Bhuminder Singh

Department of Medicine
Epithelial Biology Center (EBC)
Department of Cell and Developmental Biology
Vanderbilt Ingram Cancer Center (VICC)
Program in Cancer Biology
Gastrointestinal Cancer Research Program
Vanderbilt Digestive Disease Research Center
Vanderbilt Center for Mucosal Inflammation and Cancer

Our lab studies receptor tyrosine kinase (RTK) signaling in human health and disease with an emphasis on epidermal growth factor receptor (EGFR) signaling. The research may broadly be divided into two areas: 1. Trafficking of EGFR ligands in polarized epithelial cells: Spatial cues to regulate EGFR signaling are best appreciated in three-dimensional (3D) cultures (e.g. Transwell, type I collagen, and Matrigel cultures) than conventional 2D plastic cultures, where EGFR ligands are delivered and secreted in a polarized manner (apical vs basolateral trafficking). A major focus within this area is to understand the loss of epithelial polarity induced by loss of polarized trafficking of the EGFR ligand, epiregulin, and role of novel epiregulin-interacting proteins in the observed phenotypes. 2. Cetuximab resistance in colorectal cancer: Using 3D cultures of colorectal cancer (CRC) cells, we study novel resistance mechanisms to cetuximab, which is an FDA-approved EGFR neutralizing monoclonal antibody. We have discovered two non-genetic modes of cetuximab resistance and identified means to overcome this resistance by addition of a dual MET/RON RTK inhibitor, crizotinib. We are committed to elucidating the mechanistic underpinnings of this mode of cetuximab resistance, its scope in human CRC, and the therapeutic benefit of combined blockade of EGFR with RTKs, MET and RON. This multi-disciplinary and collaborative research integrates approaches like molecular cell biology, live or fixed (confocal) microscopy, comparative RNA-seq (single-cell or bulk), proteomic analysis, pre-clinical models (patient-derived xenografts and organoids, PDXs/PDOs), and small-animal imaging.

Keywords: Epithelial polarity , Colorectal cancer , Epithelial transformation , Receptor tyrosine kinases (EGFR, ERBBs, MET, RON) , Drug resistance , Protein trafficking

Research Area: Cancer Biology , Cell Signaling , Cell Structure , Epithelial Biology