Metastasis, the spread of cancer cells from primary tumors to distant organs, in the main cause of cancer death. Metastasis is initiated and sustained by a subset of cancer cells with stem-like and immune evasive properties, called metastasis initiating cells (MICs). We are investigating the mechanisms underlying the emergence and selection of MICs within primary tumors, and their microenvironment interactions during metastasis formation and resistance to therapy. Our recent progress suggests that MICs in carcinomas result from the adoption of a normal regenerative progenitor phenotype by malignant cells, a phenotype with intrinsic programs to survive the stresses of the metastatic process, undergo epithelial-mesenchymal transitions, enter a slow-cycling state for dormancy, evade immune surveillance, establish profitable interactions with organ-specific niches, and co-opt systemic factors to establish metastatic growth and recurrence after therapy. Our current work on lung adenocarcinoma and breast cancer MICs is providing insights into the emergence and regenerative phenotype of these cells and their mechanisms of brain colonization and avoidance of immune surveillance. An improved understanding of the molecular detereminant of MIC phenotypes and their host ecosystems could yield therapeutic approaches to improve patient outcomes.

Citation Format: Joan Massagué. Metastasis initiating cells and ecosystems [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA006.