Genetic Phenomena Commons^™

Astrocyte-Induced Cdk5 Expedites Breast Cancer Brain Metastasis By Suppressing Mhc-I Expression To Evade Immune Recognition, Arseniy E Yuzhalin, Frank J Lowery, Yohei Saito, Xiangliang Yuan, Jun Yao, Yimin Duan, Jingzhen Ding, Sunil Acharya, Chenyu Zhang, Abigail Fajardo, Hao-Nien Chen, Yongkun Wei, Yutong Sun, Lin Zhang, Yi Xiao, Ping Li, Philip L Lorenzi, Jason T Huse, Huihui Fan, Zhongming Zhao, Mien-Chie Hung, Dihua Yu

Faculty, Staff and Student Publications

Brain metastases (BrMs) evade the immune response to develop in the brain, yet the mechanisms of BrM immune evasion remains unclear. This study shows that brain astrocytes induce the overexpression of neuronal-specific cyclin-dependent kinase 5 (Cdk5) in breast cancer-derived BrMs, which facilitates BrM outgrowth in mice. Cdk5-overexpressing BrMs exhibit reduced expression and function of the class I major histocompatibility complex (MHC-I) and antigen-presentation pathway, which are restored by inhibiting Cdk5 genetically or pharmacologically, as evidenced by single-cell RNA sequencing and functional studies. Mechanistically, Cdk5 suppresses MHC-I expression on the cancer cell membrane through the Irf2bp1-Stat1-importin α-Nlrc5 pathway, enabling BrMs to …

Targeting The Peripheral Neural-Tumour Microenvironment For Cancer Therapy, Dan Yaniv, Brandi Mattson, Sebastien Talbot, Frederico O Gleber-Netto, Moran Amit

Faculty, Staff and Student Publications

As the field of cancer neuroscience expands, the strategic targeting of interactions between neurons, cancer cells and other elements in the tumour microenvironment represents a potential paradigm shift in cancer treatment, comparable to the advent of our current understanding of tumour immunology. Cancer cells actively release growth factors that stimulate tumour neo-neurogenesis, and accumulating evidence indicates that tumour neo-innervation propels tumour progression, inhibits tumour-related pro-inflammatory cytokines, promotes neovascularization, facilitates metastasis and regulates immune exhaustion and evasion. In this Review, we give an up-to-date overview of the dynamics of the tumour microenvironment with an emphasis on tumour innervation by the peripheral …

Inhibition Of Hepatic Oxalate Overproduction Ameliorates Metabolic Dysfunction-Associated Steatohepatitis, Sandeep Das, Alexandra C Finney, Sumit Kumar Anand, Sumati Rohilla, Yuhao Liu, Nilesh Pandey, Alia Ghrayeb, Dhananjay Kumar, Kelley Nunez, Zhipeng Liu, Fabio Arias, Ying Zhao, Brenna H Pearson-Gallion, M Peyton Mckinney, Koral S E Richard, Jose A Gomez-Vidal, Chowdhury S Abdullah, Elizabeth D Cockerham, Joseph Eniafe, Andrew D Yurochko, Tarek Magdy, Christopher B Pattillo, Christopher G Kevil, Babak Razani, Md Shenuarin Bhuiyan, Erin H Seeley, Gretchen E Galliano, Bo Wei, Lin Tan, Iqbal Mahmud, Ida Surakka, Minerva T Garcia-Barrio, Philip L Lorenzi, Eyal Gottlieb, Eduardo Salido, Jifeng Zhang, A Wayne Orr, Wanqing Liu, Monica Diaz-Gavilan, Y Eugene Chen, Nirav Dhanesha, Paul T Thevenot, Ari J Cohen, Arif Yurdagul, Oren Rom

Faculty, Staff and Student Publications

The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. Here we show that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator-activated receptor-α (PPARα) transcription and fatty acid β-oxidation and induces monocyte chemotaxis via C-C motif chemokine ligand 2. In …

Temporal Recording Of Mammalian Development And Precancer, Mirazul Islam, Yilin Yang, Alan J Simmons, Vishal M Shah, Krushna Pavan Musale, Yanwen Xu, Naila Tasneem, Zhengyi Chen, Linh T Trinh, Paola Molina, Marisol A Ramirez-Solano, Iannish D Sadien, Jinzhuang Dou, Andrea Rolong, Ken Chen, Mark A Magnuson, Jeffrey C Rathmell, Ian G Macara, Douglas J Winton, Qi Liu, Hamim Zafar, Reza Kalhor, George M Church, Martha J Shrubsole, Robert J Coffey, Ken S Lau

