How do metabolites function as signaling molecules independent of their metabolic pathways?
Metabolites and other small molecules often accumulate during diseases, such as cancer, infection, and inflammation. Their roles as metabolic substrates have been studied for over a century, yet their non-metabolic functions are largely unexplored. We propose that independent of their metabolic reactions and pathways, metabolites have unexplored, yet critical functions as allosteric signaling molecules in cancer and other diseases. Using questions guided by human patient data, we conduct hypothesis-driven research through a combination of cell-based, in vitro, and ultimately in vivo models. We collaborate with biochemists, structural biologists, and to develop new methods to study protein-metabolite interactions.
Cancer and Inflammation are diseases of abnormal cell growth, proliferation, and signaling which are dependent on extracellular nutrients and instructions. While metabolites serve as nutrients, they are foremost small molecules that can directly bind to proteins to allosterically regulate protein function, thereby serving as signaling molecules. We aim to provide insight into cancer and cell biology by studying the mechanisms of how small molecule metabolites directly regulate cellular growth, proliferation, and signal transduction independent of their known metabolic pathways.
Allosteric regulation of mitochondria metabolism and innate immune signaling.
Lactate is the second most abundant circulating carbon and is often elevated in cancer and other diseases. While most studies focus on its known metabolic functions, we recently found that lactate is also a mitochondrial signaling molecule. Using a combination of genetic CRISPR screening, protein mass spectrometry, cell biology and biochemical approaches, we are dissecting the mechanisms by which lactate and other monocarboxylates signal to the mitochondria.
Metabolic signaling as a regulator of cell fate decision.
Infectious and commensal bacteria collectively outnumber host cells. They produce metabolites that are typically not metabolized by the host. We hypothesize that these small molecules serve essential signaling functions, either as pro-inflammatory or disease tolerance molecules, and can provide insight into how small molecule signals alter protein functions in general. We are using in vitro and in vivo systems to characterize the signaling functions of bacterial metabolites in cell proliferation, differentiation, and signaling.
From bench to bedside: guided by clinical questions
As a physician-scientist who also treats patients with central nervous system tumors and conditions, Dr. Cai is passionate about studying questions driven by clinical observations from patients. Our lab uses clinical observations to generate testable hypothesis that can be dissected using a combination of tissue culture, biochemistry, molecular and cell biology, and mass spectrometry assays. We also collaborate with the Siqi Liu lab, Zhijian Chen lab, Javier Garcia-Bermudez lab, and Stephen Chung lab to develop new in vitro and in vivo methodologies.