Grant: Project Grant

The process of apoptosis, also known as programmed cell death, allows for the removal of damaged or redundant cells from a tissue without triggering inflammatory responses. During apoptotic cell death, dying cells undergo a number of characteristic changes shape, including rapid contraction, membrane blebbing, destruction of the integrity of the nucleus, and the release of small cell fragments called apoptotic bodies. Apoptotic cell death is markedly different from necrotic cell death, in which there is loss of cell membrane integrity and the release of cellular contents leading to inflammation. In 2001, we discovered the mechanism that drives the dramatic morphological changes which occur during apoptotic cell death. Caspase cleavage of the ROCK1 kinase results in the release of a constitutively-active protein fragment that promotes actin-myosin contraction, which provides force that powers cell contraction, membrane blebbing, nuclear disintegration and apoptotic body formation. By mutating a single amino acid in the ROCK1 caspase cleavage site in a genetically-modified (GM) mouse model, normal kinase activity was not affected, but ROCK1 cleavage and activation during apoptotic cell death were blocked. In a chemically-induced model of liver cancer, there were fewer primary and metastatic tumors in ROCK1 mutant mice relative to wild-type mice. In ROCK1 mutant liver tumors, there were immunological profiles consistent with those associated with better outcomes and recurrence free survival in human liver cancer patients. These results suggest that altering the pattern of ROCK1-mediated morphological changes during apoptotic cell death helps the immune system to fight cancer more effectively. An implication of these findings is that treatment with ROCK inhibitors converts immunologically "cold" tumors into "hot" tumors that would enable the immune system to more effectively suppress tumor growth and spread, and which could improve chemotherapeutic responses.