Signaling networks in cancer stromal senescent cells establish malignant microenvironment
Abstract
The tumor microenvironment (TME) encompasses various cell types, blood and lymphatic vessels, and noncellular constituents like extracellular matrix (ECM) and cytokines. These intricate interactions between cellular and noncellular components contribute to the development of a malignant TME, such as immunosuppressive, desmoplastic, angiogenic conditions, and the formation of a niche for cancer stem cells, but there is limited understanding of the specific subtypes of stromal cells involved in this process. Here, we utilized p16-Cre ERT2 -tdTomato mouse models to investigate the signaling networks established by senescent cancer stromal cells, contributing to the development of a malignant TME. In pancreatic ductal adenocarcinoma (PDAC) allograft models, these senescent cells were found to promote cancer fibrosis, enhance angiogenesis, and suppress cancer immune surveillance. Notably, the selective elimination of senescent cancer stromal cells improves the malignant TME, subsequently reducing tumor progression in PDAC. This highlights the antitumor efficacy of senolytic treatment alone and its synergistic effect when combined with conventional chemotherapy. Taken together, our findings suggest that the signaling crosstalk among senescent cancer stromal cells plays a key role in the progression of PDAC and may be a promising therapeutic target.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (14)
Yue Zhang
Teh-Wei Wang
Division of Cancer Cell Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
Maho Tamatani
Division of Cancer Cell Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
Xinyi Zeng
Division of Cancer Cell Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
Lindo Nakamura
Division of Cancer Cell Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
Satotaka Omori
Division of Cancer Cell Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
Kiyoshi Yamaguchi
Division of Clinical Genome Research, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
Seira Hatakeyama
Division of Clinical Genome Research, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
Eigo Shimizu
Satoshi Yamazaki
Laboratory for Stem Cell Therapy, Faculty of Medicine, Tsukuba University
Yoichi Furukawa
Division of Clinical Genome Research, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
Seiya Imoto
Yoshikazu Johmura
Division of Cancer and Senescence Biology, Cancer Research Institute, Kanazawa University
Makoto Nakanishi
Division of Cancer Cell Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo