Preparing historically underrepresented trainees for biomedical cancer research careers at Huntsman Cancer Institute/University of Utah Health.

Given the well-documented inequities in health care outcomes by race, ethnicity, and gender, many health career pipeline programs have focused on supporting the development of a diverse and inclusive workforce. The State of Utah, is vast, but sparsely populated outside the Salt Lake City metropolitan area. More than 96% of our nearly 85,000 square miles is designated rural (<100 people/square mile) or frontier (<7 people/square mile). The Salt Lake City area is home to the Hunsman Cancer Institute, the only NCI-designated Comprehensive Cancer Center in the region, also noted the limited diversity in the biomedical cancer research workforce. Our primary objective was to increase the number of underrepresented trainees who pursue higher education with the goal of a career in cancer research. PathMaker is a regional, competitive pipeline program that nurtures high school or undergraduate trainees from historically underrepresented backgrounds towards a career in cancer research. Our faculty and staff team collaboratively developed a cohort model curriculum that increased student awareness of research career options; provided academic and professional development, cultural and social support, evolutionary success strategies, active mentorship, and leadership skill development; and fostered an environment of continuous evaluation and improvement. Since pilot program initiation in May 2016, the PathMaker Research Program (PathMaker) has engaged a total of 44 underrepresented trainees in cancer research labs at Huntsman Cancer Institute, the majority still in college. Eleven trainees graduated college: five employed in STEM, one pursuing a PhD in STEM; two in medical school, and three are lost to follow-up. Alumni report high levels of satisfaction with PathMaker and will be followed and supported for academic success. PathMaker is a replicable model to increase diversity and inclusion in the biomedical cancer research workforce.

Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA.

Although lactic acidosis is a prominent feature of solid tumors, we still have limited understanding of the mechanisms by which lactic acidosis influences metabolic phenotypes of cancer cells. We compared global transcriptional responses of breast cancer cells in response to three distinct tumor microenvironmental stresses: lactic acidosis, glucose deprivation, and hypoxia. We found that lactic acidosis and glucose deprivation trigger highly similar transcriptional responses, each inducing features of starvation response. In contrast to their comparable effects on gene expression, lactic acidosis and glucose deprivation have opposing effects on glucose uptake. This divergence of metabolic responses in the context of highly similar transcriptional responses allows the identification of a small subset of genes that are regulated in opposite directions by these two conditions. Among these selected genes, TXNIP and its paralogue ARRDC4 are both induced under lactic acidosis and repressed with glucose deprivation. This induction of TXNIP under lactic acidosis is caused by the activation of the glucose-sensing helix-loop-helix transcriptional complex MondoA:Mlx, which is usually triggered upon glucose exposure. Therefore, the upregulation of TXNIP significantly contributes to inhibition of tumor glycolytic phenotypes under lactic acidosis. Expression levels of TXNIP and ARRDC4 in human cancers are also highly correlated with predicted lactic acidosis pathway activities and associated with favorable clinical outcomes. Lactic acidosis triggers features of starvation response while activating the glucose-sensing MondoA-TXNIP pathways and contributing to the "anti-Warburg" metabolic effects and anti-tumor properties of cancer cells. These results stem from integrative analysis of transcriptome and metabolic response data under various tumor microenvironmental stresses and open new paths to explore how these stresses influence phenotypic and metabolic adaptations in human cancers.