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<p>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 (<i>CDH1)</i>-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, <i>CDH1</i>-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 <i>CDH1</i>-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 <i>CDH1</i>-inactivated cancer types.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月12日

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  • Lounes Djerroudi,
  • Rana Mhaidly,
  • Yann Kieffer,
  • Isabelle Damei,
  • Hugo Croizer,
  • Vithuzane Selvarasa,
  • Geraldine Gentric,
  • Laetitia Fuhrmann,
  • Andreia Goncalves,
  • Martial Caly,
  • Camille Richardot,
  • Renaud Leclere,
  • Enora Laas,
  • Caroline Malhaire,
  • Kim Cao,
  • Julia M. Houthuijzen,
  • Pim Kloosterman,
  • Jos Jonkers,
  • Camille Benoist,
  • Victor Renault,
  • François-Clément Bidard,
  • Anne Vincent-Salomon,
  • Fatima Mechta-Grigoriou

摘要

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.