Project 3: Obesity-related Metabolic Reprogramming in Endometrial Cancer Disparities

PROJECT ABSTRACT – PROJECT 3 The incidence and mortality of endometrial cancer (EC) continues to increase at an alarming rate. Dramatic EC disparities show that Black women experience the highest increases in EC rates and worse outcomes across all stages and grades. There is a critical and urgent need to understand molecular drivers behind EC disparities so that agents can be tested to prevent or intercept the onset or progression of EC and improve outcomes. Obesity is tightly linked with EC risk, but decades of research on obesity have yielded modest insight into the specific mechanisms driving EC development, especially in understanding disparities. Roughly 40% of women in the US are classified as having obesity, but only a small fraction of these women develop EC. Heterogeneity in systemic and tissue-level metabolic disruptions related to obesity and cumulative physiologic stressors may be a key factor for EC risk and contribute to aggressive tumors. Black women experience higher rates of obesity and type 2 diabetes, higher circulating markers of systemic inflammation (e.g., TNFα, C-reactive protein, IL-6), and increased rates of other cardiometabolic risk factors compared to White women. We propose that measurable social and environmental factors contribute to chronic metabolic and pro-inflammatory conditions to disrupt endometrial signaling and stress responses. Allostatic load has been used to assess cumulative physiologic exposure to measurable social and environmental factors, and is scored using markers of metabolic, cardiovascular, and inflammatory stressors, among others. Allostatic load is associated with morbidity and mortality in aging-related disease, cardiovascular disease, and cancers. At the cellular level, mitochondrial allostatic load describes cumulative stressors or exposures disrupting mitochondrial metabolism and cellular signaling. Our overall hypothesis is that endometrial adaptations to metabolic disruptions in obesity and physiologic stress increase tumorigenesis and promote aggressive tumor behavior underlying EC disparities. The long-term goals are to identify biomarkers for improved EC risk stratification, and to provide candidate targets for cancer interception to improve EC outcomes. Our study utilizes multiple models and measures for these cumulative stressors at the systemic, tissue, and cellular (mitochondrial) levels to define pro-tumorigenic signaling with the following aims: Aim 1. Compare cumulative systemic measures of metabolic disruption and physiologic stress (allostatic load) across Black and White women with EC versus women with benign endometrium. Aim 2. Define endometrial tissue-level reprogramming based on systemic metabolic and physiologic stress to identify regional pathway alterations underlying disparities. Aim 3. Define the impact of disrupted mitochondrial function on endometrial stress responses and aggressive tumor behavior using EC patient-derived organoid models.