Abstract 1591: Hepatocytes compensate for the loss of PHGDH in pancreatic cancer cells during liver metastasis
Authors: Ganguly Koelina , Yamamoto Keisuke , Rosado Joel Encarnacion , Sohn Albert , Biancur Douglas , Lin Elaine , White Elshadai , Kimmelman Alec C. 
Published: March 2024

Background: Pancreatic cancer (PC), one of the deadliest malignancies, exhibits a high rate of distant metastasis that directly correlates with the mortality rate. Liver serves as one of the most predominant sites of metastasis in PC patients. The nutrient availabilities at the metastatic organ and the metabolic dependencies of the invading tumor cells play pivotal role in shaping the metastatic tumor microenvironment (TME) and establishing metastatic colonies. We observed an elevated expression of PHGDH, the first rate-limiting enzyme of the serine (Ser) biosynthesis pathway, in the hepatocytes (most abundant liver-resident cells) isolated from murine pancreatic liver-metastasis (LM), as compared to normal livers. Hence, we hypothesized that hepatocytes may promote the growth of PC cells by sufficing for their Ser-requirement during LM.

Methods: Murine PC line (HY19636 derived from LSL-KrasG12D; p53 L/+, Ptf1a-Cre+ tumors), were used to generate LMs in B6 mice via hemi-splenic route. PHGDH was knocked-out by lentiviral and AAV-mediated delivery of CRISPR-Cas9 gRNAs in vitro and in vivo, respectively. RNA-seq, immunoblot, immunohistochemistry, confocal microscopy, ELISA, flow cytometry, chromatin immunoprecipitation and promoter-reporter analyses were performed to identify the molecular axis, followed by functional validations using genetic and pharmacologic inhibitions in murine and human lines. Frozen homogenates with matched formalin-fixed sections of LMs from PC patients provided a unique correlative platform for the study.

Results: A significant portion of the LM tissues (68% in our cohort of 32 PC patients) demonstrated no to very low expression of PHGDH in the cancer cells, rendering them as exogeneous Ser (exSer)-dependent. Notably, loss of PHGDH in the tumor cells induced an elevated PI3K/AKT signaling, downstream of a CXCL5/CXCR2 axis, in the neighboring hepatocytes. This led to FOXO3A’s cytoplasmic sequestration and decline in its occupancy on PHGDH promoter, causing a transcriptional upregulation of PHGDH in these hepatocytes, which enabled them to supply Ser and support the growth of exSer-dependent cancer cells in the liver. Abrogation of each node in the CXCR2-PI3K-FOXO3A axis and hepatocyte-specific deletion of PHGDH, led to a significant decline in the metastatic burden of exSer-dependent cells in the liver with a significant increase in overall mice survival, particularly under Ser-deprived dietary conditions.

Conclusion: Our findings demonstrate a novel cancer cell-hepatocytes crosstalk necessary for the growth of PC cells in Ser-depleted conditions. Here, we have identified several actionable signaling nodes in the liver that serve as compensatory metabolic allies for PC cells during liver metastasis, and can be considered as potential therapeutic targets in adjuvant setting.

Citation Format: Koelina Ganguly, Keisuke Yamamoto, Joel Encarnacion Rosado, Albert Sohn, Douglas Biancur, Elaine Lin, Elshadai White, Alec C. Kimmelman. Hepatocytes compensate for the loss of PHGDH in pancreatic cancer cells during liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1591.