Biochemical Phenomena, Metabolism, and Nutrition Commons^™

Comprehensive Analysis Of Transcription Factor-Based Molecular Subtypes And Their Correlation To Clinical Outcomes In Small-Cell Lung Cancer, Sehhoon Park, Tae Hee Hong, Soohyun Hwang, Simon Heeke, Carl M Gay, Jiyeon Kim, Hyun-Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Jong Ho Cho, Yong Soo Choi, Jhingook Kim, Young Mog Shim, Hong Kwan Kim, Lauren Averett Byers, John V Heymach, Yoon-La Choi, Se-Hoon Lee, Keunchil Park

Faculty, Staff and Student Publications

BACKGROUND: Recent studies have reported the predictive and prognostic value of novel transcriptional factor-based molecular subtypes in small-cell lung cancer (SCLC). We conducted an in-depth analysis pairing multi-omics data with immunohistochemistry (IHC) to elucidate the underlying characteristics associated with differences in clinical outcomes between subtypes.

METHODS: IHC (n = 252), target exome sequencing (n = 422), and whole transcriptome sequencing (WTS, n = 189) data generated from 427 patients (86.4% males, 13.6% females) with SCLC were comprehensively analysed. The differences in the mutation profile, gene expression profile, and inflammed signatures were analysed according to the IHC-based molecular subtype.

FINDINGS: IHC-based …

The Fatigue-Inducing Effects Of Cancer And Its Therapy Are Characterized By Decreased Physical Activity In The Absence Of Any Motivational Deficit, Thien T Phan, Kiersten S Scott, Brandon Chelette, A Phillip West, Robert Dantzer

Faculty, Staff and Student Publications

Although cancer and its therapy are well known to be associated with fatigue, the exact nature of cancer-related fatigue remains ill-defined. We previously reported that fatigue-like behavior induced independently by tumor growth and by the chemotherapeutic agent cisplatin is characterized by reduced voluntary wheel running and an intact motivation to expand effort for food rewards. The present set of experiments was initiated to characterize the functional consequences of fatigue induced by chemoradiotherapy in tumor-bearing mice and relate them to changes in the expression of genes coding for inflammation, mitochondria dynamics and metabolism. Two syngeneic murine models of cancer were selected …

Bispecific Bcma/Cd24 Car-T Cells Control Multiple Myeloma Growth, Fumou Sun, Yan Cheng, Visanu Wanchai, Wancheng Guo, David Mery, Hongwei Xu, Dongzheng Gai, Eric Siegel, Clyde Bailey, Cody Ashby, Samer Al Hadidi, Carolina Schinke, Sharmilan Thanendrarajan, Yupo Ma, Qing Yi, Robert Z Orlowski, Maurizio Zangari, Frits Van Rhee, Siegfried Janz, Gail Bishop, Guido Tricot, John D Shaughnessy, Fenghuang Zhan

Faculty, Staff and Student Publications

Anti-multiple myeloma B cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapies represent a promising treatment strategy with high response rates in myeloma. However, durable cures following anti-BCMA CAR-T cell treatment of myeloma are rare. One potential reason is that a small subset of minimal residual myeloma cells seeds relapse. Residual myeloma cells following BCMA-CAR-T-mediated treatment show less-differentiated features and express stem-like genes, including CD24. CD24-positive myeloma cells represent a large fraction of residual myeloma cells after BCMA-CAR-T therapy. In this work, we develop CD24-CAR-T cells and test their ability to eliminate myeloma cells. We find that CD24-CAR-T cells …

Serine Synthesis Via Reversed Shmt2 Activity Drives Glycine Depletion And Acetaminophen Hepatotoxicity In Masld, Alia Ghrayeb, Alexandra C Finney, Bella Agranovich, Daniel Peled, Sumit Kumar Anand, M Peyton Mckinney, Mahasen Sarji, Dongshan Yang, Natan Weissman, Shani Drucker, Sara Isabel Fernandes, Jonatan Fernández-García, Kyle Mahan, Zaid Abassi, Lin Tan, Philip L Lorenzi, James Traylor, Jifeng Zhang, Ifat Abramovich, Y Eugene Chen, Oren Rom, Inbal Mor, Eyal Gottlieb

