mitchell E Fane, Yash Chhabra, Jelan I Haj, Jessica Lf Teh, Rama Kadamb, Weijia Cai, Sheera R Rosenbaum, Vivian Chua, Nir Hacohen, Michael A Davies, Jessie Villanueva, Inna Chervoneva, Ashani T Weeraratna, Dan A Erkes, Claudia Capparelli, Julio A Aguirre-Ghiso, Andrew E Aplin

Faculty, Staff and Student Publications

Despite the success of targeted inhibitors in cutaneous melanoma, therapeutic responses are limited by the aged tumor microenvironment and drug-tolerant residual cells. Given the similarities between drug tolerance and cellular dormancy, we studied the dormancy marker, nuclear receptor subfamily 2 group F member 1 (NR2F1), in response to BRAF-V600E inhibitors (BRAFi) plus MEK inhibitors (MEKi) in BRAF-mutant melanoma models. Transcriptomic analysis of melanoma patient samples treated with BRAFi + MEKi showed increased NR2F1. NR2F1 was highly expressed in the drug-tolerant invasive cell state of minimal residual disease in patient-derived and mouse-derived xenografts on BRAFi + MEKi. NR2F1 over-expression was sufficient …

Setd2 Suppresses Tumorigenesis In A Krasg12c-Driven Lung Cancer Model, And Its Catalytic Activity Is Regulated By Histone Acetylation, Ricardo J Mack, Natasha M Flores, Geoffrey C Fox, Hanyang Dong, Metehan Cebeci, Simone Hausmann, Tourkian Chasan, Jill M Dowen, Brian D Strahl, Pawel K Mazur, Or Gozani

Faculty, Staff and Student Publications

Histone H3 trimethylation at lysine 36 (H3K36me3) is a key chromatin modification that regulates fundamental physiological and pathological processes. In humans, SETD2 is the only known enzyme that catalyzes H3K36me3 in somatic cells and is implicated in tumor suppression across multiple cancer types. While there is considerable crosstalk between the SETD2-H3K36me3 axis and other epigenetic modifications, much remains to be understood. Here, we show that Setd2 functions as a potent tumor suppressor in a KRASG12C-driven lung adenocarcinoma (LUAD) mouse model, and that acetylation enhances SETD2 in vitro methylation of H3K36 on nucleosome substrates. In vivo, Setd2 ablation accelerates lethality in …

Developmental Transformations Of Purkinje Cells Tracked By Dna Electrokinetic Mobility, Cheryl Brandenburg, Garrett W Crutcher, Andrea J Romanowski, Sarah G Donofrio, Lita R Duraine, Richard N A Owusu-Mensah, Benjamin H Cooper, Izumi Sugihara, Gene J Blatt, Roy V Sillitoe, Alexandros Poulopoulos

Duncan NRI Faculty and Staff Publications

Brain development begins with neurogenesis in progenitor zones and ends with expansive, intricately-patterned cellular diversity in the adult brain. We took advantage of bioelectric interactions between DNA and embryonic tissue to perform "stereo-tracking," a developmental targeting strategy that differentially labels cells at different depths within progenitor zones. This 3D labeling was achieved by delivery of plasmids with distinct electrokinetic mobilities in utero. We applied stereo-tracking with light sheet imaging in the cerebellum and identified that Purkinje cells follow embryonically committed developmental trajectories, linking distinct progenitor zone subfields to the mature topography of the cerebellar cortex. We additionally identified an unexpected …

Infusion Of Blood From Young And Old Mice Modulates Amyloid Pathology, Matias Pizarro, Ruben Gomez-Gutierrez, Ariel Caviedes, Catalina Valdes, Ute Woehlbier, Cristian Vargas, Mauricio Hernandez, Claudia Duran-Aniotz, Rodrigo Morales

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the accumulation of misfolded proteins in the brain. Recently, the impact of blood components in the progression of this disease has come to attention. This study investigates the effects of infusing blood from young and old wild-type mice into transgenic mice that model AD brain amyloidosis. Impaired memory and Aβ accumulation were observed in mice infused with blood from old donors. A proteomic analysis in the brain of these mice identified alterations in components related to synaptogenesis and the endocannabinoid system. The α2δ2 protein, associated with neuronal calcium regulation, was validated …

Loss Of Ptdss1 In Tumor Cells Improves Immunogenicity And Response To Anti-Pd-1 Therapy, Jielin Liu, Shelley Herbrich, Sreyashi Basu, Yulong Chen, Ashwat Nagarajan, Swetha Anandhan, Sangeeta Goswami, Liangwen Xiong, Baoxiang Guan, Padmanee Sharma

Faculty, Staff and Student Publications

PTDSS1 (phosphatidylserine synthase 1) encodes an enzyme that facilitates production of phosphatidylserine (PS), which mediates a global immunosuppressive signal. Here, based on in vivo CRISPR screen, we identified PTDSS1 as a target to improve anti-PD-1 therapy. Depletion of Ptdss1 in tumor cells increased expression of interferon-γ (IFN-γ)-regulated genes, including B2m, Cxcl9, Cxcl10, and Stat1, even in the absence of IFN-γ stimulation in vitro. Loss of Ptdss1 in tumor cells also led to increased expression of MHC-I, enhanced cytotoxicity of CD8+ T cells, and increased frequency of an iNOS+ myeloid subset. A gene signature derived from the …

Computationally Resolved Neuroprogenitor Cell Biomarkers Associate With Human Disorders, Gerarda Cappuccio, William T Choi, Fatih Semerci, Jill A Rosenfeld, Toni Claire Tacorda, Guantong Qi, Anthony W Zoghbi, Yi Zhong, Hu Chen, Pengfei Liu, Zhandong Liu, Mirjana Maletić-Savatić

Duncan NRI Faculty and Staff Publications

Adult hippocampal neurogenesis, the process of generating new neurons, relies on a rare population of neural stem and progenitor cells (NPCs) within the dentate gyrus complex microenvironment. Discovering the specific genes that define these cells is vital yet challenging due to overlapping expression patterns, limiting detection of rare cell populations using traditional approaches. By employing the computational digital sorting algorithm (DSA) that deconvolves complex gene expression data based on pattern recognition, we identified 129 genes enriched in murine NPCs. We validated these genes against published single-cell RNA sequencing (scRNA-seq) data and discovered that 25 human orthologs were known to cause …

Human Papillomavirus Integration Induces Oncogenic Host Gene Fusions In Oropharyngeal Cancers, Nusrat Khan, Keiko Akagi, Shiming Jiang, Joe Dan Dunn, Bo Jiang, Weihong Xiao, Madison P O'Hara, Li Shen, Qi Wang, Vakul Mohanty, Jing Wang, Sara Goodwin, Jamie L Hutchins, Kevin R Coombes, Jagannadha K Sastry, David E Symer, Maura L Gillison

Faculty, Staff and Student Publications

HPV integration disrupts host genomic structure and expression, but whether these alterations promote cancer development remains unclear. Multiple genomic analyses of oropharyngeal cancers identified several host fusion genes, including recurrent FGFR3-TACC3 fusions, expressed from rearranged genomic loci adjacent to HPV integration sites. Evolutionary modeling implicated integration of virus concatemers into the host genome as a common initiating event in fusion formation. Co-expression of HPV16 E6/E7 and FGFR3-TACC3, but neither alone, was sufficient for tumor development in both xenograft and syngeneic mouse models and led to unique transcriptional programs implicated in carcinogenesis. FGFR3-TACC3 expression decreased the ubiquitination and degradation of …