Abstract：
Diffuse-type gastric cancer (DGC) is a subtype of gastric cancer that is prone to peritoneal dissemination, with poor patient prognosis. Although intercellular adhesion loss between cancer cells is a major characteristic of DGCs, the mechanism underlying the alteration in cell-to-extracellular matrix (ECM) adhesion is unclear. We investigated how DGCs progress and cause peritoneal dissemination through interactions between DGC cells and the tumour microenvironment (TME). P53 knockout and KRASG12V-expressing (GAN-KP) cells and Cdh1-deleted GAN-KP (GAN-KPC) cells were orthotopically transplanted into the gastric wall to mimic peritoneal dissemination. The GAN-KPC tumour morphology was similar to that of human DGCs containing abundant stroma. RNA sequencing revealed that pathways related to Rho GTPases and integrin-ECM interactions were specifically increased in GAN-KPC cells compared with GAN-KP cells. Notably, we found that Rac Family Small GTPase 1 (RAC1) induces Integrin Subunit Alpha 6 (ITGA6) trafficking, leading to its enrichment on the GC cell membrane. Fibroblasts activate the FAK/AKT pathway in GC cells by mediating extracellular matrix (ECM)-Itga6 interactions, exacerbating the malignant phenotype. In turn, GC cells induce abnormal expression of fibroblast collagen and its transformation into cancer-associated fibroblasts (CAFs), resulting in DGC-like subtypes. These findings indicate that Cdh1 gene loss leads to abnormal expression and changes in the subcellular localization of ITGA6 through RAC1 signalling. The latter, through interactions with CAFs, allows for peritoneal dissemination.
摘要：
弥漫型胃癌（DGC）是胃癌的一种亚型，易发生腹膜播散，患者预后差。尽管癌细胞之间的细胞间粘附丧失是DGC的主要特征，细胞-细胞外基质(ECM)粘附改变的潜在机制尚不清楚.我们研究了DGC如何通过DGC细胞与肿瘤微环境（TME）之间的相互作用而进展并引起腹膜传播。将p53敲除和KRASG12V表达（GAN-KP）细胞和Cdh1缺失的GAN-KP（GAN-KPC）细胞原位移植到胃壁中以模拟腹膜播散。GAN-KPC肿瘤形态与含有丰富基质的人DGC相似。RNA测序显示，与GAN-KP细胞相比，GAN-KPC细胞中与RhoGTP酶和整联蛋白-ECM相互作用相关的途径特异性增加。值得注意的是,我们发现Rac家族小GTP酶1（RAC1）诱导整合素亚基α6（Itga6）运输，导致其在GC细胞膜上的富集。成纤维细胞通过介导细胞外基质（ECM）-Itga6相互作用激活GC细胞中的FAK/AKT通路，恶化的恶性表型。反过来,GC细胞诱导成纤维细胞胶原异常表达并转化为癌相关成纤维细胞(CAFs),导致类似DGC的子类型。这些发现表明Cdh1基因丢失导致异常表达和通过RAC1信号传导的ITGA6亚细胞定位的变化。后者,通过与CAF的相互作用，允许腹膜传播。