Faculty, Staff and Student Publications

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of the global population. Understanding the metabolic pathways involved can provide insights into disease progression and treatment. Untargeted metabolomics of livers from mice with early-stage steatosis uncovered decreased methylated metabolites, suggesting altered one-carbon metabolism. The levels of glycine, a central component of one-carbon metabolism, were lower in mice with hepatic steatosis, consistent with clinical evidence. Stable-isotope tracing demonstrated that increased serine synthesis from glycine via reverse serine hydroxymethyltransferase (SHMT) is the underlying cause for decreased glycine in steatotic livers. Consequently, limited glycine availability in steatotic livers impaired glutathione synthesis under acetaminophen-induced oxidative …

Gut Microbiome And Hepatic Transcriptomic Determinants Of Hcc Development In Mice With Metabolic Dysfunction-Associated Steatohepatitis, Lillian I Dolapchiev, Kristyn A Gonzales, Lorenzo R Cruz, Mihai Gagea, Heather L Stevenson, Suet-Ying Kwan, Laura Beretta

Faculty, Staff and Student Publications

Purpose: Hepatocellular carcinoma (HCC) related to metabolic dysfunction-associated steatotic liver disease (MASLD) is often diagnosed at a late stage, and its incidence is increasing. Predictive biomarkers are therefore needed to identify individuals at high risk of HCC. We aimed to characterize the gut microbiome and hepatic transcriptome associated with HCC development in female mice with hepatocyte-deletion of Pten (HepPten -). These mice present with large variations in HCC development, making them a powerful model for biomarker discovery.

Methods & results: Sequencing of stool 16S and hepatic RNA was performed on a first set of mice. Among all liver histology …

Diet-Stimulated Marrow Adiposity Fails To Worsen Early, Age-Related Bone Loss, Cody Mcgrath, Sarah E Little-Letsinger, Gabriel M Pagnotti, Buer Sen, Zhihui Xie, Gunes Uzer, Guniz B Uzer, Xiaopeng Zong, Martin A Styner, Janet Rubin, Maya Styner

Faculty, Staff and Student Publications

Introduction: Longitudinal effect of diet-induced obesity on bone is uncertain. Prior work showed both no effect and a decrement in bone density or quality when obesity begins prior to skeletal maturity. We aimed to quantify long-term effects of obesity on bone and bone marrow adipose tissue (BMAT) in adulthood.

Methods: Skeletally mature, female C57BL/6 mice (n = 70) aged 12 weeks were randomly allocated to low-fat diet (LFD; 10% kcal fat; n = 30) or high-fat diet (HFD; 60% kcal fat; n = 30), with analyses at 12, 15, 18, and 24 weeks (n = 10/group). Tibial microarchitecture was analyzed …

Cardiovascular Risk Factors In Sheehan's Syndrome: A Case-Control Study, Mayur Agrawal, Subhash C Yadav, Swish K Singh, Sheo Kumar, Krishnarpan Chatterjee, Naveen K Garg

Faculty, Staff and Student Publications

INTRODUCTION: Obesity, dyslipidaemia and insulin resistance are associated with hypopituitarism. The association between these conditions and Sheehan's syndrome (SS) caused by post-partum pituitary gland necrosis is poorly understood. This study aimed to assess cardiovascular risk surrogate markers in SS patients, and we compared clinical, biochemical and radiological testing with healthy controls.

METHODS: In this cross-sectional study, we studied 45 patients with SS on standard replacement therapy and compared them with healthy controls. All subjects underwent anthropometric, inflammatory marker and hormonal measurement (adrenocorticotropic hormone (ACTH), stimulated cortisol, insulin-like growth factor-1 (IGF-1), thyroxine (T4), follicle-stimulating hormone (FSH), luteinising hormone (LH), oestradiol (E2), …

Glp1 Receptor Agonists-Effects Beyond Obesity And Diabetes, Sydney S Wilbon, Mikhail G Kolonin

