GAS2L1 Is a Potential Biomarker of Circulating Tumor Cells in Pancreatic Cancer

SIMPLE SUMMARY: The analysis of circulating tumor cells (CTC) is a mainstay of liquid biopsy of solid malignancies. However, research to date has not yet determined a universal and specific marker for CTCs of pancreatic cancer. Genetically engineered mouse models (GEMMs) of pancreatic cancer, can mimic the human disease very closely. This study aimed to identify potential biomarkers for CTCs in a GEMM of pancreatic cancer and further validate markers in human samples. Therefore, we analyzed single-cell RNA sequencing data of murine pancreatic CTCs and performed advanced bioinformatic analyses. We demonstrated that the focal adhesion pathway is functionally enriched in pancreatic CTCs. In addition, we suggest Gas2l1/GAS2L1 as a potential surface marker of pancreatic CTCs. In combination with Epcam/EPCAM, Gas2l1/GAS2L1 identify the majority of pancreatic CTCs. Furthermore, pancreatic cancer patients with overexpression of GAS2L1 have an unfavorable prognostic outcome. ABSTRACT: Pancreatic cancer is a malignant disease with high mortality and a dismal prognosis. Circulating tumor cell (CTC) detection and characterization have emerged as essential techniques for early detection, prognostication, and liquid biopsy in many solid malignancies. Unfortunately, due to the low EPCAM expression in pancreatic cancer CTCs, no specific marker is available to identify and isolate this rare cell population. This study analyzed single-cell RNA sequencing profiles of pancreatic CTCs from a genetically engineered mouse model (GEMM) and pancreatic cancer patients. Through dimensionality reduction analysis, murine pancreatic CTCs were grouped into three clusters with different biological functions. CLIC4 and GAS2L1 were shown to be overexpressed in pancreatic CTCs in comparison with peripheral blood mononuclear cells (PBMCs). Further analyses of PBMCs and RNA-sequencing datasets of enriched pancreatic CTCs were used to validate the overexpression of GAS2L1 in pancreatic CTCs. A combinatorial approach using both GAS2L1 and EPCAM expression leads to an increased detection rate of CTCs in PDAC in both GEMM and patient samples. GAS2L1 is thus proposed as a novel biomarker of pancreatic cancer CTCs.