Identification of Genes Associated with Liver Metastasis in Pancreatic Cancer Reveals PCSK6 as a Crucial Mediator

Abstract

Liver metastasis occurs frequently in patients with pancreatic cancer. We analyzed the molecular profiling in liver metastatic lesions aiming to uncover novel genes responsible for tumor progression. Bioinformatics analysis was applied to identify genes directing liver metastasis. CRISPR/Cas9 technology was used to knock out the candidate gene. Proliferation assays, colony formation assays, cell cycle analysis, migration assays, wound healing assays, Immunofluorescence analysis, and the tumor xenograft model of intrasplenic injection were adopted to evaluate the effects of PCSK6 inactivation on cell growth, migration and liver metastasis. GSEA and Western blot were used to investigate the corresponding signaling pathway. PCSK6 was one of the obtained liver-metastasis-related genes in pancreatic cancer. PCSK6 inactivation inhibited cell growth and cell migration, due to G0/G1 cell cycle arrest and the remodeling of cell–cell junctions or the cell skeleton, respectively. PCSK6 inactivation led to fewer counts and lower outgrowth rates of liver metastatic niches in vivo. The Raf-MEK1/2-ERK1/2 axis was repressed by PCSK6 inactivation. Accordingly, we found PCSK6 inactivation could inhibit cell growth, cell migration, and liver metastasis, and explored the role of the Raf-MEK1/2-ERK1/2 axis in PCSK6 inactivation. PCSK6-targeted therapy might represent a novel approach for combatting liver metastasis in pancreatic cancer.

Single-cell and spatial transcriptomic analyses reveal the cellular origins and drivers of liver metastasis from pancreatic cancer

“…The best course of treatment for localized pancreatic cancer is surgery, although most cases of the disease return following surgery, and most patients pass away within 10 years of being diagnosed 18,19 . Moreover, the most common event of tumor development in pancreatic cancer is LM, and current treatments have not produced satisfying results 20,21 . Thus, it is particularly important to explore the mechanism of LM and identify novel biomarker at an early stage of pancreatic cancer.…”

Pancreatic Cancer: From Genetic Mechanisms to Translational Challenges

“…He H. provide an elegant demonstration of the role of the PCSK6 gene as one crucial mediator of tumor progression, suggesting a possible target for tackling liver metastases that frequently occur in PDAC [ 9 ].…”