Therapies that prevent metastatic dissemination and tumor growth in secondary organs are severely lacking. A better understanding of the mechanisms that drive metastasis will lead to improved therapies that increase patient survival. Within a tumor, cancer cells are equipped with different phenotypic and functional capacities that can impact their ability to complete the metastatic cascade. That phenotypic heterogeneity can be derived from a combination of factors, in which the genetic make-up, interaction with the environment, and ability of cells to adapt to evolving microenvironments and mechanical forces play a major role. In this review, we discuss the specific properties of those cancer cell subgroups and the mechanisms that confer or restrict their capacity to metastasize.

Cancer cells invoke phenotypic plasticity programs to drive disease progression and evade chemotherapeutic insults, yet until now there have been no validated clinical therapies targeting this process. Here, we identify a phenotypic plasticity signature associated with poor survival in basal/triple-negative breast cancer, in which androgen signalling is prominent. We establish that anti-androgen therapies block cancer stem cell function and prevent chemotherapy-induced emergence of new cancer stem cells. In particular, the anti-androgen agent seviteronel synergizes with chemotherapy to improve chemotherapeutic inhibition of primary and metastatic tumour growth and prevent the emergence of chemotherapy-resistant disease. We validate cytoplasmic AR expression as a clinical phenotypic plasticity biomarker that predicts poor survival and poor response to chemotherapy, and positive response to seviteronel plus chemotherapy. This new targeted combination therapy validates modulating phenotypic plasticity as an effective strategy to prevent and treat chemotherapy-resistant cancers with transformative clinical potential.