PROGRAM TITLE: Determinants of Liver Metastasis
Liver metastasis indicates a terminal illness for many cancers and is a leading cause of cancer death in the
United States. There is currently no integrated research program devoted to mechanisms of liver metastasis.
While common in certain cancer types (such as pancreas and colon), metastasis is less common but highly
malignant in other cancer types (such as prostate cancer). The long-term goal of our Program is to
understand and address the shared and unique drivers of liver metastasis in colon, pancreas, and
prostate primary tumor types. Published work and preliminary data from the four integrated projects point to
key roles for four critical molecular signaling axes in mediating liver metastasis, through mechanisms likely
common across many primary tumor types. To complement this mechanistic expertise, this Program assembles
clinical expertise across different tumor types and liver microenvironment models.
Together, this collaborative Program investigates the hypothesis that normal liver tissue is inherently suppressive
of metastatic tumor expansion, unless alterations in the liver microenvironment result in the loss of metastatic
suppressors. Project 1 explores the acquisition of features that enable metastasis from circulating saturated fat
and subsequent endoglin signaling in hepatocytes and cancer epithelia. The pro-metastatic impact of hepatic
stellate cell (HSC)-derived hyaluronic acids in non-alcoholic fatty liver disease is examined in Project 2. Thought
to activate pro-cancer phenotypes of HSCs and macrophages, Project 3 investigates the regulation and
contribution of yes-associated protein (YAP) and downstream signaling pathways to create a pro-metastatic liver
microenvironment. Project 4 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. By
examining these four intersecting signaling pathways and comparing findings across models, this Program will
augment current understanding of factors in the liver microenvironment and tumor that permit the development
of liver metastases.
This 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
(prostate, colon, and pancreas). The Program adopts a unique approach, investigating the role of the normal
liver microenvironment and leveraging each project team’s substantial expertise along with essential resources,
including pharmacologic means of addressing the signaling axes, partnerships with healthcare providers to
validate the findings in animal models through human tissue specimens, and innovative technology to isolate
and analyze metastatic factors including circulating tumor cells and extracellular vesicles. Successful completion
of the Program will establish new paradigms in liver metastasis and test novel therapeutic strategies.