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

Jun Zhang, Lingfeng Fu, Huaitao Wang, Atsuko Yonemura, Takashi Semba, Noriko Yasuda-Yoshihara, Akiho Nishimura, Takuya Tajiri, Yilin Tong, Tadahito Yasuda, Tomoyuki Uchihara, Masaya Yamazaki, Yuya Okamoto, Juntaro Yamasaki, Osamu Nagano, Hideo Baba, Takatsugu Ishimoto

研究成果: ジャーナルへの寄稿学術論文査読

2 被引用数 (Scopus)

抄録

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.

本文言語英語
論文番号216901
ジャーナルCancer Letters
591
DOI
出版ステータス出版済み - 01-06-2024

All Science Journal Classification (ASJC) codes

  • 腫瘍学
  • 癌研究

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