Dangerous Links Between Cancer Cells and Tumor Microenvironment in Lobular Breast Cancers

Among breast cancers, about 15% of cases are lobular, thus constituting the 2nd most frequent histological type. These develop within the breast in the form of tumor cells independent of one another, as their distinctive feature is the loss of E-cadherin—a protein that enables cells to adhere to one another. The tumor cells then infiltrate the breast tissue, insidiously resulting in an often late diagnosis. "One of the particularities of lobular breast cancers is the increased risk of long-term recurrence, occurring more than 10 years after the end of treatments. Our study, which therefore aims to understand certain specificities of this cancer, is necessary to adapt the management of patients," explains Dr. Fatima Mechta-Grigoriou, Inserm Director of Exceptional Class Research, Director of the Chemistry-Biology of Cancers Unit (Institut Curie, Inserm, CNRS). This work is carried out within the framework of the RHU Cassiopeia¹ and supported by the Women's Cancer Institute².

Immune Infiltration and Prognosis

Immune infiltration, or the presence of immune cells in the tumor microenvironment³, is a powerful prognostic tool in oncology. Indeed, in the majority of cases, a significant infiltration is associated with a very good prognosis: it is the immune cells that fight against the tumor cells and respond to treatments, whether immunotherapy or chemotherapy. 
On the contrary, as was previously shown at Institut Curie in a study conducted by Dr. Anne Vincent-Salomon, pathologist at Institut Curie, Director of the Women's Cancer Institute: the presence of numerous intra-tumor lymphocytes in lobular breast cancers is associated with a poor prognosis. To understand this paradox, Dr. Lounes Djerroudi, pathologist at Institut Curie, Dr. Anne Vincent-Salomon and Dr. Fatima Mechta-Grigoriou combined their knowledge in biology, computer science, and medicine. To do this, they studied cohorts of patients with lobular breast cancer and applied cutting-edge techniques such as single-cell sequencing, spatial transcriptomic analyses, and immunohistochemical labeling. They have thus identified the mechanisms at play in these cancers.

An Infernal Cell Trio in Lobular Breast Cancers

Their results reveal deleterious interactions between three distinct cell populations: cancer cells, T lymphocytes, and fibroblasts associated with cancer⁴ (CIF). Lobular cancer cells, characterized by the loss of E-cadherin—a cell adhesion protein—lock CAFs in an inflammatory state. "We show that this inflammatory state of CAF, maintained by the action of lobular cancer cells, attracts immune cells. These will therefore accumulate in the tumor. But, unfortunately, lobular cancer cells block them in a precursor state and prevent them from becoming functional and killing cancer cells. Thus, these lobular cancers are composed of an infernal cell trio. It is like a fortified city, but the numerous ramparts, which are the inflammatory CAFs and immune cells in this metaphor, become ineffective in the face of the enemy," illustrates Dr. Fatima Mechta-Grigoriou.

Towards an adaptive and increasingly personalized medicine

This study makes it possible to understand why the abundance of immune cells in lobular breast cancers is associated with a poor prognosis. Adaptive and personalized medicine, at the heart of Institut Curie's medical-scientific program, is based, among other things, on the identification of biomarkers allowing the treatment to be adapted to the specificities of the patients and the pathology itself. "It is important for us to develop strategies that will be transposable to the clinic. In addition to identifying particular cellular mechanisms, our work shows that it is possible to distinguish four subgroups of patients with lobular breast cancer, each with different prognoses. However, these four subgroups are characterized by different microenvironment profiles. Each individual could thus benefit from specific treatments—targeting fibroblasts, immune cells, or vascular cells—or enabling a therapeutic de-escalation based on the characteristics of the disease. "This paves the way for the precise adjustment of treatments, and more generally, of long-term patient care," concludes Dr. Fatima Mechta-Grigoriou.

[1] RHU: University Hospital Research https://curie.fr/cassiopeia 

[2] Co-founded by Institut Curie, PSL University and Inserm, the Women's Cancer Institute is a University Hospital Institute (IHU), label of excellence of France 2030 https://curie.fr/ihu-institut-des-cancers-des-femmes

[3] The tumor microenvironment is defined by all the cells or biological constituents (blood vessels, immune cells, fibroblasts, signaling molecules, extracellular matrix), which are located around the cancer cells and which interact strongly with them.

[4] Cell type that secretes fibers. They can block or, on the contrary, facilitate tumor growth. They are not targeted by any treatment to date.