When people consider disease etiology, they often think about genetic or pathological causes of disease. To us, these are one of the many stressors that can affect the way cells behave. These changes, intrinsic to the cell or its milieu or the organism as a whole, accumulate over a lifetime, eventually leading to proteome changes, causing misfunction. This in turn has a negative effect on cell behavior and its network connections. In this context, we think of disease states as embodiments of exposure of cells to stressors.
We use the chemical tools created by our lab to understand the complex proteome alterations that occur in specific chronically stressed cells/organisms such as in cancer, neurodegenerative diseases and microorganisms living in conditions of stress. Examples are the discovery of mechanisms behind: transforming ability of BCL6 in a subset of BCL6-driven Diffuse Large B-Cell Lymphomas (DLBCL) [Nature Medicine 2009] (collaboration with A. Melnick lab); regulation of apoptosis in small-cell lung carcinomas [Nature Chem Biol 2007] (collaboration with Jiang and Massague labs); the altered proteome and its addiction to tumor HSP90 in a subset of triple negative breast cancer [PNAS 2009]; regulation of HER2 activity in HER2 overexpressing breast cancers [Nature Chem Biol 2013, Cell Reports 2020]; transformation in JAK2-driven MPDs and potential mechanisms associated with resistance to JAK inhibitors [J Clinical Investigation 2010, Nature 2012, Blood 2014]; (collaboration with R. Levine lab); regulation of the viral oncoproteome in Kaposi sarcoma herpes virus (KHSV)-associated lymphomas [Blood 2013]; (collaboration with E. Cesarman lab); regulation of the activated STAT5 signaling and increased transcriptional activity in chronic myeloid leukemia [Nature Chem Biol 2011]; molecular signature of HSP90-addicted AML [Cell Reports 2015] (collaboration with M Guzman lab); the biochemical nature of the epichaperome networks in cancer and their therapeutic implications (interdisciplinary multimember team Nature 2016 and Nature Medicine 2018); PPI network alterations in Parkinson’s disease neurons (Nature Communications 2018, collaboration with Studer lab); mechanism of synaptic plasticity dysregulation in Alzheimer’s disease (Nature Communications 2020), to list a few.