U01CA272541

Determining the Contribution of Microbial-Derived Metabolites to Protective Immunity in Obesity-Driven Cancer Risk

Summary:
Obesity is associated with increased risk for 13 cancers. Critical questions are how and to what extent underlying mechanisms of obesity-mediated increases in chronic inflammation may increase cancer risk in a failure of "protective immunity". This knowledge gap represents an untapped opportunity that our multidisciplinary team is uniquely qualified to explore with a mission to improve understanding of cancer risk. We have previously shown obesity alters T cell and macrophage functions that could decrease anti-tumor protections and have expertise in human studies essential for this interdisciplinary challenge.

Our objective is to identify associations in human subjects and test mechanisms of mediators of cancer risk in various pre-clinical models along an "obesity-microbes metabolites protective immunity" axis. Our hypothesis is that obesity-altered gut microbes enhance cancer risk through dysregulated protective immunity that allows increased initiation.

Aim 1 will define obesity-mediated dysregulation of microbial-derived metabolites and impacts on immune phenotypes and protective immunity in human subjects at greater risk for cancer by examining diverse subjects 1A) of varied age and adiposity; and 1B) obese patients pre- and post-bariatric surgery. Donors will be drawn from the Memphis area, which offers a highly diverse population with 65% African Americans with a high incidence of obesity. Patient analyses will inform studies in complementary pre-clinical models to allow for mechanistic investigation to identify conserved mechanisms in the pre-cancer microenvironment.

Aim 2 will determine the impact of microbially-derived metabolites on cancer risk by examining immune cells in spontaneous transgenic models of breast cancer with established heterogeneity in latency, obesogenic response to high-fat diet, circulating bile acids, and gut microbes.

Aim 3 will test dietary administration of a specific microbially-derived metabolite or microbe on protective immunity in complementary carcinogenic and syngeneic models of obesity-mediated breast cancer, respectively. Human subject and murine model studies complemented by ex vivo and in vitro studies will test underlying mechanisms to determine how microbially-modified metabolites may impact immune-cancer cell crosstalk.

Collaborative funds for cross-consortium activities are reserved for risk assessment across heterogeneous lean and obese populations and models across aims to add synergistic impact to our findings through NCI's Metabolic Dysregulation and Cancer Risk Program.

In sum, outcomes will define beneficial microbially-derived metabolites that impact protective immunity to reduce cancer initiation. Thus, the strategy of this proposal is conceptually original, innovative, and significant to define conserved underlying mechanisms that suppress cancer risk. Findings generated will have high impact because the obesity-associated etiological impacts on risk will be heterogeneous and this study is designed to investigate those varied mechanisms to translate to better risk management to improve patient outcomes.

University Of Tennessee

TO PROVIDE FUNDAMENTAL INFORMATION ON THE CAUSE AND NATURE OF CANCER IN PEOPLE, WITH THE EXPECTATION THAT THIS WILL RESULT IN BETTER METHODS OF PREVENTION, DETECTION AND DIAGNOSIS, AND TREATMENT OF NEOPLASTIC DISEASES. CANCER BIOLOGY RESEARCH INCLUDES THE FOLLOWING RESEARCH PROGRAMS: CANCER CELL BIOLOGY, CANCER IMMUNOLOGY, HEMATOLOGY AND ETIOLOGY, DNA AND CHROMOSOMAL ABERRATIONS, TUMOR BIOLOGY AND METASTASIS, AND STRUCTURAL BIOLOGY AND MOLECULAR APPLICATIONS.

93.396 - Cancer Biology Research

National Cancer Institute (NCI) [HHS - NIH]

Tennessee United States

State-Wide

Metabolic Dysregulation and Cancer Risk Program, Research Grants: a Transdisciplinary Approach to Obesity-Associated Research (U01 Clinical Trial Optional) (RFA-CA-21-021)

Amendment Since initial award the total obligations have increased 189% from $1,050,313 to $3,032,842.