What question did this study set out to answer?

This study aims to understand how E-cadherin inactivation influences the tumor microenvironment in invasive lobular breast cancer.

May 15, 2026Open Access

E-cadherin inactivation shapes tumor microenvironment specificities in invasive lobular breast cancer

LDLounes DjerroudiCentre National de la Recherche Scientifique RMRana MhaidlyCentre National de la Recherche Scientifique YKYann KiefferCentre National de la Recherche Scientifique

Key Points

This study aims to understand how E-cadherin inactivation influences the tumor microenvironment in invasive lobular breast cancer.
Performed single-cell analysis and immunohistochemistry on breast cancer samples
Deconvoluted bulk RNA-sequencing data from a large female ILC cohort
Conducted functional assays to evaluate fibroblast differentiation and immune interactions
E-cadherin loss prevents differentiation of inflammatory cancer-associated fibroblasts into myofibroblasts, leading to increased accumulation of inflammatory fibroblasts
Increased FAP+ iCAF attracted tumor-infiltrating lymphocytes into the tumor center, affecting their spatial organization
CDH1-inactivated ILC cells promote immune escape by reducing retention and activation of resident memory CD8 + T lymphocytes

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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