Faculty, Staff and Student Publications

Temporal ordering of cellular events offers fundamental insights into biological phenomena. Although this is traditionally achieved through continuous direct observations1,2, an alternative solution leverages irreversible genetic changes, such as naturally occurring mutations, to create indelible marks that enables retrospective temporal ordering3–5. Using a multipurpose, single-cell CRISPR platform, we developed a molecular clock approach to record the timing of cellular events and clonality in vivo, with incorporation of cell state and lineage information. Using this approach, we uncovered precise timing of tissue-specific cell expansion during mouse embryonic development, unconventional developmental relationships between cell …

Development Of An Engineered Extracellular Vesicles-Based Vaccine Platform For Combined Delivery Of Mrna And Protein To Induce Functional Immunity, Xin Luo, Kathleen M Mcandrews, Kent A Arian, Sami J Morse, Viktoria Boeker, Shreyasee V Kumbhar, Yingying Hu, Krishnan K Mahadevan, Kaira A Church, Sriram Chitta, Nicolas T Ryujin, Janine Hensel, Jianli Dai, Dara P Dowlatshahi, Hikaru Sugimoto, Michelle L Kirtley, Valerie S Lebleu, Shabnam Shalapour, Joe H Simmons, Raghu Kalluri

Faculty, Staff and Student Publications

mRNA incorporated in lipid nanoparticles (LNPs) became a new class of vaccine modality for induction of immunity against COVID-19 and ushered in a new era in vaccine development. Here, we report a novel, easy-to-execute, and cost effective engineered extracellular vesicles (EVs)-based combined mRNA and protein vaccine platform (EVX-M+P vaccine) and explore its utility in proof-of-concept immunity studies in the settings of cancer and infectious disease. As a first example, we engineered EVs, natural nanoparticle carriers shed by all cells, to contain ovalbumin mRNA and protein (EVOvaM+P vaccine) to serve as cancer vaccine against ovalbumin-expressing melanoma tumors. EVOvaM+P administration to mice …

Usf2 And Tfeb Compete In Regulating Lysosomal And Autophagy Genes, Jaebeom Kim, Young Suk Yu, Yehwa Choi, Do Hui Lee, Soobin Han, Junhee Kwon, Taichi Noda, Masahito Ikawa, Dongha Kim, Hyunkyung Kim, Andrea Ballabio, Keun Il Kim, Sung Hee Baek

Duncan NRI Faculty and Staff Publications

Autophagy, a highly conserved self-digestion process crucial for cellular homeostasis, is triggered by various environmental signals, including nutrient scarcity. The regulation of lysosomal and autophagy-related processes is pivotal to maintaining cellular homeostasis and basal metabolism. The consequences of disrupting or diminishing lysosomal and autophagy systems have been investigated; however, information on the implications of hyperactivating lysosomal and autophagy genes on homeostasis is limited. Here, we present a mechanism of transcriptional repression involving upstream stimulatory factor 2 (USF2), which inhibits lysosomal and autophagy genes under nutrient-rich conditions. We find that USF2, together with HDAC1, binds to the CLEAR motif within lysosomal …

B Cells Drive Neuropathic Pain-Related Behaviors In Mice Through Igg-Fc Gamma Receptor Signaling, Michael J Lacagnina, Kendal F Willcox, Nabila Boukelmoune, Alexis Bavencoffe, Ishwarya Sankaranarayanan, Daniel T Barratt, Younus A Zuberi, Dorsa Dayani, Melissa V Chavez, Jonathan T Lu, Alex Bersellini Farinotti, Stephanie Shiers, Allison M Barry, Juliet M Mwirigi, Diana Tavares-Ferreira, Geoffrey A Funk, Anna M Cervantes, Camilla I Svensson, Edgar T Walters, Mark R Hutchinson, Cobi J Heijnen, Theodore J Price, Nathan T Fiore, Peter M Grace

