TGFβ signaling activated by cancer-associated fibroblasts determines the histological signature of lung adenocarcinoma

Ryo Sato, Kosuke Imamura, Takashi Semba, Yusuke Tomita, Sho Saeki, Koei Ikeda, Yoshihiro Komohara, Makoto Suzuki, Takuro Sakagami, Hideyuki Saya, Yoshimi Arima

研究成果: Article査読

4 被引用数 (Scopus)

抄録

Invasive lung adenocarcinoma (LADC) can be classified histologically as lepidic, acinar, papillary, micropapillary, or solid. Most LADC tumors manifest several of these histological subtypes, with heterogeneity being related to therapeutic resistance. We report here that in immunodeficient mice, human LADC cells form tumors with distinct histological features, MUC5AC-expressing solid-type or cytokeratin 7 (CK7)-expressing acinar-type tumors, depending on the site of development, and that a solid-to-acinar transition (SAT) could be induced by the tumor microenvironment. The TGFβ-Smad signaling pathway was activated in both tumor and stromal cells of acinar-type tumors. Immortalized cancerassociated fibroblasts (CAF) derived from acinar-type tumors induced SAT in 3D cocultures with LADC cells. Exogenous TGFβ1 or overexpression of an active form of TGFβ1 increased CK7 expression and reduced MUC5AC expression in LADC cells, and knockdown of Tgfb1 mRNA in CAFs attenuated SAT induction. RNA-sequencing analysis suggested that angiogenesis and neutrophil recruitment are associated with SAT in vivo. Our data indicate that CAF-mediated paracrine TGFβ signaling induces remodeling of tumor tissue and determines the histological pattern of LADC, thereby contributing to tumor heterogeneity.

本文言語English
ページ(範囲)4751-4765
ページ数15
ジャーナルCancer Research
81
18
DOI
出版ステータスPublished - 2021 9月 15

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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