Year 3

Cancers are often treated based on their underlying disease phenotype or molecular drivers.  While these targeted strategies may provide some initial benefit, they tend to fail over time as tumors develop resistance mechanisms.  Cancer stem cells, traditionally defined as a small population of “pre-existing” cells responsible for initiating a tumor, have been implicated as a major contributor to drug resistance.  Although small in number, it is thought the population of cancer stem cells within a tumor could survive therapy to regenerate an entire tumor over time or spread to distant sites. 

We suggest an alternate scenario in which any cell within a tumor could be “converted” or “reprogrammed” into a cancer stem-like cell.  In fact, cellular stresses typically found within the tumor microenvironment, including cancer therapies, induce a subset of markers and functions attributed to traditional cancer stem cells.  Our project has revealed how a protein called CD61 drives this reprogramming event, and we show how interfering with this pathway can lock cancer cells into a less aggressive and more therapy-responsive state. 

We have determined how stress changes the CD61 gene promoter region to allow for the induction of CD61 gene expression, and we have identified specific ways to impede this process.  We have also identified a mechanism by which CD61 forms clusters on the surface of cancer cells, and show that blocking this event has can prevent stem-like reprogramming, and we have also identified several important downstream signaling pathways that can be disrupted to prevent the conversion toward a cancer stem cell phenotype.  These findings offer a direct translational direction, since clinical trials are being planned to disrupt Galectin-3/αvβ3/KRAS clustering with a drug that targets Galectin-3.  We anticipate this agent should sensitize drug-resistant tumors to the EGFR inhibitors such as erlotinib.