Breast cancer cells cooperate during invasion and metastasis

Abstract

Metastasis continues to be the leading cause of breast cancer-related deaths. Metastasis is a multistep process during which cancer cells leave the primary tumor, invade and seed inside secondary tissues, leading to lethal organ failure. Currently, no efficient method exists for the elimination of invasive cancer cells, which poses a major clinical challenge. Indeed, while localized cancers are clinically manageable, invasive breast cancer is largely an uncurable disease. Understanding how cancer cells sustain an invasive behavior may lead to the development of novel potent therapies.A vast genetic and phenotypic heterogeneity exists among invasive cancer cells. This heterogeneity is important to investigate as, in breast cancer patients, most metastatic nodules are polyclonal and consist of cancer cells that invaded and disseminated collectively. While recent studies demonstrated that collective invasion can be cooperative, where leader cells enable the invasion of otherwise non-invasive follower cells, the mechanisms regulating their cooperativity have been poorly investigated. Additionally, it is not known whether cooperative invasion can lead to metastasis, where metastatic cells enable the dissemination of non-metastatic cells. Our laboratory previously showed that breast cancer cells can locally degrade the extracellular matrix using invadopodia, which are membrane protrusions enriched in matrix metalloproteinases. Importantly, invadopodia are required for metastasis of single cancer cells. However, whether invadopodia enable the collective invasion and metastasis of cancer cell clusters remains unknown. Further, the role of invadopodia-mediated matrix degradation in leader vs. follower cells is unclear. In this dissertation, we aim to understand how cancer clones with and without invadopodia may cooperate during invasion and metastasis. Our results suggest that a few cells with invadopodia can drive the metastasis of cell clusters from multiclonal tumors. From this work, we believe that a more detailed understanding of how cancer cells cooperate may help in identifying new targets for preventing metastasis.