Faculty, Staff and Student Publications

Neuroimmune interactions are essential for the development of neuropathic pain, yet the contributions of distinct immune cell populations have not been fully unraveled. Here, we demonstrate the critical role of B cells in promoting mechanical hypersensitivity (allodynia) after peripheral nerve injury in male and female mice. Depletion of B cells with a single injection of anti-CD20 monoclonal antibody at the time of injury prevented the development of allodynia. B cell-deficient (muMT) mice were similarly spared from allodynia. Nerve injury was associated with increased immunoglobulin G (IgG) accumulation in ipsilateral lumbar dorsal root ganglia (DRGs) and dorsal spinal cords. IgG was …

Stimulation Of An Entorhinal-Hippocampal Extinction Circuit Facilitates Fear Extinction In A Post-Traumatic Stress Disorder Model, Ze-Jie Lin, Xue Gu, Wan-Kun Gong, Mo Wang, Yan-Jiao Wu, Qi Wang, Xin-Rong Wu, Xin-Yu Zhao, Michael X Zhu, Lu-Yang Wang, Quanying Liu, Ti-Fei Yuan, Wei-Guang Li, Tian-Le Xu

Faculty, Staff and Student Publications

Effective psychotherapy of post-traumatic stress disorder (PTSD) remains challenging owing to the fragile nature of fear extinction, for which the ventral hippocampal CA1 (vCA1) region is considered as a central hub. However, neither the core pathway nor the cellular mechanisms involved in implementing extinction are known. Here, we unveil a direct pathway, where layer 2a fan cells in the lateral entorhinal cortex (LEC) target parvalbumin-expressing interneurons (PV-INs) in the vCA1 region to propel low-gamma-band synchronization of the LEC-vCA1 activity during extinction learning. Bidirectional manipulations of either hippocampal PV-INs or LEC fan cells sufficed for fear extinction. Gamma entrainment of vCA1 …

In Vivo Crispr Screens Identify Mga As An Immunotherapy Target In Triple-Negative Breast Cancer, Xu Feng, Chang Yang, Yuanjian Huang, Dan Su, Chao Wang, Lori Lyn Wilson, Ling Yin, Mengfan Tang, Siting Li, Zhen Chen, Dandan Zhu, Shimin Wang, Shengzhe Zhang, Jie Zhang, Huimin Zhang, Litong Nie, Min Huang, Jae-Il Park, Traver Hart, Dadi Jiang, Kuirong Jiang, Junjie Chen

Faculty, Staff and Student Publications

Understanding the mechanisms underlying immune evasion is crucial for developing novel anticancer modalities. To systematically uncover tumor-intrinsic genetic modulators involved in immune escape in tumor microenvironment, we performed genome-scale in vivo CRISPR screens in two syngeneic models and later expanded up to seven syngeneic models with a focused validation library. These data help us better understand tumor immune evasion and pave the way for developing effective therapeutics. Importantly, we uncovered that Mga depletion elicited an antitumor immune response and inhibited tumor growth in triple-negative breast cancer. Our findings suggest that Mga may play a role in modulating the tumor immune …

Strategic Stabilization Of Arousal Boosts Sustained Attention, Jan Willem De Gee, Zakir Mridha, Marisa Hudson, Yanchen Shi, Hannah Ramsaywak, Spencer Smith, Nishad Karediya, Matthew Thompson, Kit Jaspe, Hong Jiang, Wenhao Zhang, Matthew J Mcginley

Duncan NRI Faculty and Staff Publications

Arousal and motivation interact to profoundly influence behavior. For example, experience tells us that we have some capacity to control our arousal when appropriately motivated, such as staying awake while driving a motor vehicle. However, little is known about how arousal and motivation jointly influence decision computations, including if and how animals, such as rodents, adapt their arousal state to their needs. Here, we developed and show results from an auditory, feature-based, sustained-attention task with intermittently shifting task utility. We use pupil size to estimate arousal across a wide range of states and apply tailored signal detection theoretic, hazard function …

Protocol For Establishing And Evaluating A Cancer Cachexia Mouse Model, Zhijun Zhou, Jingxuan Yang, Mingyang Liu, Yu Ren, Xiuhui Shi, Yang Cai, Alex X Arreola, Yi-Ping Li, Yuqing Zhang, Min Li