Faculty, Staff and Student Publications

Glucagon-like peptide-1 receptor agonists (GLP1RA) have been transformative for patients and clinicians in treating type-2 diabetes and obesity. Drugs of this class, the bioavailability of which is continuously improving, enable weight loss and control blood glucose with minimal unwanted side effects. Since adopting GLP1RA for treating metabolic diseases, animal and clinical studies have revealed their beneficial effects on several other pathologies, including cardiovascular diseases, neurodegeneration, kidney disease, and cancer. A notable commonality between these diseases is their association with older age. Clinical trials and preclinical data suggest that GLP1RA may improve outcomes in these aging-related diseases. Some of the benefits …

Formate Supplementation Enhances Antitumor Cd8+ T-Cell Fitness And Efficacy Of Pd-1 Blockade, Jared H Rowe, Ilaria Elia, Osmaan Shahid, Emily F Gaudiano, Natalia E Sifnugel, Sheila Johnson, Amy G Reynolds, Megan E Fung, Shakchhi Joshi, Martin W Lafleur, Joon Seok Park, Kristen E Pauken, Joshua D Rabinowitz, Gordon J Freeman, Marcia C Haigis, Arlene H Sharpe

Faculty, Staff and Student Publications

UNLABELLED: The tumor microenvironment (TME) restricts antitumor CD8+ T-cell function and immunotherapy responses. Cancer cells compromise the metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate that one-carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T-cell fitness and antitumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T-cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti-PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for …

Loss Of The Methylarginine Reader Function Of Snd1 Confers Resistance To Hepatocellular Carcinoma, Tanner Wright, Yalong Wang, Sabrina A Stratton, Manu Sebastian, Bin Liu, David G Johnson, Mark T Bedford

Faculty, Staff and Student Publications

Staphylococcal nuclease Tudor domain containing 1 (SND1) protein is an oncogene that 'reads' methylarginine marks through its Tudor domain. Specifically, it recognizes methylation marks deposited by protein arginine methyltransferase 5 (PRMT5), which is also known to promote tumorigenesis. Although SND1 can drive hepatocellular carcinoma (HCC), it is unclear whether the SND1 Tudor domain is needed to promote HCC. We sought to identify the biological role of the SND1 Tudor domain in normal and tumorigenic settings by developing two genetically engineered SND1 mouse models, an Snd1 knockout (Snd1 KO) and an Snd1 Tudor domain-mutated (Snd1 KI) mouse, whose mutant SND1 can …

Pmca Screening Of Retropharyngeal Lymph Nodes In White-Tailed Deer And Comparisons With Elisa And Ihc, Rebeca Benavente, J Hunter Reed, Mitch Lockwood, Rodrigo Morales

Faculty, Staff and Student Publications

Chronic wasting disease (CWD) is a prion disease affecting cervids. CWD diagnosis is conducted through enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) in retropharyngeal lymph nodes. Unfortunately, these techniques have limited sensitivity against the biomarker (CWD-prions). Two in vitro prion amplification techniques, real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), have shown promise in detecting CWD-prions in tissues and bodily fluids. Recent studies have demonstrated that RT-QuIC yields similar results compared to ELISA and IHC. Here, we analyzed 1003 retropharyngeal lymph nodes (RPLNs) from Texas white-tailed deer. PMCA detected CWD at a higher rate compared to ELISA/IHC, identified …

Identification Of Exosome Protein Panels As Predictive Biomarkers For Non-Small Cell Lung Cancer, Bin Luo, Zujun Que, Xinyi Lu, Dan Qi, Zhi Qiao, Yun Yang, Fangfang Qian, Yi Jiang, Yan Li, Ronghu Ke, Xiaoyun Shen, Hua Xiao, Hegen Li, Erxi Wu, Jianhui Tian

Children’s Nutrition Research Center Staff Publications

Background: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related deaths worldwide, primarily due to its propensity for metastasis. Patients diagnosed with localized primary cancer have higher survival rates than those with metastasis. Thus, it is imperative to discover biomarkers for the early detection of NSCLC and the timely prediction of tumor metastasis to improve patient outcomes.

Methods: Here, we utilized an integrated approach to isolate and characterize plasma exosomes from NSCLC patients as well as healthy individuals. We then conducted proteomics analysis and parallel reaction monitoring to identify and validate the top-ranked proteins of plasma exosomes.

