1. Hippo pathway in cancer cells induces NCAM1+αSMA+ fibroblasts to modulate tumor microenvironment.
- Author
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Thinyakul, Chanida, Sakamoto, Yasuhisa, Shimoda, Mayuko, Liu, Yanliang, Thongchot, Suyanee, Reda, Omnia, Nita, Akihiro, Sakamula, Romgase, Sampattavanich, Somponnat, Maeda, Ayato, Chunthaboon, Paweenapon, Nduru, David, Niimura, Mayumi, Kanamori, Yohei, Thuwajit, Peti, Nakayama, Keiichi, Guan, Kun-Liang, Satou, Yorifumi, Thuwajit, Chanitra, and Moroishi, Toshiro
- Subjects
Tumor Microenvironment ,Animals ,Mice ,Hippo Signaling Pathway ,Actins ,Humans ,Female ,CD56 Antigen ,Protein Serine-Threonine Kinases ,Cancer-Associated Fibroblasts ,Cell Line ,Tumor ,Mice ,Inbred BALB C ,Signal Transduction ,Fibroblasts ,Breast Neoplasms - Abstract
Cancer cells adeptly manipulate the tumor microenvironment (TME) to evade host antitumor immunity. However, the role of cancer cell-intrinsic signaling in shaping the immunosuppressive TME remains unclear. Here, we found that the Hippo pathway in cancer cells orchestrates the TME by influencing the composition of cancer-associated fibroblasts (CAFs). In a 4T1 mouse breast cancer model, Hippo pathway kinases, large tumor suppressor 1 and 2 (LATS1/2), promoted the formation of neural cell adhesion molecule 1 (NCAM1)+alpha-smooth muscle actin (αSMA)+ CAFs expressing the transforming growth factor-β, which is associated with T cell inactivation and dysfunction. Depletion of LATS1/2 in cancer cells resulted in a less immunosuppressive TME, indicated by the reduced proportions of NCAM1+αSMA+ CAFs and dysfunctional T cells. Notably, similar Hippo pathway-induced NCAM1+αSMA+ CAFs were observed in human breast cancer, highlighting the potential of TME-manipulating strategies to reduce immunosuppression in cancer immunotherapy.
- Published
- 2024