Faculty, Staff and Student Publications

Cancer cachexia mouse models are needed to recapitulate the clinical features of patients with cachexia. Here, we present a protocol for the establishment and evaluation of cancer cachexia mouse models. We delineate the steps in preparing tumor cells for inoculation and surgical procedures. After the establishment of these mouse models, we describe essential techniques to assess cancer cachexia, including grip strength evaluation, tissue collection, and the calculation of cross-sectional areas of muscle tissue. For complete details on the use and execution of this protocol, please refer to Liu et al.,

Tumor-Infiltrating Nerves Functionally Alter Brain Circuits And Modulate Behavior In A Mouse Model Of Head-And-Neck Cancer, Jeffrey Barr, Austin Walz, Anthony C Restaino, Moran Amit, Sarah M Barclay, Elisabeth G Vichaya, William C Spanos, Robert Dantzer, Sebastien Talbot, Paola D Vermeer

Faculty, Staff and Student Publications

Cancer patients often experience changes in mental health, prompting an exploration into whether nerves infiltrating tumors contribute to these alterations by impacting brain functions. Using a mouse model for head and neck cancer and neuronal tracing, we show that tumor-infiltrating nerves connect to distinct brain areas. The activation of this neuronal circuitry altered behaviors (decreased nest-building, increased latency to eat a cookie, and reduced wheel running). Tumor-infiltrating nociceptor neurons exhibited heightened calcium activity and brain regions receiving these neural projections showed elevated Fos as well as increased calcium responses compared to non-tumor-bearing counterparts. The genetic elimination of nociceptor neurons decreased …

Loss Of Hd-Ptp Function Results In Lipodystrophy, Defective Cellular Signaling And Altered Lipid Homeostasis, Destiny F Schultz, Brian A Davies, Johanna A Payne, Cole P Martin, Annabel Y Minard, Bennett G Childs, Cheng Zhang, Karthik B Jeganathan, Ines Sturmlechner, Thomas A White, Alain De Bruin, Liesbeth Harkema, Huiqin Chen, Michael A Davies, Sarah Jachim, Nathan K Lebrasseur, Robert C Piper, Hu Li, Darren J Baker, Jan Van Deursen, Daniel D Billadeau, David J Katzmann

Faculty, Staff and Student Publications

His domain protein tyrosine phosphatase (HD-PTP; also known as PTPN23) facilitates function of the endosomal sorting complexes required for transport (ESCRTs) during multivesicular body (MVB) formation. To uncover its role in physiological homeostasis, embryonic lethality caused by a complete lack of HD-PTP was bypassed through generation of hypomorphic mice expressing reduced protein, resulting in animals that are viable into adulthood. These mice exhibited marked lipodystrophy and decreased receptor-mediated signaling within white adipose tissue (WAT), involving multiple prominent pathways including RAS/MAPK, phosphoinositide 3-kinase (PI3K)/AKT and receptor tyrosine kinases (RTKs), such as EGFR. EGFR signaling was dissected in vitro to assess the …

Longitudinal Intravascular Antibody Labeling Identified Regulatory T Cell Recruitment As A Therapeutic Target In A Mouse Model Of Lung Cancer, Sean-Luc Shanahan, Nikesh Kunder, Charles Inaku, Natalie B Hagan, Grace Gibbons, Nicolas Mathey-Andrews, Gayathri Anandappa, Shawn Soares, Kristen E Pauken, Tyler Jacks, Jason M Schenkel

Faculty, Staff and Student Publications

Anticancer immunity is predicated on leukocyte migration into tumors. Once recruited, leukocytes undergo substantial reprogramming to adapt to the tumor microenvironment. A major challenge in the field is distinguishing recently recruited from resident leukocytes in tumors. In this study, we developed an intravascular Ab technique to label circulating mouse leukocytes before they migrate to tissues, providing unprecedented insight into the kinetics of recruitment. This approach unveiled the substantial role of leukocyte migration in tumor progression using a preclinical mouse model of lung adenocarcinoma. Regulatory T cells (Tregs), critical mediators of immunosuppression, were continuously and rapidly recruited into tumors throughout cancer …

