Abstract
The interplay between apoptotic cancer cells and the tumor microenvironment modulates cancer progression and metastasis. Cancer-associated fibroblasts (CAFs) play a crucial role in promoting these events through paracrine communication. Here, we demonstrate that conditioned medium (CM) from lung CAFs exposed to apoptotic cancer cells suppresses TGF-β1-induced migration and invasion of cancer cells and CAFs. Direct exposure of CAFs to apoptotic 344SQ cells (ApoSQ) inhibited CAF migration and invasion and the expression of CAF activation markers. Enhanced secretion of Wnt‐induced signaling protein 1 (WISP-1) by CAFs exposed to ApoSQ was required for these antimigratory and anti-invasive effects. Pharmacological inhibition of Notch1 activation or siRNA-mediated Notch1 silencing prevented WISP-1 production by CAFs and reversed the antimigratory and anti-invasive effects. Enhanced expression of the Notch ligand delta-like protein 1 on the surface of ultraviolet-irradiated apoptotic lung cancer cells triggered Notch1-WISP-1 signaling. Phosphatidylserine receptor brain-specific angiogenesis inhibitor 1 (BAI1)-Rac1 signaling, which facilitated efferocytosis by CAFs, participated in crosstalk with Notch1 signaling for optimal production of WISP-1. In addition, a single injection of ApoSQ enhanced WISP-1 production, suppressed the expression of CAF activation markers in isolated Thy1+ CAFs, and inhibited lung metastasis in syngeneic immunocompetent mice via Notch1 signaling. Treatment with CM from CAFs exposed to ApoSQ suppressed tumor growth and lung metastasis, whereas treatment with WISP-1-immunodepleted CM from CAFs exposed to ApoSQ reversed the antitumorigenic and antimetastatic effects. Therefore, treatment with CM from CAFs exposed to apoptotic lung cancer cells could be therapeutically applied to suppress CAF activation, thereby preventing cancer progression and metastasis.
Original language | English |
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Pages (from-to) | 1373-1391 |
Number of pages | 19 |
Journal | Cellular and Molecular Immunology |
Volume | 19 |
Issue number | 12 |
DOIs | |
State | Published - Dec 2022 |
Bibliographical note
Funding Information:The authors thank Dr J.M. Kurie (University of Texas MD Anderson Cancer Center, USA) for providing 344SQ cells and syngeneic (129/Sν) mice and Dr D. Park (Gwangju Institute of Science and Technology, Gwangju, Korea) for providing the pEBB-BAI-Flag plasmid. This work was supported by National Research Foundation of Korea (NRF) grants (2020R1A5A2019210 and 2020R1A2B5B02001686) funded by the Korean Ministry of Science and ICT.
Funding Information:
The authors thank Dr J.M. Kurie (University of Texas MD Anderson Cancer Center, USA) for providing 344SQ cells and syngeneic (129/Sν) mice and Dr D. Park (Gwangju Institute of Science and Technology, Gwangju, Korea) for providing the pEBB-BAI-Flag plasmid. This work was supported by National Research Foundation of Korea (NRF) grants (2020R1A5A2019210 and 2020R1A2B5B02001686) funded by the Korean Ministry of Science and ICT.
Publisher Copyright:
© 2022, The Author(s).
Keywords
- Apoptotic lung cancer cells
- CAFs
- Efferocytosis
- Invasion
- Metastasis
- Migration
- Notch1
- WISP-1