Browsing School of Medicine by Author "Zhan, Steven"
Investigating the Role of Metastasis Suppressor 1 (MTSS1/MIM) in Cancer BiologyBaxter, Shaneen; Zhan, Steven (2020)Metastasis suppressor 1 (MTSS1/MIM) is a multi-domain, membrane-associated protein that has been linked to progression and poor prognosis of several types of cancer. It was initially thought to be metastasis suppressor, but it has been shown to be overexpressed as well as downregulated in both metastatic and non-metastatic cancer, making its role in tumorigenesis unclear. There are also questions about how MIM becomes deregulated in certain types of cancer. In this study, we hypothesized that factors within the microenvironment such as inflammation, nutrient availability, chemokine gradients and autophagy are major contributors to the role of MIM in cancer progression and metastasis. As a member of the BAR domain superfamily, a family of proteins that bind and deform membranes, MIM is thought to be involved in intracellular membrane trafficking pathways such as endocytosis and autophagy. This lab previously reported that MIM interacts with E3 ubiquitin ligase, AIP4, and endocytic Rabs to regulate cell surface expression of the CXCR4 receptor. In this study, we further investigated the role of MIM in CXCR4 endocytosis by examining the interaction of MIM with Rab7 and Rab11. Upon internalization, CXCR4 may be guided into the lysosomal degradation pathway or the recycling pathway. We found that an interaction with Rab7 (a marker for late endosomes of the lysosomal pathway) is necessary for MIM to function in CXCR4 endocytosis. We also found that MIM does not interact with Rab11 (a marker for recycling endosomes), instead, another I-BAR domain protein, IRTKS, seems to mediate CXCR4 recycling. We examined the role inflammation may play in aberrant MIM expression and function, and discovered that inflammatory cytokines downregulate MIM in macrophages, indirectly leading to CXCR4 cell surface overexpression and increased migration of these cells towards a SDF-1 gradient. This is of significance because SDF-1 is often secreted by stromal cells within the tumor microenvironment and at common metastatic sites. We also investigated the role of MIM in autophagy, and found that overexpression of MIM inhibits basal autophagy, which has the potential to promote tumorigenesis. Overall, our results provided further insights into how MIM deregulation can lead to cancer progression and metastasis.