Results: …

In Situ Profiling Reveals Metabolic Alterations In The Tumor Microenvironment Of Ovarian Cancer After Chemotherapy, Sara Corvigno, Sunil Badal, Meredith L Spradlin, Michael Keating, Igor Pereira, Elaine Stur, Emine Bayraktar, Katherine I Foster, Nicholas W Bateman, Waleed Barakat, Kathleen M Darcy, Thomas P Conrads, G Larry Maxwell, Philip L Lorenzi, Susan K Lutgendorf, Yunfei Wen, Li Zhao, Premal H Thaker, Michael J Goodheart, Jinsong Liu, Nicole Fleming, Sanghoon Lee, Livia S Eberlin, Anil K Sood

Faculty, Staff and Student Publications

In this study, we investigated the metabolic alterations associated with clinical response to chemotherapy in patients with ovarian cancer. Pre- and post-neoadjuvant chemotherapy (NACT) tissues from patients with high-grade serous ovarian cancer (HGSC) who had poor response (PR) or excellent response (ER) to NACT were examined. Desorption electrospray ionization mass spectrometry (DESI-MS) was performed on sections of HGSC tissues collected according to a rigorous laparoscopic triage algorithm. Quantitative MS-based proteomics and phosphoproteomics were performed on a subgroup of pre-NACT samples. Highly abundant metabolites in the pre-NACT PR tumors were related to pyrimidine metabolism in the epithelial regions and oxygen-dependent proline …

Human Intestinal Organoids From Cronkhite-Canada Syndrome Patients Reveal Link Between Serotonin And Proliferation, Victoria Poplaski, Carolyn Bomidi, Amal Kambal, Hoa Nguyen-Phuc, Sara C Di Rienzi, Heather A Danhof, Xi-Lei Zeng, Linda A Feagins, Nan Deng, Eduardo Vilar, Florencia Mcallister, Cristian Coarfa, Soyoun Min, Hyun Jung Kim, Richa Shukla, Robert Britton, Mary K Estes, Sarah E Blutt

Faculty, Staff and Student Publications

Cronkhite-Canada Syndrome (CCS) is a rare, noninherited polyposis syndrome affecting 1 in every million individuals. Despite over 50 years of CCS cases, the etiopathogenesis and optimal treatment for CCS remains unknown due to the rarity of the disease and lack of model systems. To better understand the etiology of CCS, we generated human intestinal organoids (HIOs) from intestinal stem cells isolated from 2 patients. We discovered that CCS HIOs are highly proliferative and have increased numbers of enteroendocrine cells producing serotonin (also known as 5-hydroxytryptamine or 5HT). These features were also confirmed in patient tissue biopsies. Recombinant 5HT increased proliferation …

Enolase Inhibitors As Early Lead Therapeutics Against Trypanosoma Brucei, Colm P Roster, Danielle Lavigne, Jillian E Milanes, Emily Knight, Heidi D Anderson, Sabrina Pizarro, Elijah M Harding, Meredith T Morris, Victoria C Yan, Cong-Dat Pham, Florian Muller, Samuel Kwain, Kerrick C Rees, Brian Dominy, Daniel C Whitehead, Md Nasir Uddin, Steven W Millward, James C Morris

Faculty, Staff and Student Publications

Glucose metabolism is critical for the African trypanosome, Trypanosoma brucei, serving as the lone source of ATP production for the bloodstream form (BSF) parasite in the glucose-rich environment of the host blood. Recently, phosphonate inhibitors of human enolase (ENO), the enzyme responsible for the interconversion of 2-phosphoglycerate (2-PG) to phosphoenolpyruvate (PEP) in glycolysis or PEP to 2-PG in gluconeogenesis, have been developed for the treatment of glioblastoma multiforme (GBM). Here, we have tested these agents against T. brucei ENO (TbENO) and found the compounds to be potent enzyme inhibitors and trypanocides. For example, (1-hydroxy-2-oxopyrrolidin-3-yl) phosphonic acid (deoxy-SF2312) …