Bacteroides Ovatus Alleviates Dysbiotic Microbiota-Induced Graft-Versus-Host Disease, Eiko Hayase, Tomo Hayase, Akash Mukherjee, Stuart C Stinson, Mohamed A Jamal, Miriam R Ortega, Christopher A Sanchez, Saira S Ahmed, Jennifer L Karmouch, Chia-Chi Chang, Ivonne I Flores, Lauren K Mcdaniel, Alexandria N Brown, Rawan K El-Himri, Valerie A Chapa, Lin Tan, Bao Q Tran, Yao Xiao, Christopher Fan, Dung Pham, Taylor M Halsey, Yimei Jin, Wen-Bin Tsai, Rishika Prasad, Israel K Glover, Altai Enkhbayar, Aqsa Mohammed, Maren Schmiester, Katherine Y King, Robert A Britton, Pavan Reddy, Matthew C Wong, Nadim J Ajami, Jennifer A Wargo, Samuel Shelburne, Pablo C Okhuysen, Chen Liu, Stephanie W Fowler, Margaret E Conner, Zoe Katsamakis, Natalie Smith, Marina Burgos Da Silva, Doris M Ponce, Jonathan U Peled, Marcel R M Van Den Brink, Christine B Peterson, Gabriela Rondon, Jeffrey J Molldrem, Richard E Champlin, Elizabeth J Shpall, Philip L Lorenzi, Rohtesh S Mehta, Eric C Martens, Amin M Alousi, Robert R Jenq

Faculty, Staff and Student Publications

Acute lower gastrointestinal GVHD (aLGI-GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation. Although the intestinal microbiota is associated with the incidence of aLGI-GVHD, how the intestinal microbiota impacts treatment responses in aLGI-GVHD has not been thoroughly studied. In a cohort of patients with aLGI-GVHD (n = 37), we found that non-response to standard therapy with corticosteroids was associated with prior treatment with carbapenem antibiotics and a disrupted fecal microbiome characterized by reduced abundances of Bacteroides ovatus. In a murine GVHD model aggravated by carbapenem antibiotics, introducing B. ovatus reduced GVHD severity and improved survival. These beneficial effects …

Batf Is A Major Driver Of Nk Cell Epigenetic Reprogramming And Dysfunction In Aml, Bijender Kumar, Anand Singh, Rafet Basar, Nadima Uprety, Ye Li, Huihui Fan, Ana Karen Nunez Cortes, Mecit Kaplan, Sunil Acharya, Hila Shaim, Anna C Xu, Manrong Wu, Emily Ensley, Dexing Fang, Pinaki P Banerjee, Luciana Melo Garcia, Silvia Tiberti, Paul Lin, Hind Rafei, Maliha Nuzhat Munir, Madison Moore, Mayra Shanley, Mayela Mendt, Lucila N Kerbauy, Bin Liu, Alexander Biederstädt, Elif Gokdemir, Susmita Ghosh, Kiran Kundu, Francia Reyes-Silva, Xin Ru Jiang, Xinhai Wan, April L Gilbert, Merve Dede, Vakul Mohanty, Jinzhuang Dou, Patrick Zhang, Enli Liu, Luis Muniz-Feliciano, Gary M Deyter, Abhinav K Jain, Juan Jose Rodriguez-Sevilla, Simona Colla, Guillermo Garcia-Manero, Elizabeth J Shpall, Ken Chen, Hussein A Abbas, Kunal Rai, Katayoun Rezvani, May Daher

Faculty, Staff and Student Publications

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) belong to a continuous disease spectrum of myeloid malignancies with poor prognosis in the relapsed/refractory setting necessitating novel therapies. Natural killer (NK) cells from patients with myeloid malignancies display global dysfunction with impaired killing capacity, altered metabolism and exhausted phenotype at the single cell transcriptomic and proteomic levels. In this study we identified that this dysfunction was mediated through a crosstalk between NK cells and myeloid blasts necessitating cell-cell contact. NK cell dysfunction could be prevented by targeting the αvβ integrin/TGF-β/SMAD pathway but, once established, was persistent due to profound epigenetic reprogramming. …

Parp-1 Selectively Impairs Kras-Driven Phenotypic And Molecular Features In Intrahepatic Cholangiocarcinoma, Friederike L Keggenhoff, Darko Castven, Diana Becker, Stojan Stojkovic, Jovana Castven, Carolin Zimpel, Beate K Straub, Tiemo Gerber, Harald Langer, Patricia Hähnel, Thomas Kindler, Jörg Fahrer, Colm J O'Rourke, Ursula Ehmer, Anna Saborowski, Lichun Ma, Xin Wei Wang, Timo Gaiser, Matthias S Matter, Christian Sina, Stefanie Derer, Ju-Seog Lee, Stephanie Roessler, Bernd Kaina, Jesper B Andersen, Peter R Galle, Jens U Marquardt

