Research
Fibrillogenesis in renal and cancer cell hypoxia and fibrosis
In the last few decades it has become increasingly well accepted that the extracellular matrix (ECM) functions not just as an inert scaffold but also as an active signaling site impacting cellular response and behavior. Fibronectin is an ECM protein that affects the rigidity of the matrix by signaling through its transmembrane integrin α5β1 receptor resulting in the self-assembly of dimeric FN into polymeric fibrils –a process called fibrillogenesis.
One area of interest in the lab is to investigate the interplay between FN and VHL in hypoxia. The VHL (Von Hippel Lindau) protein is a tumor suppressor that is either mutated or lost in renal cancers. VHL is a RING ligase that degrades the hypoxia inducible factor (HIF1α) under normoxic conditions but shows independent binding to FN upon neddylation. This interaction between FN and VHL is critical in determining the formation of a fibronectin matrix to influence invasive/migratory properties of the cell. In renal cancers due to the frequent mutation or loss of VHL, HIF1α is stabilized and a cancer hypoxic state is induced. Tissue hypoxia as seen during states of extreme oxygen deprivation has also been shown to alter fibronectin into an aligned matrix. Our goal is to differentiate the mediators of the aligned matrix as seen in pathological states of hypoxia during renal cancers versus non-pathological tissue hypoxia.
Another area of interest in the lab is the investigation of VHL-mediated fibrosis resolution. Bleomycin, a successful anti-cancer drug has been shown to cause Idiopathic pulmonary fibrosis (IPF). IPF is a devastating disease characterized by progressive loss of lung function and no therapeutic options. At a molecular level, during fibrosis, fibroblast cells in the lung differentiate into myofibroblasts, producing vast amounts of ECM proteins including fibronectin. The role of the VHL-FN axis will be explored in dermal and lung fibroblasts to study fibrosis resolution.
Caki-1 renal cancer cells immunostained for fibronectin (red) & nuclei (blue). Scale 5µm.