Endocrine Therapy Synergizes With Smac Mimetics To Potentiate Antigen Presentation And Tumor Regression In Hormone Receptor-Positive Breast Cancer, Francisco Hermida-Prado, Yingtian Xie, Shira Sherman, Zsuzsanna Nagy, Douglas Russo, Tara Akhshi, Zhengtao Chu, Avery Feit, Marco Campisi, Minyue Chen, Agostina Nardone, Cristina Guarducci, Klothilda Lim, Alba Font-Tello, Irene Lee, Juana García-Pedrero, Israel Cañadas, Judith Agudo, Ying Huang, Tal Sella, Qingchun Jin, Nabihah Tayob, Elizabeth A Mittendorf, Sara M Tolaney, Xintao Qiu, Henry Long, William F Symmans, Jia-Ren Lin, Sandro Santagata, Isabelle Bedrosian, Denise A Yardley, Ingrid A Mayer, Edward T Richardson, Giacomo Oliveira, Catherine J Wu, Eugene F Schuster, Mitch Dowsett, Alana L Welm, David Barbie, Otto Metzger, Rinath Jeselsohn

Faculty, Staff and Student Publications

Immunotherapies have yet to demonstrate significant efficacy in the treatment of hormone receptor-positive (HR+) breast cancer. Given that endocrine therapy (ET) is the primary approach for treating HR+ breast cancer, we investigated the effects of ET on the tumor immune microenvironment (TME) in HR+ breast cancer. Spatial proteomics of primary HR+ breast cancer samples obtained at baseline and after ET from patients enrolled in a neoadjuvant clinical trial (NCT02764541) indicated that ET upregulated β2-microglobulin and influenced the TME in a manner that promotes enhanced immunogenicity. To gain a deeper understanding of the underlying mechanisms, the intrinsic effects of …

Unfolding The Secrets Of Small Cell Lung Cancer Progression: Novel Approaches And Insights Through Rapid Autopsies, Zsolt Megyesfalvi, Simon Heeke, Benjamin J Drapkin, Anna Solta, Ildiko Kovacs, Kristiina Boettiger, Lilla Horvath, Busra Ernhofer, Janos Fillinger, Ferenc Renyi-Vamos, Clemens Aigner, Karin Schelch, Christian Lang, Gyorgy Marko-Varga, Carl M Gay, Lauren A Byers, Benjamin B Morris, John V Heymach, Peter Van Loo, Fred R Hirsch, Balazs Dome

Faculty, Staff and Student Publications

The understanding of small cell lung cancer (SCLC) biology has increased dramatically in recent years, but the processes that allow SCLC to progress rapidly remain poorly understood. Here, we advocate the integration of rapid autopsies and preclinical models into SCLC research as a comprehensive strategy with the potential to revolutionize current treatment paradigms.

Characterizing Cancer Metabolism From Bulk And Single-Cell Rna-Seq Data Using Metaflux, Yuefan Huang, Vakul Mohanty, Merve Dede, Kyle Tsai, May Daher, Li Li, Katayoun Rezvani, Ken Chen

Faculty, Staff and Student Publications

Cells often alter metabolic strategies under nutrient-deprived conditions to support their survival and growth. Characterizing metabolic reprogramming in the tumor microenvironment (TME) is of emerging importance in cancer research and patient care. However, recent technologies only measure a subset of metabolites and cannot provide in situ measurements. Computational methods such as flux balance analysis (FBA) have been developed to estimate metabolic flux from bulk RNA-seq data and can potentially be extended to single-cell RNA-seq (scRNA-seq) data. However, it is unclear how reliable current methods are, particularly in TME characterization. Here, we present a computational framework METAFlux (METAbolic Flux balance analysis) …

Differential Effects Of Bariatric Surgery And Caloric Restriction On Hepatic One-Carbon And Fatty Acid Metabolism, Arnon Haran, Michael Bergel, Doron Kleiman, Liron Hefetz, Hadar Israeli, Sarah Weksler-Zangen, Bella Agranovich, Ifat Abramovich, Rachel Ben-Haroush Schyr, Eyal Gottlieb, Danny Ben-Zvi