Faculty, Staff and Student Publications

Objective: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer with limited therapeutic options. KRAS mutations are among the most abundant genetic alterations in iCCA associated with poor clinical outcome and treatment response. Recent findings indicate that Poly(ADP-ribose)polymerase1 (PARP-1) is implicated in KRAS-driven cancers, but its exact role in cholangiocarcinogenesis remains undefined.

Design: PARP-1 inhibition was performed in patient-derived and established iCCA cells using RNAi, CRISPR/Cas9 and pharmacological inhibition in KRAS-mutant, non-mutant cells. In addition, Parp-1 knockout mice were combined with iCCA induction by hydrodynamic tail vein injection to evaluate an impact on phenotypic and molecular …

Fibrotic Response To Anti-Csf-1r Therapy Potentiates Glioblastoma Recurrence, Spencer S Watson, Anoek Zomer, Nadine Fournier, Joao Lourenco, Manfredo Quadroni, Agnieszka Chryplewicz, Sina Nassiri, Pauline Aubel, Simona Avanthay, Davide Croci, Erik Abels, Marike L D Broekman, Douglas Hanahan, Jason T Huse, Roy T Daniel, Monika E Hegi, Krisztian Homicsko, Giulia Cossu, Andreas F Hottinger, Johanna A Joyce

Faculty, Staff and Student Publications

Glioblastoma recurrence is currently inevitable despite extensive standard-of-care treatment. In preclinical studies, an alternative strategy of targeting tumor-associated macrophages and microglia through CSF-1R inhibition was previously found to regress established tumors and significantly increase overall survival. However, recurrences developed in ∼50% of mice in long-term studies, which were consistently associated with fibrotic scars. This fibrotic response is observed following multiple anti-glioma therapies in different preclinical models herein and in patient recurrence samples. Multi-omics analyses of the post-treatment tumor microenvironment identified fibrotic areas as pro-tumor survival niches that encapsulated surviving glioma cells, promoted dormancy, and inhibited immune surveillance. The fibrotic treatment …

Neoadjuvant Parpi Or Chemotherapy In Ovarian Cancer Informs Targeting Effector Treg Cells For Homologous-Recombination-Deficient Tumors, Yikai Luo, Yu Xia, Dan Liu, Xiong Li, Huayi Li, Jiahao Liu, Dongchen Zhou, Yu Dong, Xin Li, Yiyu Qian, Cheng Xu, Kangjia Tao, Guannan Li, Wen Pan, Qing Zhong, Xingzhe Liu, Sen Xu, Zhi Wang, Ronghua Liu, Wei Zhang, Wanying Shan, Tian Fang, Siyuan Wang, Zikun Peng, Ping Jin, Ning Jin, Shennan Shi, Yuxin Chen, Mengjie Wang, Xiaofei Jiao, Mengshi Luo, Wenjian Gong, Ya Wang, Yue Yao, Yi Zhao, Xinlin Huang, Xuwo Ji, Zhaoren He, Guangnian Zhao, Rong Liu, Mingfu Wu, Gang Chen, Li Hong, Cocpo Consortium, Ding Ma, Yong Fang, Han Liang, Qinglei Gao

Faculty, Staff and Student Publications

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD …

G Protein Selectivity Profile Of Gpr56/Adgrg1 And Its Effect On Downstream Effectors, Raida Jallouli, Ana L Moreno-Salinas, Andréanne Laniel, Brian Holleran, Charlotte Avet, Joan Jacob, Trang Hoang, Christine Lavoie, Kendra S Carmon, Michel Bouvier, Richard Leduc

