Epigenetic Control of Anoikis in Lung Cancer

The loss of adhesion of epithelial and endothelial cells from the extracellular matrix causes a specialized form of apoptosis called anoikis.

In transformed cells, a large number of studies now demonstrate that cancer cells must first disable anoikis in order to gain metastatic capability. The examination of genes and proteins which mediate anoikis has yielded important insights into the origins of metastatic behavior.

In our studies of the Shc proteins, we found that p66Shc specifically mediates anoikis and is therefore commonly silenced in metastatic lung cancers. We found that this isoform is controlled by three upstream enhancer regions which cooperatively reconfigure chromatin to cis-activate p66Shc.

In metastatic cancers, a lymphocyte-restricted chromatin regulator called Aiolos interrupts this complex and silences p66Shc as well as a large number of epithelial-associated adhesion-related genes, in essence reprogramming epithelium to become more blood-cell-like.

Ongoing projects in the lab focus on the larger epigenomic patterns of lung cancers that may cause lineage distortion and promote metastatic behavior