Faculty, Staff and Student Publications

Weight loss interventions, including dietary changes, pharmacotherapy, or bariatric surgery, prevent many of the adverse consequences of obesity, and may also confer intervention-specific benefits beyond those seen with decreased weight alone. We compared the molecular effects of different interventions on liver metabolism to understand the mechanisms underlying these benefits. Male rats on a high-fat, high-sucrose diet underwent sleeve gastrectomy (SG) or intermittent fasting with caloric restriction (IF-CR), achieving equivalent weight loss. The interventions were compared to

Enhancement Of Tki Sensitivity In Lung Adenocarcinoma Through M6a-Dependent Translational Repression Of Wnt Signaling By Circ-Fbxw7, Kai Li, Zi Yang Peng, Rui Wang, Xiang Li, Ning Du, Da Peng Liu, Jia Zhang, Yun Feng Zhang, Lei Ma, Ye Sun, Shou Ching Tang, Hong Ren, Yi Ping Yang, Xin Sun

School of Medicine Faculty Publications

Background: Tyrosine kinase inhibitors (TKIs) that specifically target mutational points in the EGFR gene have significantly reduced suffering and provided greater relief to patients with lung adenocarcinoma (LUAD). The third-generation EGFR-TKI, Osimertinib, has been successfully employed in clinical treatments to overcome resistance to both original and acquired T790M and L858R mutational points. Nevertheless, the issue of treatment failure response has emerged as an insurmountable problem. Methods: By employing a combination of multiple and integrated approaches, we successfully identified a distinct population within the tumor group that plays a significant role in carcinogenesis, resistance, and recurrence. Our research suggests that addressing …

Slc7a11 Expression Level Dictates Differential Responses To Oxidative Stress In Cancer Cells, Yuelong Yan, Hongqi Teng, Qinglei Hang, Lavanya Kondiparthi, Guang Lei, Amber Horbath, Xiaoguang Liu, Chao Mao, Shiqi Wu, Li Zhuang, M James You, Masha V Poyurovsky, Li Ma, Kellen Olszewski, Boyi Gan

Faculty, Staff and Student Publications

The cystine transporter solute carrier family 7 member 11 (SLC7A11; also called xCT) protects cancer cells from oxidative stress and is overexpressed in many cancers. Here we report a surprising finding that, whereas moderate overexpression of SLC7A11 is beneficial for cancer cells treated with H2O2, a common oxidative stress inducer, its high overexpression dramatically increases H2O2-induced cell death. Mechanistically, high cystine uptake in cancer cells with high overexpression of SLC7A11 in combination with H2O2 treatment results in toxic buildup of intracellular cystine and other disulfide molecules, NADPH depletion, redox system collapse, and rapid cell death (likely disulfidptosis). We further show …

Metabolic Adaptation To Consume Butyrate Under Prolonged Resource Exhaustion, Sophia Katz, Claudia Grajeda-Iglesias, Bella Agranovich, Alia Ghrayeb, Ifat Abramovich, Sabrin Hilau, Eyal Gottlieb, Ruth Hershberg

Faculty, Staff and Student Publications

Bacteria must often survive following the exhaustion of their external growth resources. Fitting with this need, many bacterial species that cannot sporulate, can enter a state known as long term stationary phase (LTSP) in which they can persist for years within spent media. Several recent studies have revealed the dynamics of genetic adaptation of Escherichia coli under LTSP. Yet, the metabolic consequences of such genetic adaptation were not addressed. Here, we characterized the metabolic changes LTSP populations experience, over the first 32 days under LTSP. This allowed us to link genetic adaptations observed in a convergent manner across LTSP populations …

Correction Of T-Cell Repertoire And Autoimmune Diabetes In Nod Mice By Non-Myeloablative T-Cell Depleted Allogeneic Hsct, Rakefet Sidlik Muskatel, Bar Nathansohn-Levi, Shlomit Reich-Zeliger, Michal Mark, Liat Stoler-Barak, Chava Rosen, Irit Milman-Krentsis, Esther Bachar Lustig, Robert Pete Gale, Nir Friedman, Yair Reisner

