E-cadherin inactivation shapes tumor microenvironment specificities in invasive lobular breast cancer
Invasive lobular breast carcinoma (ILC) shows specific stromal features, and a high tumor-infiltrating lymphocyte (TIL) content being associated with poor patient prognosis. Here, we reveal the underlying mechanism by performing single-cell analysis, immunohistochemistry, deconvolution of bulk RNA-sequencing in a large female ILC series and functional assays. We show that E-cadherin (CDH1)-loss in breast cancer cells prevents differentiation of FAP+ inflammatory cancer-associated fibroblasts (iCAF) into FAP+ myofibroblastic CAF, leading to iCAF accumulation in ILC. In turn, FAP+ iCAF attract TILs into the tumor center, shaping their spatial organization. Subsequently, CDH1-inactivated ILC cancer cells promote immune escape through a lack of retention and activation of ITGAE-expressing resident memory CD8 + T lymphocytes (TRM). Hence, our study uncovers reciprocal interactions between CDH1-inactivated cancer cells, FAP+ iCAF and CD8 + TRM, providing insights into the ILC stromal reaction and revealing why and how TILs are associated with poor prognosis in ILC patients, a mechanism generalizable to other CDH1-inactivated cancer types.
Authors
- Martial Caly
- François‐Clément Bidard (ORCID: https://orcid.org/0000-0001-5932-8949)
- Victor Renault (ORCID: https://orcid.org/0000-0001-8351-7168)
- Rana Mhaidly (ORCID: https://orcid.org/0000-0003-2029-1215)
- Isabelle Damei (ORCID: https://orcid.org/0000-0001-6569-6027)
- Enora Laas (ORCID: https://orcid.org/0000-0003-3875-4011)
- Géraldine Gentric (ORCID: https://orcid.org/0000-0002-7558-8705)
- Caroline Malhaire (ORCID: https://orcid.org/0000-0002-9235-9816)
- Camille Benoist (ORCID: https://orcid.org/0000-0003-1366-9507)
- Julia M. Houthuijzen (ORCID: https://orcid.org/0000-0003-0404-1961)
- Laetitia Fuhrmann (ORCID: https://orcid.org/0000-0003-1755-6307)
- Renaud Leclère (ORCID: https://orcid.org/0000-0001-8737-6817)
- Camille Richardot
- Fatima Mechta‐Grigoriou (ORCID: https://orcid.org/0000-0002-3751-6989)
- Lounes Djerroudi (ORCID: https://orcid.org/0000-0002-5007-2964)
- Kim Cao (ORCID: https://orcid.org/0000-0003-2475-1821)
- Pim Kloosterman
- Yann Kieffer (ORCID: https://orcid.org/0000-0003-2722-3071)
- Hugo Croizer
- Anne Vincent-Salomon (ORCID: https://orcid.org/0000-0001-5754-5771)
- Andreia Goncalves
- Vithuzane Selvarasa
- Jos Jonkers (ORCID: https://orcid.org/0000-0002-9264-9792)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Paris Sciences et Lettres (FR)
- Université Paris-Saclay (FR)
- The Netherlands Cancer Institute (NL)
- La Ligue Contre le Cancer (FR)
- Oncode Institute (NL)
- Institut Curie (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-05-12
- DOI
- https://doi.org/10.1038/s41467-026-72844-4
- Primary Topic
- Wnt/β-catenin signaling in development and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Institut National de la Santé et de la Recherche Médicale