DataSheet_1_SEMA3C Supports Pancreatic Cancer Progression by Regulating the Autophagy Process and Tumor Immune Microenvironment.pdf

To date, driver genes for pancreatic cancer treatment are difficult to pursue therapeutically. Targeting mutated KRAS, the most renowned driver gene in pancreatic cancer, is an active area of study. We discovered a gene named SEMA3C was highly expressed in pancreatic cancer cell lines and patients with a G12D mutation in KRAS. High expression of SEMA3C in patients was significantly associated with the decreased survival of pancreatic cancer patients based on the TCGA database. In pancreatic cancer cells, SEMA3C knockdown or inhibition exhibited growth/colony inhibition and cell cycle arrest. In addition, SEMA3C inhibition sensitized KRAS or MEK1/2 inhibition in pancreatic cancer cells. Overexpression of SEMA3C resulted in the induction of autophagy, whereas depletion of SEMA3C compromised induction of autophagy. SEMA3C modified the PD-L1 expression in tumor and immune cells and is correlated with the M2-like macrophage marker ARG1/CD163 expression, which could reshape the tumor microenvironment. Inhibition of SEMA3C decreased tumor formation in the xenograft model in vivo. Taken together, our data suggest that SEMA3C plays a substantial role in promoting cancer cell survival by regulating the autophagy process and impacting the tumor environment immune response. SEMA3C can be used as a novel target or marker with therapeutic or diagnostic potential in pancreatic cancer especially in tumors harboring the specific KRAS G12D mutation.

迄今为止，胰腺癌治疗的驱动基因难以实现治疗性探索。针对胰腺癌中最著名的驱动基因KRAS的突变体，已成为研究的热点领域。我们发现，名为SEMA3C的基因在胰腺癌细胞系及KRAS G12D突变患者的胰腺癌组织中高度表达。根据TCGA数据库，SEMA3C在患者中的高表达与胰腺癌患者的生存率显著降低密切相关。在胰腺癌细胞中，SEMA3C的敲低或抑制表现出对生长/集落形成和细胞周期停滞的抑制作用。此外，SEMA3C的抑制增强了胰腺癌细胞中KRAS或MEK1/2抑制的敏感性。SEMA3C的过表达诱导自噬，而SEMA3C的耗竭则损害了自噬的诱导。SEMA3C可调节肿瘤和免疫细胞中的PD-L1表达，并与M2样巨噬细胞标志物ARG1/CD163的表达相关，从而重塑肿瘤微环境。在异种移植模型中，SEMA3C的抑制降低了肿瘤的形成。综上所述，我们的数据表明，SEMA3C通过调节自噬过程和影响肿瘤环境免疫反应，在促进癌细胞存活中发挥着重要作用。SEMA3C可作为胰腺癌新型治疗靶点或诊断标志物，特别是在携带特定KRAS G12D突变的肿瘤中具有治疗或诊断潜力。