When breast cancer hits a nerve - Neural involvement as a hallmark of tumor progression

The aim of this project is to investigate nerve involvement in primary breast cancer and brain metastatic breast cancer. Our hypothesis is that a subset of aggressive breast cancers engages the nervous system to drive tumor progression, including metastases to the brain tissue, the most neurogenic niche in the body. Breast cancer (BC) is the most frequent female malignancy and leading cause of cancer-related deaths worldwide, with triple-negative or basal-like BC being the most challenging subtypes, due to lack of effective treatment targets. Studies of nerve fiber density in breast cancer have shown that highly innervated tumors are more aggressive, and presence of nerve elements is associated with increased metastasis and impaired patient prognosis. Our own preliminary data, from tissue analysis of two breast cancer cohorts, confirm these findings. We therefore consider nerve involvement a missing hallmark in our understanding of aggressive breast cancer. Nerves are tiny structures in tumors like needles in a haystack and difficult to detect under the microscope by regular histology. This has contributed to the lack of automatic screening for their presence and clinico-pathologic significance. In this project we will develop more sensitive methods to extract neural elements in tumor tissues by advanced imaging technologies. Interaction between breast cancer cells and nerves will be examined in functional studies. We suggest that aggressive breast cancer cells express yet unknown markers that control attraction to nerves in the primary tumor, and that this attraction induces changes in a subset of breast cancer cells that make them prone to brain metastases.

Recent data indicate that nerves might play an active role in the initiation and progress of cancer. In the breast, research by us and others has demonstrated that enhanced innervation is associated with more aggressive tumors, such as the triple negative subtype (TNBC) supporting the formation of a neurogenic niche in primary tumors. However, the detailed clinical relevance of this phenomenon, and the mechanisms by which nerves are attracted to breast tumors and how breast cancer-nerve interaction promotes aggressive tumor features, remain unexplored. Moreover, we lack good experimental models for breast cancer innervation in a human setting. TNBCs with a basal-like phenotype are also prone to metastasize to the brain, the most neurogenic niche in the body, but the preference for the brain as a metastatic site is not understood, neither are the phenotypic alterations that breast cancer cells undergo in brain tissue. Here, we launch a new concept - epithelial-to-neural transition (ENT) – linking cancer cell plasticity and nerve involvement in primary and brain metastatic breast cancer. We suggest that aggressive breast cancer cells express yet unknown markers that control attraction of nerves at the primary site, and that some breast cancer cells even transform by acquiring neural-like properties and spread to the brain. Epithelial-to-neural transition will be investigated both clinically and experimentally in primary and brain metastatic breast cancer by combining large clinical cohorts, spatial omics technology, and stem cell methods to establish cutting-edge models. This project has the potential to change the way we view neural elements in breast cancer and provide the field with new clinical relevance, models and technologies to study them.