Determinants of Liver Metastasis Program
Liver metastasis is a leading cause of cancer deaths in the United States. The Determinants of Liver Metastasis Program at Cedars-Sinai seeks to understand and address the shared and unique drivers of liver metastasis in colon, pancreas and prostate primary tumor types, a significant cause of morbidity and mortality in multiple cancer types. By examining four intersecting signaling pathways and comparing findings across models, our program will augment current understanding of factors in the liver microenvironment and tumor that permit the development of liver metastases. We hypothesize that normal liver tissue is inherently suppressive of metastatic tumor expansion, unless alterations in the liver microenvironment result in the loss of metastatic suppressors.
This National Cancer Institute supported P01 program unites essential expertise in the fields of liver and cancer pathobiology to represent the first multi-investigator effort focused on common mechanisms involved in liver metastasis from disparate tumor models. Program success will establish new paradigms in liver metastasis and test novel therapeutic strategies.
The four projects examines different aspects of liver disease, but study overlapping signaling pathways common to the support or metastatic
Projects
Explores the acquisition of features that enable metastasis from circulating saturated fat and endoglin signaling in hepatocytes and cancer epithelia.
- A high-fat diet can make the liver a tumor-permissive niche and promote epithelial survival in an endoglin-dependent manner.
- Address the role of bone morphogenetic protein/endoglin signaling through therapeutic intervention of liver metastasis.
Examines the pro-metastatic impact of hepatic stellate cell (HSC)-derived hyaluronic acids in non-alcoholic fatty liver disease.
- Non-alcoholic fatty liver disease accelerates liver metastasis by promoting stellate cells and hyaluronic acids.
- The liver niche is primed by microRNA in extracellular vesicles generated by the fatty hepatocytes.
Studies the regulation and contribution of yes-associated protein (YAP) in creating a pro-metastatic liver microenvironment through the activation of a pro-cancer phenotypes of HSCs and macrophages.
- YAP and macrophage-stimulating protein (MSP)/RON signaling in metastatic cancer cells reprogram the liver to overcome hepatic resistance to metastasis.
- Therapeutic targeting of histone deacetylase and glycogen synthase kinase 3 beta inhibit pro-metastatic YAP and MSP/RON signaling.
Investigates the roles of methionine adenosyltransferase (MAT) proteins in liver metastasis, from the loss of protective MAT1A to the pro-cancer elevated expression of MAT2A and MAT2B.
- While liver MAT1A activity protects against cancer metastasis, elevated MAT2A and MAT2B expression in cancer cells lowers this defense.
- Molecules that target the MAT proteins and downstream mediators inhibit liver metastasis.
Cores
- Support statistically significant preclinical studies
- Develop mathematic models for liver metastasis evaluating proteomic and transcriptomic data
- Develop preclinical models for liver metastasis
- Evaluate changes in signaling and immune changes associated with liver metastasis patient tissues using circulating tumor cell enrichment, CyTOF and GeoDx technologies