Faculty, Staff and Student Publications

GPR56, an adhesion G-protein coupled receptor (aGPCRs) with constitutive and ligand-promoted activity, is involved in many physiological and pathological processes. Whether the receptor's constitutive or ligand-promoted activation occur through the same molecular mechanism, and whether different activation modes lead to functional selectivity between G proteins is unknown. Here we show that GPR56 constitutively activates both G12 and G13. Unlike constitutive activation and activation with 3-α-acetoxydihydrodeoxygedunin (3αDOG), stimulation with an antibody, 10C7, directed against GPR56's extracellular domain (ECD) led to an activation that favors G13 over G12. An autoproteolytically deficient mutant, GPR56-T383A, was also activated by 10C7 indicating that the tethered …

Parasitic Contamination Of Soil In The Southern United States, Christine Crudo Blackburn, Sally Mingshuang Yan, David Mccormick, Lauren Nicholas Herrera, Roumen Borilov Iordanov, Mark Daniel Bailey, Maria Elena Bottazzi, Peter J Hotez, Rojelio Mejia

Faculty, Staff and Students Publications

Parasites are generally associated with lower income countries in tropical and subtropical areas. Still, they are also prevalent in low-income communities in the southern United States. Studies characterizing the epidemiology of parasites in the United States are limited, resulting in little comprehensive understanding of the problem. This study investigated the environmental contamination of parasites in the southern United States by determining each parasite's contamination rate and burden in five low-income communities. A total of 499 soil samples of approximately 50 g were collected from public parks and private residences in Alabama, Louisiana, Mississippi, South Carolina, and Texas. A technique using …

Angiotensin-(1-9) Retro-Enantiomer Peptide With Cardioprotective Activity, Yvo Flores, Gerald Zapata-Torres, Agustín Nuñez, Douglas J Matthies, Larissa Alemán, Carolina Hernández-Fuentes, Gina Sánchez, Eyleen Araya, Fanny Guzman, Zully Pedrozo, Salvador Guardiola, Mónica Varese, Ernest Giralt, Ivan Maslov, Mark Del Borgo, Robert E Widdop, Silvana Valdebenito, Eliseo A Eugenin, Mario Chiong, Joseph A Hill, María Paz Ocaranza, Marcelo J Kogan, Sergio Lavandero

Faculty, Staff and Student Publications

No abstract provided.

The Cancer-Associated Secretory Phenotype: A New Frontier In Targeted Therapeutics, Xiaochao Tan, Guan-Yu Xiao, Priyam Banerjee, Shike Wang, Jonathan M Kurie

Faculty, Staff and Student Publications

No abstract provided.

Dominant Missense Variants In Srebf2 Are Associated With Complex Dermatological, Neurological, And Skeletal Abnormalities, Matthew J Moulton, Kristhen Atala, Yiming Zheng, Debdeep Dutta, Dorothy K Grange, Wen-Wen Lin, Daniel J Wegner, Jennifer A Wambach, Angela L Duker, Michael B Bober, Lisa Kratz, Carol A Wise, Ila Oxendine, Anas Khanshour, Undiagnosed Diseases Network, Michael F Wangler, Shinya Yamamoto, F Sessions Cole, Jonathan Rios, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Purpose: We identified 2 individuals with de novo variants in SREBF2 that disrupt a conserved site 1 protease (S1P) cleavage motif required for processing SREBP2 into its mature transcription factor. These individuals exhibit complex phenotypic manifestations that partially overlap with sterol regulatory element binding proteins (SREBP) pathway-related disease phenotypes, but SREBF2-related disease has not been previously reported. Thus, we set out to assess the effects of SREBF2 variants on SREBP pathway activation.

Methods: We undertook ultrastructure and gene expression analyses using fibroblasts from an affected individual and utilized a fly model of lipid droplet (LD) formation to investigate the consequences …

Arcuate Dopaminergic/Gabaergic Neurons Project Within The Hypothalamus And To The Median Eminence, Somya Mittal, Benjamin R Arenkiel, Ariel M Lyons-Warren

Duncan NRI Faculty and Staff Publications

Cotransmission, meaning the release of multiple neurotransmitters from one synapse, allows for increased diversity of signaling in the brain. Dopamine (DA) and γ-aminobutyric acid (GABA) are known to coexpress in many regions such as the olfactory bulb and the ventral tegmental area. Tuberoinfundibular dopaminergic neurons (TIDA) in the arcuate nucleus of the hypothalamus (Arc) project to the median eminence (ME) and regulate prolactin release from the pituitary, and prior work suggests dopaminergic Arc neurons also cotransmit GABA. However, the extent of cotransmission, and the projection patterns of these neurons have not been fully revealed. Here, we used a genetic intersectional …

