Abstract 3959: MMP13 contributes to metastatic tumor growth in the steatotic liver microenvironment.

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Abstract The expanding obesity epidemic has led to an escalation in the incidence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis, which are associated with an increase in incidence of primary and metastatic liver cancer. As NAFLD progresses, it is characterized by marked inflammation in the liver described as non-alcoholic steatohepatitis (NASH). The mechanisms by which NASH increases risk of liver cancer are not fully known but complete understanding of these mediators is necessary for effective therapeutic and preventive strategies. Importantly, metastasis represents the final stage in cancer progression and is the most significant cause of cancer related mortality. Using our mouse model of diet induced steatosis, coupled with a model of experimental liver metastasis, we have previously shown a significant increase in the number of metastatic foci in the steatotic liver compared to the normal livers. Microarray analysis revealed that MMP13, a member of the Matrix Metalloproteinase (MMP) family recognized to be involved in liver disease and cancer progression, is significantly upregulated in the steatotic liver compared to normal livers. Additionally, MMP13 is expressed in several cancer cell types. Emerging data suggests that MMP13 may play a key role in priming the microenvironment for the establishment of liver metastases, by modulation of cytokine profiles and recruitment of inflammatory cells. . We hypothesize that MMP13 is a key modulator of the steatotic microenvironment, and that increased MMP13 levels favor primary tumor growth as well as the establishment of metastases. To determine the role of stromal MMP13 on metastasis to the liver, we are using the experimental splenic injection model of liver metastasis with syngeneic MC38 colon cancer cells in mice genetically deficient in MMP13. Additionally, since the tumor cells themselves express MMP13, wildtype mice are injected with either shRNA control or MMP13 knockdown MC38 colon cancer cells to determine the role of tumor cell derived MMP13. Preliminary data shows localization of MMP13 expression to the hepatic stellate cells as well as CD11b positive myeloid cells from livers with NASH. Further, invitro analysis of migration and invasion ability of parental and MMP13 shRNA knockdown MC38 cells show that MMP13 promotes the invasive and migratory properties of the metastatic cancer cells themselves. MMP13 may thus be a potential mediator of inflammation in the tumor microenvironment as well as of the metastatic capacity of cancer cells to the liver. Citation Format: Alisha M. Mendonsa, Michael VanSaun, David L. Gorden. MMP13 contributes to metastatic tumor growth in the steatotic liver microenvironment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3959. doi:10.1158/1538-7445.AM2013-3959