Faculty, Staff and Student Publications

The induction of partial tolerance toward pancreatic autoantigens in the treatment of type 1 diabetes mellitus (T1DM) can be attained by autologous hematopoietic stem cell transplantation (HSCT). However, most patients treated by autologous HSCT eventually relapse. Furthermore, allogeneic HSCT which could potentially provide a durable non-autoimmune T-cell receptor (TCR) repertoire is associated with a substantial risk for transplant-related mortality. We have previously demonstrated an effective approach for attaining engraftment without graft versus host disease (GVHD) of allogeneic T-cell depleted HSCT, following non-myeloablative conditioning, using donor-derived anti-3rd party central memory CD8 veto T cells (Tcm). In the present study, we investigated …

Enhancing Cancer Diagnosis With Real-Time Feedback: Tumor Metabolism Through Hyperpolarized 1-13c Pyruvate Mrsi, Gaurav Sharma, José S Enriquez, Ryan Armijo, Muxin Wang, Pratip Bhattacharya, Shivanand Pudakalakatti

Faculty, Staff and Student Publications

This review article discusses the potential of hyperpolarized (HP) 13C magnetic resonance spectroscopic imaging (MRSI) as a noninvasive technique for identifying altered metabolism in various cancer types. Hyperpolarization significantly improves the signal-to-noise ratio for the identification of 13C-labeled metabolites, enabling dynamic and real-time imaging of the conversion of [1-13C] pyruvate to [1-13C] lactate and/or [1-13C] alanine. The technique has shown promise in identifying upregulated glycolysis in most cancers, as compared to normal cells, and detecting successful treatment responses at an earlier stage than multiparametric MRI in breast and prostate cancer patients. The review provides a concise overview of the applications …

The Melanocortin Action Is Biased Toward Protection From Weight Loss In Mice, Hongli Li, Yuanzhong Xu, Yanyan Jiang, Zhiying Jiang, Joshua Otiz-Guzman, Jessie C Morrill, Jing Cai, Zhengmei Mao, Yong Xu, Benjamin R Arenkiel, Cheng Huang, Qingchun Tong

Faculty, Staff and Student Publications

The melanocortin action is well perceived for its ability to regulate body weight bidirectionally with its gain of function reducing body weight and loss of function promoting obesity. However, this notion cannot explain the difficulty in identifying effective therapeutics toward treating general obesity via activation of the melanocortin action. Here, we provide evidence that altered melanocortin action is only able to cause one-directional obesity development. We demonstrate that chronic inhibition of arcuate neurons expressing proopiomelanocortin (POMC) or paraventricular hypothalamic neurons expressing melanocortin receptor 4 (MC4R) causes massive obesity. However, chronic activation of these neuronal populations failed to reduce body weight. …

Ether Phospholipids Are Required For Mitochondrial Reactive Oxygen Species Homeostasis, Ziheng Chen, I-Lin Ho, Melinda Soeung, Er-Yen Yen, Jintan Liu, Liang Yan, Johnathon L Rose, Sanjana Srinivasan, Shan Jiang, Q Edward Chang, Ningping Feng, Jason P Gay, Qi Wang, Jing Wang, Philip L Lorenzi, Lucas J Veillon, Bo Wei, John N Weinstein, Angela K Deem, Sisi Gao, Giannicola Genovese, Andrea Viale, Wantong Yao, Costas A Lyssiotis, Joseph R Marszalek, Giulio F Draetta, Haoqiang Ying

Faculty, Staff and Student Publications

Mitochondria are hubs where bioenergetics, redox homeostasis, and anabolic metabolism pathways integrate through a tightly coordinated flux of metabolites. The contributions of mitochondrial metabolism to tumor growth and therapy resistance are evident, but drugs targeting mitochondrial metabolism have repeatedly failed in the clinic. Our study in pancreatic ductal adenocarcinoma (PDAC) finds that cellular and mitochondrial lipid composition influence cancer cell sensitivity to pharmacological inhibition of electron transport chain complex I. Profiling of patient-derived PDAC models revealed that monounsaturated fatty acids (MUFAs) and MUFA-linked ether phospholipids play a critical role in maintaining ROS homeostasis. We show that ether phospholipids support mitochondrial …

Clinical Outcomes Of Immune Checkpoint Inhibitor Diabetes Mellitus At A Comprehensive Cancer Center, Rebecca Jeun, Priyanka C Iyer, Conor Best, Victor Lavis, Jeena M Varghese, Sireesha Yedururi, Veronica Brady, Isabella C Glitza Oliva, Ramona Dadu, Denai R Milton, Kristy Brock, Sonali Thosani

Faculty, Staff and Student Publications

Introduction: Immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) is a rare adverse event. In this study, we characterize clinical outcomes of patients with ICI-DM and evaluate survival impact of this complication on melanoma patients.