The Cerebellum Modulates Thirst, Ila Mishra, Bing Feng, Bijoya Basu, Amanda M Brown, Linda H Kim, Tao Lin, Mir Abbas Raza, Amelia Moore, Abigayle Hahn, Samantha Bailey, Alaina Sharp, Juan C Bournat, Claire Poulton, Brian Kim, Amos Langsner, Aaron Sathyanesan, Roy V Sillitoe, Yanlin He, Atul R Chopra

Duncan NRI Faculty and Staff Publications

The cerebellum, a phylogenetically ancient brain region, has long been considered strictly a motor control structure. Recent studies have implicated the cerebellum in cognition, sensation, emotion and autonomic function, making it an important target for further investigation. Here, we show that cerebellar Purkinje neurons in mice are activated by the hormone asprosin, leading to enhanced thirst, and that optogenetic or chemogenetic activation of Purkinje neurons induces rapid manifestation of water drinking. Purkinje neuron-specific asprosin receptor (Ptprd) deletion results in reduced water intake without affecting food intake and abolishes asprosin's dipsogenic effect. Purkinje neuron-mediated motor learning and coordination were unaffected by …

Strategies For The Development Of Metalloimmunotherapies, Xiaoqi Sun, Xingwu Zhou, Xiaoyue Shi, Omar A Abed, Xinran An, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Metal ions play crucial roles in the regulation of immune pathways. In fact, metallodrugs have a long record of accomplishment as effective treatments for a wide range of diseases. Here we argue that the modulation of interactions of metal ions with molecules and cells involved in the immune system forms the basis of a new class of immunotherapies. By examining how metal ions modulate the innate and adaptive immune systems, as well as host-microbiota interactions, we discuss strategies for the development of such metalloimmunotherapies for the treatment of cancer and other immune-related diseases.

Co-Targeting Sos1 Enhances The Antitumor Effects Of Krasg12c Inhibitors By Addressing Intrinsic And Acquired Resistance, Venu Thatikonda, Hengyu Lyu, Sabine Jurado, Kaja Kostyrko, Christopher A Bristow, Christoph Albrecht, Donat Alpar, Heribert Arnhof, Oliver Bergner, Karin Bosch, Ningping Feng, Sisi Gao, Daniel Gerlach, Michael Gmachl, Melanie Hinkel, Simone Lieb, Astrid Jeschko, Annette A Machado, Thomas Madensky, Ethan D Marszalek, Mikhila Mahendra, Gabriella Melo-Zainzinger, Jessica M Molkentine, Philipp A Jaeger, David H Peng, Robyn L Schenk, Alexey Sorokin, Sandra Strauss, Francesca Trapani, Scott Kopetz, Christopher P Vellano, Mark Petronczki, Norbert Kraut, Timothy P Heffernan, Joseph R Marszalek, Mark Pearson, Irene C Waizenegger, Marco H Hofmann

Faculty, Staff and Student Publications

Combination approaches are needed to strengthen and extend the clinical response to KRASG12C inhibitors (KRASG12Ci). Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRASG12Ci seemed to be driven by …

Rewiring Cancer Cell Death: Lpcat1 Shapes Lipid Composition And Ferroptosis Resistance, Hyemin Lee, Li Zhuang, Boyi Gan

Faculty, Staff and Student Publications

No abstract provided.

Lessons Learnt From Broad-Spectrum Coronavirus Antiviral Drug Discovery, Andrew A Bolinger, Jun Li, Xuping Xie, Hongmin Li, Jia Zhou

Faculty, Staff and Student Publications

Introduction: Highly pathogenic coronaviruses (CoVs), such as severe acute respiratory syndrome CoV (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV), and the most recent SARS-CoV-2 responsible for the COVID-19 pandemic, pose significant threats to human populations over the past two decades. These CoVs have caused a broad spectrum of clinical manifestations ranging from asymptomatic to severe distress syndromes (ARDS), resulting in high morbidity and mortality.

Areas covered: The accelerated advancements in antiviral drug discovery, spurred by the COVID-19 pandemic, have shed new light on the imperative to develop treatments effective against a broad spectrum of CoVs. This perspective discusses strategies and …