Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Gregory L. Beatty

Abstract

The liver is the most common site of metastasis in cancer. While this metastatic tropism may reflect trapping of tumor cells that enter the circulation, mechanistic basis for the propensity of tumor cells to metastasize to the liver remains ill-defined. Here, we show using the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) mouse model of pancreatic adenocarcinoma (PDAC) that primary tumor development enhances the susceptibility of the liver to metastatic colonization by establishing a “pro-metastatic” niche in the liver. This niche is notable for accumulation of myeloid cells and extracellular matrix proteins, including fibronectin. 3’ mRNA sequencing of RNA isolated from the liver of KPC mice versus control LSL-Trp53R172H/+;Pdx-1-Cre (PC) mice revealed that the liver produces a specific set of myeloid chemoattractants, particularly serum amyloid A1 and A2 (SAA), early during tumorigenesis. In addition, gene set enrichment analysis (GSEA) on genes upregulated in the liver of KPC mice demonstrated a significant enrichment of the interleukin 6 (IL-6)/Signal Transducer and Activator of Transcript 3 (STAT3) signaling pathway. Consistent with this finding, phosphorylation of STAT3 was detected in 80-90% of hepatocytes. We determined a requirement for IL-6/STAT3/SAA signaling in the formation of a pro-metastatic niche by comparing the metastatic potential of wild type mice, Il-6 knockout (Il-6-/-) mice, and mice that lack Stat3 specifically in hepatocytes (Stat3flox/flox Alb-Cre) after orthotopic implantation of KPC-derived PDAC cells. Compared to wild type mice, the liver of Il-6-/- mice and Stat3flox/flox Alb-Cre mice was less susceptible to metastatic colonization and showed significantly less accumulation of myeloid cells, fibrosis, and production of SAA in the liver. Further, using Saa knockout (Saa-/-) mice, we found that SAA production by hepatocytes was required for the formation of a pro-metastatic niche in the liver and increased susceptibility to metastatic colonization. Many patients with a history of locally advanced and metastatic disease showed elevated levels of circulating SAA, which were correlated with worse overall survival. SAA overexpression was also detected in hepatocytes in liver biopsy samples collected from PDAC and colorectal cancer patients. Collectively, our data identify hepatocytes as a key driver of liver metastasis and reveal new therapeutic targets for cancer.

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