"Identifying & Counteracting the Impact of Environment Stresses on Tissue Dysfunction"
Alex Shalek Director, Institute for Medical Engineering & Science (IMES) J. W. Kieckhefer Professor, MIT Department of Chemistry Extramural Member, The Koch Institute for Integrative Cancer Research at MIT
During chronic stress, cells must support both tissue function and their own survival. Hepatocytes perform metabolic, synthetic, and detoxification roles; with chronic nutrient imbalances, metabolic stress can precipitate metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD/NASH). Despite prior work on stress-induced drivers of hepatocyte death, the functional impact of chronic stress on surviving cells remains unclear. In my talk, I will discuss how we used cross-species longitudinal single-cell multi-omic profiling to show that ongoing stress drives developmental and cancer-associated programs in non-transformed hepatocytes while reducing mature functional identity – significantly before transformation and predicting worsened human survival. Further, I will outline how we developed and applied integrative computational methods and experimental validations to uncover master regulators perturbing hepatocyte functional balance, increasing proliferation under stress, and directly priming future tumorigenesis. I will also explain how we utilized human tissue microarray spatial transcriptomics and geographic regression to reveal spatially-structured multicellular communities and signaling interactions shaping stress responses. Finally, toward counteracting these core mechanisms driving tissue dysfunction and instability, I will present our development of a new information-rich, high-throughput phenotypic screening platform, with reduced required sample, labor, and cost requirements, that can be leveraged to help discover strategies to improve tissue health and resilience.