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Cited by 50TGF-β signaling in diseasesCancer Cells and MetastasisPhagocytosis and Immune Regulation

Reprogramming of cancer-associated fibroblasts by apoptotic cancer cells inhibits lung metastasis via Notch1-WISP-1 signaling

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Kim, Hee Ja, Yang, Kyungwon, Kim, Kiyoon, Lee, Ye‐Ji, Lee, Sieun, Ahn, Sung Yong, Ahn, Young‐Ho, Kang, Jihee Lee·2022·Cellular & Molecular Immunology
DOI 10.1038/s41423-022-00930-wPMC PMC9708692
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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.

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  • In breast and lung cancers, efferocytosis is associated with tumor immune evasion and progression.

    “For instance, in breast33 and lung34 cancers, efferocytosis is associated with tumor immune evasion and progression.”

    From Macrophage efferocytosis mediated by the TP63-RAC2 pathway promotes immunosuppressive remodeling in esophageal cancer (2026) · cites this paper as [34]

    Citation 34 is attached to the lung-cancer portion of the sentence, not the breast-cancer portion. Although the Introduction says phagocyte-mediated clearance can be immunosuppressive in the tumor microenvironment, it also says tumor cells may evade surveillance by avoiding efferocytosis. The Discussion reports the opposite of the claimed progression association in this lung-cancer study: interaction with apoptotic cancer cells reprogrammed phagocytic fibroblasts and inhibited cancer-cell migration and invasion. The supplied copy gives section labels but no page numbers. (LLM, conf=0.85)

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Authors
Kim, H. J., Yang, K., Kim, K., Lee, Y., Lee, S., Ahn, S. Y., Ahn, Y., & Kang, J. L.
Affiliations
Ewha Womans University (KR)
Corresponding author
Kang, Jihee Lee
ORCID
Venue
Cellular & Molecular Immunology
Publisher
Springer Science and Business Media LLC
Published
2022-10-14
Volume
19
Issue
12
Pages
1373-1391
ISSN
  • 1672-7681 (ISSN-L)
  • 2042-0226
DOI
10.1038/s41423-022-00930-w
PMC
PMC9708692
OpenAlex
W4306165633
Cited by
50
References
57
Citations by year
2026: 6 · 2025: 17 · 2024: 21 · 2023: 5 · 2022: 1
FWCI
3.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular and Molecular Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Research Foundation of Korea (2020R1A5A2019210, 2020R1A2B5B02001686)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords
cancer-associated fibroblasts, lung metastasis, Notch1 signaling, WISP1, DLL1, efferocytosis, CAF activation, tumor microenvironment, TGF-β1, tumor cell migration and invasion, lung cancer
MeSH terms
Cancer-Associated Fibroblasts, Animals, Cell Movement, Fibroblasts, Lung Neoplasms, Cell Line, Tumor, Mice, Tumor Microenvironment, Wnt Signaling Pathway

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