RAC1-mediated integrin alpha-6 expression in E-cadherin-deficient gastric cancer cells promotes interactions with the stroma and peritoneal dissemination

• Published in: Cancer letters Vol. 591; p. 216901
• Main Authors: Zhang, Jun, Fu, Lingfeng, Wang, Huaitao, Yonemura, Atsuko, Semba, Takashi, Yasuda-Yoshihara, Noriko, Nishimura, Akiho, Tajiri, Takuya, Tong, Yilin, Yasuda, Tadahito, Uchihara, Tomoyuki, Yamazaki, Masaya, Okamoto, Yuya, Yamasaki, Juntaro, Nagano, Osamu, Baba, Hideo, Ishimoto, Takatsugu
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.06.2024
• Subjects: Cancer-associated fibroblasts; Extracellular matrix; Gastric cancer; Itga6; Peritoneal dissemination; Cancer-associated fibroblasts; Extracellular matrix; Peritoneal dissemination; Itga6; Gastric cancer; cancer-associated fibroblasts; peritoneal dissemination; extracellular matrix
• ISSN: 0304-3835; 1872-7980; 1872-7980
• DOI: 10.1016/j.canlet.2024.216901

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. Loss of the Cdh1 gene 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. The activated Itga6-FAK-AKT axis promotes cell growth and migration. [Display omitted] •GAN-KP and Cdh1-deleted GAN-KP (GAN-KPC) cells derived orthotopic tumours mimic the characteristics of human IGC and DGC.•Rac1 induces Itga6 trafficking, leading to its enrichment on the GC cell membrane.•Fibroblasts activate FAK/AKT pathway in GC cells through ECM-Itga6 interaction, thereby exacerbating the malignant phenotype.•GC cells enhance the collagen expression in fibroblast and the transformation into CAFs, resulting in DGC-like morphology.