The role of Asap1 in physiology and tumor metastasis

Abstract

Tumor progression represents an array of complex events that ultimately lead to metastasis, the end-stage of cancer that is responsible for the majority of cancer-related mortalities. Improved ways to target the spread of cancer are thus imperative to treat cancer effectively. Understanding the mechanisms that regulate the dissemination of cancer cells from the primary site to distant places is a pre-requisite for such strategies. Asap1 (Arf-GAP with SH3-domains, Ankyrin-repeats and PH-domains) was identified by our lab in an unbiased screen to identify genes whose expression is associated with the metastatic phenotype. It was shown to be functionally involved in tumor progression in experimental animal models and this expression was correlated with poor metastasisfree survival and prognosis in colorectal cancer patients. To understand the role of Asap1 in normal physiology and in cancer, in my thesis work I studied Asap1 knockout (Asap1GT/GT) mice, generated in our lab by targeted deletion of the gene. I observed that Asap1GT/GT mice can live to maturity, although there is a reduction in the expected number of homozygous knockout offspring at birth. Deletion of Asap1 results in growth retardation, respiratory distress and reduced angiogenesis in the surviving pups. This physiological phenotype in the absence of Asap1 is transient, and adult Asap1GT/GT mice are morphologically undistinguishable from the wild-type mice.I further studied breast tumor development and metastasis in Asap1GT/GT mice using autochthonous models of breast cancer. My results demonstrate that loss of Asap1 in MMTV-PyMT mice leads to an earlier tumor onset, faster tumor growth and increased metastasis to the lungs. I also examined the effect of ASAP1 deficiency on the behaviour of breast cancer cells and fibroblasts taken from Asap1+/+ and Asap1GT/GT mice. Taken together, my results show that Asap1 is a critical regulator of cellular motility and its absence gives rise to developmental defects in newborn mice.Deficiency of ASAP1 also has tumor cell non-autonomous effects, and leads to increased numbers of metastases in the MMTV-PyMT autochthonous mouse model of breast cancer.