Abstract 2689: FGF19 is a novel serum colorectal cancer biomarker that exerts endocrine paraneoplastic effects on hepatic tissue

Abstract

Abstract Despite having excellent prognosis when detected early, colorectal cancer (CRC) remains a leading cause of cancer-related deaths globally. Barriers to screening reduces compliance and negatively impacts patient outcomes, necessitating alternatives. A blood-based approach provides a more convenient and accessible modality, but serum markers are lacking. Using a meta-transcriptomics approach, we identified Fibroblast Growth Factor 19 (FGF19), an enteroendocrine FGF responsible for bile acid (BA) homeostasis, as an attractive CRC marker. However, whether FGF19 is aberrantly secreted into blood by colorectal tumors or induces endocrine-like paraneoplastic effects is unknown. To assess the strength of FGF19 as a CRC biomarker, expression data from the Genotype-Tissue Expression consortium (GTEx), The Cancer Genome Atlas (TCGA-COADREAD), and our curated Meta-dataset (E-MTAB-10089) were downloaded and analyzed for associations with prognostic indicators. Next, in silico FGF19 expression profiles were validated in vitro using a panel of five CRC cell lines via western blot with secretion quantitated by sandwich ELISA. To determine whether colorectal tumors contribute FGF19 to circulation, subcutaneous xenografts of HCT116 and Colo201 cells were established in four male and female NOD Scid gamma (NSG) mice. Tumor volume, as well as serum and urine FGF19 were assessed weekly over a 36-day period. Following euthanasia, murine liver and ileal tissue were processed for downstream mRNA and bile acid quantification. To determine if malignant FGF19 exerts paraneoplastic effects RNA sequencing was performed on hepatic mRNA using the Illumina NovaSeq 6000 system. Reads were processed, aligned, mapped, and analyzed for differential expression and functional enrichment using an integrated informatics pipeline implemented in R. Meta-transcriptomics revealed that ectopic overexpression of FGF19 was highly indicative of CRC and associated with unfavorable prognostic indicators including disease progression, treatment failure, and poor survival. In vitro testing recapitulated in silico findings, showing that that four out of five CRC cell lines constitutively express and secrete FGF19. We also readily detected FGF19 in serum and urine of mice harboring xenografts derived from Colo201, but not HCT116, cells. Moreover, circulating FGF19 levels increased with tumor size and exerted paraneoplastic effects on liver tissue such as suppression of BA synthesis, dysregulation of cholesterol metabolism, and induction of pre-neoplasia. In summary, we describe FGF19 as a putative serum CRC biomarker that exerts novel endocrine-like paraneoplastic effects on the liver. Study limitations included the lack of FGF19 quantification in CRC patient blood, in vivo experimentation using two different cell lines, and gender-related batch effects identified by RNA sequencing. Citation Format: Michael Walter Rohr, Jordan Beardsley, Sai Preethi Nakkina, Dexter Hadley, Deborah Altomare. FGF19 is a novel serum colorectal cancer biomarker that exerts endocrine paraneoplastic effects on hepatic tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2689.