Deciphering the Stemness Code for Breast Cancer Metastasis

Metastasis is the primary cause of cancer-related deaths. Manipulating this process in cancer patients remains a central goal in the development of anti-cancer therapeutics. Importantly, metastasis can develop years to decades after primary tumor removal, supporting that disseminated cancer/tumor cells (DCCs/DTCs) can remain dormant for long periods before reactivating. Metastasis grow from cancer cells with versatile self-reprogramming capabilities to transit from the epithelial to the mesenchymal state (EMT), enter and exit dormancy, and acquire plastic stemness states. EMT has also been reported to produce cells with stem cell-like properties. Definition of the exact molecular mechanisms that are involved in the generation of stem cells through EMT could lead to the identification of new potential therapeutic targets and enable the development of more efficient strategies for particular patient groups. The EMT and cancer stem cell (CSC)-like features of metastatic cancer cells are thought to be regulated by transcription factors (TFs) notably including SNAIL, SLUG, ZEB family proteins and self-renewal capability of tissue/adult stem cells acting together to drive the metastatic cascade. However, how these EMT-TFs and CSC-TFs-driven stemness programs decide and regulate the ability of dormant DCCs/DTCs to eventually escape from dormancy and fuel metastasis remains to be defined.

Our studies in embryonic stem cell pluripotency and somatic cell reprogramming as well as recent preliminary studies on breast cancer cell and animal models have provided some important hints to tackle this important question in understanding cancer metastasis. While published literature documented the correlation of ZNF281 with poor prognosis of a number of cancers and implicated ZNF281 in EMT regulation, a detailed understanding and better appreciation of its roles in breast cancer metastasis control is currently lacking. Thus, understanding how the EMT- and CSC-TFs control this epigenetic plasticity will generate further therapeutic advantage through co-treatment and offer insights into the development of anti-cancer therapies' refractory phenotypes in cancer cells. While the research is largely basic but not clinically orientated, the identification of underlying molecular mechanisms and the knowledge gained in this study will significantly advance the field. It will also serve as a valuable resource for identifying new therapeutic targets for treating drug-resistant and recurrent metastatic tumors and developing strategies/drugs to selectively target disseminating and/or metastasis initiating cells. Understanding the control mechanisms underlying the ability of tumor cells to remain epigenetically plastic and adopt dormant, motile, invasive and/or proliferative phenotypes resulting in subsequent cancer relapse would likely yield substantial direct benefits in cancer treatment. Our research proposal is thus align well with BCRP's mission of ending breast cancer.