Medicine and Health Sciences Commons^™

Tumor-Resident Lactobacillus Iners Confer Chemoradiation Resistance Through Lactate-Induced Metabolic Rewiring, Lauren E Colbert, Molly B El Alam, Rui Wang, Tatiana Karpinets, David Lo, Erica J Lynn, Timothy A Harris, Jacob H Elnaggar, Kyoko Yoshida-Court, Katarina Tomasic, Julianna K Bronk, Julie Sammouri, Ananta V Yanamandra, Adilene V Olvera, Lily G Carlin, Travis Sims, Andrea Y Delgado Medrano, Tatiana Cisneros Napravnik, Madison O'Hara, Daniel Lin, Chike O Abana, Hannah X Li, Patricia J Eifel, Anuja Jhingran, Melissa Joyner, Lilie Lin, Lois M Ramondetta, Andrew M Futreal, Kathleen M Schmeler, Geena Mathew, Stephanie Dorta-Estremera, Jianhua Zhang, Xiaogang Wu, Nadim J Ajami, Matthew Wong, Cullen Taniguchi, Joseph F Petrosino, K Jagannadha Sastry, Pablo C Okhuysen, Sara A Martinez, Lin Tan, Iqbal Mahmud, Philip L Lorenzi, Jennifer A Wargo, Ann H Klopp

Student and Faculty Publications

Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in patients with cervical cancer using a combined approach of deep microbiome sequencing, targeted bacterial culture, and in vitro assays. We identify that an obligate L-lactate-producing lactic acid bacterium found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring, or alterations in multiple metabolic pathways, in tumors. Genomically similar L-lactate-producing lactic acid bacteria commensal to other …

Tumor-Resident Lactobacillus Iners Confer Chemoradiation Resistance Through Lactate-Induced Metabolic Rewiring, Lauren E. Colbert, Molly B. El Alam, Rui Wang, Tatiana Karpinets, David Lo, Erica J. Lynn, Timothy A. Harris, Jacob H. Elnaggar, Kyoko Yoshida-Court, Katarina Tomasic, Julianna K. Bronk, Julie Sammouri, Ananta V. Yanamandra, Adilene V. Olvera, Lily G. Carlin, Travis Sims, Andrea Y. Delgado Medrano, Tatiana Cisneros Napravnik, Madison O'Hara, Daniel Lin, Chike O. Abana, Hannah X. Li, Patricia J. Eifel, Anuja Jhingran, Melissa Joyner, Lilie Lin, Lois M. Ramondetta, Andrew M. Futreal

School of Medicine Faculty Publications

Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in patients with cervical cancer using a combined approach of deep microbiome sequencing, targeted bacterial culture, and in vitro assays. We identify that an obligate L-lactate-producing lactic acid bacterium found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring, or alterations in multiple metabolic pathways, in tumors. Genomically similar L-lactate-producing lactic acid bacteria commensal to other …

Structural Basis Of Impaired Disaggregase Function In The Oxidation-Sensitive Skd3 Mutant Causing 3-Methylglutaconic Aciduria, Sukyeong Lee, Sang Bum Lee, Nuri Sung, Wendy W Xu, Changsoo Chang, Hyun-Eui Kim, Andre Catic, Francis T F Tsai

Student and Faculty Publications

Mitochondria are critical to cellular and organismal health. To prevent damage, mitochondria have evolved protein quality control machines to survey and maintain the mitochondrial proteome. SKD3, also known as CLPB, is a ring-forming, ATP-fueled protein disaggregase essential for preserving mitochondrial integrity and structure. SKD3 deficiency causes 3-methylglutaconic aciduria type VII (MGCA7) and early death in infants, while mutations in the ATPase domain impair protein disaggregation with the observed loss-of-function correlating with disease severity. How mutations in the non-catalytic N-domain cause disease is unknown. Here, we show that the disease-associated N-domain mutation, Y272C, forms an intramolecular disulfide bond with Cys267 and …

Mapping The Metabolic Reprogramming Induced By Sodium-Glucose Cotransporter 2 Inhibition, Aviram Kogot-Levin, Yael Riahi, Ifat Abramovich, Ofri Mosenzon, Bella Agranovich, Liat Kadosh, Rachel Ben-Haroush Schyr, Doron Kleiman, Liad Hinden, Erol Cerasi, Danny Ben-Zvi, Ernesto Bernal-Mizrachi, Joseph Tam, Eyal Gottlieb, Gil Leibowitz

