Abstract 6452: Exosomal Let 7 and its downstream protein targets may serve as predictive biomarkers in peritoneal carcinomatosis

The prognosis for patients with colorectal cancer with peritoneal carcinomatosis (PC) is dismal. Current biomarkers and imaging studies lack sensitivity and specificity to identify PC at early stages. Predictive and diagnostic serum biomarkers that help diagnose PC at early stages is necessary to improve patient outcomes. In the rapidly evolving field of liquid biopsy, exosomes show significant promise. The objective of our study is to identify exosomal biomarkers that are differentially expressed in patients with PC compared to visceral metastases (VM). Proteomic and miRNA analysis were performed using mass spectrometry and next generation sequencing on plasma exosomes from ten patients with colorectal cancer VM and nine patients with PC. Multiple members of the Let-7 family had differential levels of expression between these two patient groups. Specifically, Let-7 isoforms (Let-7a, Let-7d, Let-7e, Let-7f, Let-7g, Let-7i) were upregulated in plasma exosomes of patients with PC compared to those with VM. In addition, 33 exosomal proteins that are downstream targets of Let-7 were also found to be differentially expressed. Correlative investigation was conducted using cell lines representative of PC, VM and control to investigate the possible origins for this exosomal profile. RT-PCR was performed on cell lysates taken from normal colon (CCD-33-CO) and colorectal cancer (SK-CO-1, SNU-C1, and T84) cell lines to further identify Let-7 isoforms in these samples. Let-7 isoforms (Let 7a, Let-7b, Let-7d, Let-7e, Let-7f, Let-7i) were identified at increased levels in the colorectal cancer PC cell line in comparison to cells lines of non-PC colorectal cancer and normal colon. In-vivo and in-vitro studies demonstrate plasma exosomal Let-7 and its downstream protein targets are differentially expressed in colorectal PC compared to VM. Let-7 has been previously implicated in cancer progression and chemoresistance. While this differential expression suggests possible mechanistic differences between colorectal PC and VM, it may also offer a potential liquid biopsy for predicting peritoneal metastasis at a much earlier and treatable time.Citation Format: Mei Li M. Kwong, Paul A. Vallejos, Vola-Masoandro Andrianarijaona, Audrey Choi, Matthew J. Selleck, Tiantian Liu, Janviere Kabagwira, Charles Wang, William Langridge, Nathan R. Wall, Maheswari Senthil. Exosomal Let 7 and its downstream protein targets may serve as predictive biomarkers in peritoneal carcinomatosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6452.