Abstract
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.
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Acknowledgements
We would like to thank Profs. Christine Desmedt (KU Leuven), Steffi Oesterreich and Adrian Lee (University of Pittsburgh) and Patrick Derksen (Utrecht University) for fruitful discussions within the frame of the ELBCC (European Lobular Breast Cancer Consortium) that inspired our work. We are grateful to institute Curie colleagues, including Charlotte Martinat and Khadidja Klouch for collecting clinical data of the patients (SIRIC, INCa-DGOS-4654); Jean-Christophe Tille and Amel Bendali for their help for pathological review of the slides; Laetitia Lesage, Gabriel Champenois and André Nicolas for their help at the experimental pathology platform and Coralie Guerin and Lea Guyonnet at the cytometry core. F.M.-G. and G.G. are permanent scientists at Inserm. R.M. was supported by the Foundation de France (00119142/WB − 2021-36276) and Y.K. by the Institut National du Cancer and INCa (CAFHeros, INCa-16101). The experimental work was supported by grants from the Ligue Nationale Contre le Cancer (LNCC, Labelisation), Inserm, INCa (CAFHeros INCa-16101; ChemoCAF, INCa-16086), ITMO Cancer of Aviesan (2021–2030 cancer control strategy framework, Pre-Caution), SIGN’it 2019 from the Foundation ARC, the European TRANSCAN-3 ERA-NET and the ARC Foundation for the CHRYSALIS funding (ARCPARTN-TRANS2022080005422) and Magnolia (INCa-16786), as well as the MSDAvenir program HoLOGRAM and BC-DigitalPath. L.D. thanks La Ligue contre le Cancer, Institut Servier and Foundation ARC for their support. This work has been supported by a Ruban Rose grant attributed to A.V.-S. This work is presented on behalf of the IHU sein working group; the IHU Institute of Women’s Cancer is funded by the Agence Nationale de la Recherche (ANR) in the frame of France 2030 (grant number ANR-23-IHU-006). We are also grateful to the ANR for the funding of the CASSIOPEIA RHU (ANR-21-RHUS-0002) program as part of the PIA France 2030. The ICGex NGS platform was supported by the ANR-10-EQPX-03 (Equipex) and ANR-10-INBS-09-08 (France Genomic Consortium) grants. F.M.-G. acknowledges the French “Pink Ribbon” association and the “Simone and Cino del Duca Foundation” for attribution of their respective Grand Prix, as well as the FRM for the Rozen Prize and the LNCC for the Duquesne Price and the association “Christelle Bouillot”. F.M.-G. is very grateful to all her funders for providing support throughout the years. The graphical abstract in Fig. 6 was created with Biorender.com.
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F.M.-G. and A.V.-S received research support from Roche, Institut Roche and the MSD Foundation. L.D. received research mobility support from Institut Servier. F.-C.B. reports research funding from GE Healthcare, Menarini Silicon Biosystems, Merck KGaA, MSD, Natera, Novartis, Personalis, Pfizer, Prolynx, Roche, SAGADx and Tempus; has served on advisory boards for AstraZeneca, Carrick Therapeutics, Daiichi Sankyo, Hengrui, Inatherys, Lilly, Menarini Silicon Biosystems, Novartis, Pfizer, Relay Therapeutics, Roche and Tempus; and has received speaker honoraria and travel support from AstraZeneca, Daiichi Sankyo, Lilly, Novartis, Pfizer and Roche. Other authors declare no potential competing interests.
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Djerroudi, L., Mhaidly, R., Kieffer, Y. et al. E-cadherin inactivation shapes tumor microenvironment specificities in invasive lobular breast cancer. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72844-4
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DOI: https://doi.org/10.1038/s41467-026-72844-4