Student and Faculty Publications

Diabetes is associated with increased risk for kidney disease, heart failure, and mortality. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) prevent these adverse outcomes; however, the mechanisms involved are not clear. We generated a roadmap of the metabolic alterations that occur in different organs in diabetes and in response to SGLT2i. In vivo metabolic labeling with 13C-glucose in normoglycemic and diabetic mice treated with or without dapagliflozin, followed by metabolomics and metabolic flux analyses, showed that, in diabetes, glycolysis and glucose oxidation are impaired in the kidney, liver, and heart. Treatment with dapagliflozin failed to rescue glycolysis. SGLT2 inhibition increased glucose oxidation …

Conditioned Place Avoidance Is Associated With A Distinct Hippocampal Phenotype, Partly Preserved Pattern Separation, And Reduced Reactive Oxygen Species Production After Stress, D. Parker Kelley, Lucas Albrechet-Souza, Shealan Cruise, Rajani Maiya, Aspasia Destouni, Siva S.V.P. Sakamuri, Alexander Duplooy, Meghan Hibicke, Charles Nichols, Prasad V.G. Katakam, Nicholas W. Gilpin, Joseph Francis

School of Medicine Faculty Publications

Stress is associated with contextual memory deficits, which may mediate avoidance of trauma-associated contexts in posttraumatic stress disorder. These deficits may emerge from impaired pattern separation, the independent representation of similar experiences by the dentate gyrus-Cornu Ammonis 3 (DG-CA3) circuit of the dorsal hippocampus, which allows for appropriate behavioral responses to specific environmental stimuli. Neurogenesis in the DG is controlled by mitochondrial reactive oxygen species (ROS) production, and may contribute to pattern separation. In Experiment 1, we performed RNA sequencing of the dorsal hippocampus 16 days after stress in rats that either develop conditioned place avoidance to a predator urine-associated …

Obesity Is Associated With Altered Tumor Metabolism In Metastatic Melanoma, Andrew W Hahn, Ashley V Menk, Dayana B Rivadeneira, Ryan C Augustin, Mingchu Xu, Jun Li, Xiaogang Wu, Aditya K Mishra, Tuba N Gide, Camelia Quek, Yan Zang, Christine N Spencer, Alexander M Menzies, Carrie R Daniel, Courtney W Hudgens, Theodore Nowicki, Lauren E Haydu, M A Wadud Khan, Vancheswaran Gopalakrishnan, Elizabeth M Burton, Jared Malke, Julie M Simon, Chantale Bernatchez, Nagireddy Putluri, Scott E Woodman, Y N Vashisht Gopal, Renato Guerrieri, Grant M Fischer, Jian Wang, Khalida M Wani, John F Thompson, Jeffrey E Lee, Patrick Hwu, Nadim Ajami, Jeffrey E Gershenwald, Georgina V Long, Richard A Scolyer, Michael T Tetzlaff, Alexander J Lazar, Dirk Schadendorf, Jennifer A Wargo, John M Kirkwood, Ralph J Deberardinis, Han Liang, Andrew Futreal, Jianhua Zhang, James S Wilmott, Weiyi Peng, Michael A Davies, Greg M Delgoffe, Yana G Najjar, Jennifer L Mcquade

Student and Faculty Publications

PURPOSE: Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICI) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient body mass index (BMI).

EXPERIMENTAL DESIGN: Associations between BMI [normal (NL < 25) or OW/OB (BMI ≥ 25)] and tumor or microbiome characteristics were examined in specimens from 782 patients with metastatic melanoma across 7 cohorts. DNA associations were evaluated in The Cancer Genome Atlas cohort. RNA sequencing from 4 cohorts (n = 357) was batch corrected and gene set enrichment analysis (GSEA) by BMI category was performed. Metabolic profiling was conducted in a subset of patients (x = 36) by LC/MS, and in flow-sorted melanoma tumor cells (x = 37) and patient-derived melanoma cell lines (x = 17) using the Seahorse XF assay. Gut microbiome features were examined in an independent cohort (n = 371).

RESULTS: DNA mutations and copy number variations were not associated with BMI. GSEA demonstrated that tumors from OW/OB patients were metabolically quiescent, with downregulation of oxidative phosphorylation and multiple other metabolic pathways. Direct metabolite analysis and functional metabolic profiling confirmed decreased …