| Added by | jacques.colinge |
|---|---|
| Group name | EquipeJC |
| Item Type | Journal Article |
| Title | Cancer-associated fibroblast spatial heterogeneity and EMILIN1 expression in the tumor microenvironment modulate TGF-? activity and CD8+ T-cell infiltration in breast cancer |
| Creator | Honda et al. |
| Author | Chikako Kanno Honda |
| Author | Sasagu Kurozumi |
| Author | Takaaki Fujii |
| Author | Didier Pourquier |
| Author | Lakhdar Khellaf |
| Author | Jun Horiguchi |
| Author | Tetsunari Oyama |
| Author | Ken Shirabe |
| Author | Jacques Colinge |
| Author | Takehiko Yokobori |
| Author | Andrei Turtoi |
| Abstract | Rationale: The tumor microenvironment (TME) and its multifaceted interactions with cancer cells are major targets for cancer treatment. Single-cell technologies have brought major insights into the TME, but the resulting complexity often precludes conclusions on function. Methods: We combined single-cell RNA sequencing and spatial transcriptomic data to explore the relationship between different cancer-associated fibroblast (CAF) populations and immune cell exclusion in breast tumors. The significance of the findings was then evaluated in a cohort of tumors (N=75) from breast cancer patients using immunohistochemistry analysis. Results: Our data show for the first time the degree of spatial organization of different CAF populations in breast cancer. We found that IL-iCAFs, Detox-iCAFs, and IFN?-iCAFs tended to cluster together, while Wound-myCAFs, TGF?-myCAFs, and ECM-myCAFs formed another group that overlapped with elevated TGF-? signaling. Differential gene expression analysis of areas with CD8+ T-cell infiltration/exclusion within the TGF-? signaling-rich zones identified elastin microfibrillar interface protein 1 (EMILIN1) as a top modulated gene. EMILIN1, a TGF-? inhibitor, was upregulated in IFN?-iCAFs directly modulating TGF? immunosuppressive function. Histological analysis of 75 breast cancer samples confirmed that high EMILIN1 expression in the tumor margins was related to high CD8+ T-cell infiltration, consistent with our spatial gene expression analysis. High EMILIN1 expression was also associated with better prognosis of patients with breast cancer, underscoring its functional significance for the recruitment of cytotoxic T cells into the tumor area. Conclusion: Our data show that correlating TGF-? signaling to a CAF subpopulation is not enough because proteins with TGF-?-modulating activity originating from other CAF subpopulations can alter its activity. Therefore, therapeutic targeting should remain focused on biological processes rather than on specific CAF subtypes. |
| Publication | Theranostics |
| Volume | 14 |
| Issue | 5 |
| Pages | 1873-1885 |
| Date | 2024 |
| Journal Abbr | Theranostics |
| Language | eng |
| DOI | 10.7150/thno.90627 |
| ISSN | 1838-7640 |
| Library Catalog | PubMed |
| Extra | PMID: 38505604 PMCID: PMC10945331 |
| Tags | arc, Breast Neoplasms, CAF subpopulations, cancer invasion, CD8-Positive T-Lymphocytes, corresponding, Female, Humans, mabimprove, Membrane Glycoproteins, original, patient outcome, spatial transcriptomics, top, Transforming Growth Factor beta, tumor immunity, Tumor Microenvironment |
| Date Added | 2024/09/08 - 16:55:42 |
| Date Modified | 2024/09/08 - 17:08:37 |
| Notes and Attachments | Full Text (Attachment) PubMed entry (Attachment) |
Institut de Recherche en Cancérologie de