Research design & methods: We conducted a retrospective review of 76 patients diagnosed with ICI-DM from April 2014 to December 2020.

Results: 68% of patients presented in diabetic ketoacidosis, 16% had readmissions for hyperglycemia, and hypoglycemia occurred in 70% of patients after diagnosis. Development of ICI-DM did not impact overall survival or progression-free survival in melanoma patients.

Conclusion: Development of ICI-DM is associated with long-term insulin dependence …

Reverse Phase Protein Array Profiling Identifies Recurrent Protein Expression Patterns Of Dna Damage-Related Proteins Across Acute And Chronic Leukemia: Samples From Adults And The Children's Oncology Group, Fieke W Hoff, Ti'ara L Griffen, Brandon D Brown, Terzah M Horton, Jan Burger, William Wierda, Stefan E Hubner, Yihua Qiu, Steven M Kornblau

Faculty, Staff and Student Publications

DNA damage response (DNADR) recognition and repair (DDR) pathways affect carcinogenesis and therapy responsiveness in cancers, including leukemia. We measured protein expression levels of 16 DNADR and DDR proteins using the Reverse Phase Protein Array methodology in acute myeloid (AML) (n = 1310), T-cell acute lymphoblastic leukemia (T-ALL) (n = 361) and chronic lymphocytic leukemia (CLL) (n = 795) cases. Clustering analysis identified five protein expression clusters; three were unique compared to normal CD34+ cells. Individual protein expression differed by disease for 14/16 proteins, with five highest in CLL and nine in T-ALL, and by age in …

Dysregulated Amino Acid Sensing Drives Colorectal Cancer Growth And Metabolic Reprogramming Leading To Chemoresistance, Sumeet Solanki, Katherine Sanchez, Varun Ponnusamy, Vasudha Kota, Hannah N Bell, Chun-Seok Cho, Allison H Kowalsky, Michael Green, Jun Hee Lee, Yatrik M Shah

Faculty, Staff and Student Publications

BACKGROUND & AIMS: Colorectal cancer (CRC) is a devastating disease that is highly modulated by dietary nutrients. Mechanistic target of rapamycin complex 1 (mTORC1) contributes to tumor growth and limits therapy responses. Growth factor signaling is a major mechanism of mTORC1 activation. However, compensatory pathways exist to sustain mTORC1 activity after therapies that target oncogenic growth factor signaling. Amino acids potently activate mTORC1 via amino acid-sensing GTPase activity towards Rags (GATOR). The role of amino acid-sensing pathways in CRC is unclear.

METHODS: Human colon cancer cell lines, preclinical intestinal epithelial-specific GATOR1 and GATOR2 knockout mice subjected to colitis-induced or sporadic …

Tracking The Evolution Of Esophageal Squamous Cell Carcinoma Under Dynamic Immune Selection By Multi-Omics Sequencing, Sijia Cui, Nicholas Mcgranahan, Jing Gao, Peng Chen, Wei Jiang, Lingrong Yang, Li Ma, Junfang Liao, Tian Xie, Congying Xie, Tariq Enver, Shixiu Wu

Children’s Nutrition Research Center Staff Publications

Intratumoral heterogeneity (ITH) has been linked to decreased efficacy of clinical treatments. However, although genomic ITH has been characterized in genetic, transcriptomic and epigenetic alterations are hallmarks of esophageal squamous cell carcinoma (ESCC), the extent to which these are heterogeneous in ESCC has not been explored in a unified framework. Further, the extent to which tumor-infiltrated T lymphocytes are directed against cancer cells, but how the immune infiltration acts as a selective force to shape the clonal evolution of ESCC is unclear. In this study, we perform multi-omic sequencing on 186 samples from 36 primary ESCC patients. Through multi-omics analyses, …