Hippo pathway in cancer cells induces NCAM1+αSMA+ fibroblasts to modulate tumor microenvironment
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)<sup>+</sup>alpha-smooth muscle actin (αSMA)<sup>+</sup> 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<sup>+</sup>αSMA<sup>+</sup> CAFs and dysfunctional T cells. Notably, similar Hippo pathway-induced NCAM1<sup>+</sup>αSMA<sup>+</sup> CAFs were observed in human breast cancer, highlighting the potential of TME-manipulating strategies to reduce immunosuppression in cancer immunotherapy.
Authors
- Suyanee Thongchot (ORCID: https://orcid.org/0000-0003-3159-0464)
- Peti Thuwajit (ORCID: https://orcid.org/0000-0003-0798-1510)
- Mayumi Niimura
- Somponnat Sampattavanich (ORCID: https://orcid.org/0000-0001-7783-6103)
- Mayuko Shimoda (ORCID: https://orcid.org/0009-0009-6681-502X)
- Yanliang Liu
- Kun‐Liang Guan (ORCID: https://orcid.org/0000-0003-1892-0174)
- Romgase Sakamula (ORCID: https://orcid.org/0009-0006-9666-0709)
- Akihiro Nita (ORCID: https://orcid.org/0000-0003-2647-5445)
- Omnia Reda (ORCID: https://orcid.org/0000-0002-1260-0527)
- Yasuhisa Sakamoto (ORCID: https://orcid.org/0000-0003-1833-6197)
- Chanida Thinyakul (ORCID: https://orcid.org/0000-0002-2927-0595)
- Ayato Maeda
- Toshiro Moroishi (ORCID: https://orcid.org/0000-0001-6419-3882)
- Yohei Kanamori (ORCID: https://orcid.org/0009-0003-4062-5910)
- Yorifumi Satou (ORCID: https://orcid.org/0000-0002-1495-7810)
- Keiichi I. Nakayama
- Chanitra Thuwajit (ORCID: https://orcid.org/0000-0001-9506-6405)
- Paweenapon Chunthaboon (ORCID: https://orcid.org/0009-0005-6614-030X)
- David Nduru
Institutions
- Siriraj Hospital (TH)
- Kyushu University (JP)
- Kumamoto Health Science University (JP)
- Mahidol University (TH)
- Westlake University (CN)
- Institute of Science Tokyo (JP)
- The University of Tokyo (JP)
- Kumamoto University (JP)
Publication Details
- Journal
- Communications Biology
- Published
- 2024-10-17
- DOI
- https://doi.org/10.1038/s42003-024-07041-4
- Citations
- 11
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 3.59
Funders
- Takeda Science Foundation
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- Canadian Mental Health Association
- Kumamoto University
- Mahidol University
- National Research Council of Thailand
- Kobayashi Foundation for Cancer Research
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency