SEMA5A-PLXNB3 axis promotes PDAC liver metastasis outgrowth through enhancing Warburg effect

Background: Patients bearing liver metastasis of pancreatic adeno carcinoma (PDAC) suffer from poor prognosis due to its short duration and high mortality. Complex tumor microenvironment (TME) exists in liver metastatic niches and tumor associated macrophages (TAMs) have play vital roles in metastasis generation and outgrowth. Methods: : We set off from investigating the aggregation and infiltration of TAMs at metastasis sites of PDAC and further evaluated related prognosis using clinical samples, discovering the critical roles of SEMA5A-PLXNB3 axis have played in PDAC liver metastasis. We thus performed intrasplenic injection mouse models assessed by CT combined in vivo imaging with organ reconstruction and Kras G12D / Trp53 R172H / Pdx1 -Cre (KPC) mouse models for in vivo study and CCK-8 assays for in vitro study. In mechanism investigation, we observed the alterations of glucose consumptions, lactate productions and expression of key enzymes involved in glycolysis induced by SEMA5A-PLXNB3 axis. Seahorse system measuring extracellular acid rate (ECAR) was also utilized. Results: : We have demonstrated that M2 TAMs enriched liver metastatic niches predicted poor prognosis. Further studies have unveiled that TAMs derived secreted protein SEMA5A could bind to tumor cell expressed PLXNB3 and thus facilitated the proliferation ability of which. The activation of SEMA5A-PLXNB3 axis increased glucose consumption and lactate production of tumor cells via modulating location of HIF-1α and stimulating expressions of glycolysis related genes. Conclusion: We have discovered that SEMA5A-PLXNB3 axis could achieve tumor cell proliferation and survival via enhancing aerobic glycolysis termed as Warburg effects. Targeting this axis may be a potential therapeutic approach for PDAC patients with unresectable liver metastasis.