Abstract IA001: Metastasis initiating cells and ecosystems

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Abstract Metastasis is initiated and sustained through therapy by cancer cells with stem-like properties, termed metastasis initiating cells (MICs). Recent work suggests that MICs are malignant cells that adopted a regenerative stem-cell phenotype with intrinsic programs to survive the physical, immune and metabolic stresses of the metastatic process, enter a slow-cycling state for dormancy, and establish supportive interactions with organ-specific ecosystems for eventual outgrowth and recurrence. Notably, relapse frequently develops from disseminated MICs that remain dormant in distant organs after the apparently successful treatment of a primary tumor. During dormancy, MICs fluctuate between immune evasive quiescent and cell cycle reentry states, which exposes them to elimination by the immune system. By combining novel immunocompetent mouse models of lung adenocarcinoma indolent metastasis, in vivo genetic screens, immune profiling, and pre-clinical anti-tumor drug testing, we identified specific pathways in reawakened MICs that drive immune-mediated clearance and can be therapeutically activated to hasten the elimination of residual disseminated disease. Moreover, analysis of brain metastasis with advanced imaging reveals that the interplay between MICs and their host ecosystem is influenced by the architecture of metastatic colonies. Thus, lung adenocarcinoma and triple-negative breast cancer metastases grow by spreading on the basement membrane of brain capillaries, forming perivascular tumor colonies that closely interact with microglia and astrocytes. In contrast, HER2+ breast cancer cells adopt a spheroidal growth pattern that is driven by tumor-derived extracellular matrix and restricts microglia and astrocyte infiltration. The use of single-cell analytics revealed distinct microglia activation states, MIC dependencies and vulnerabilities associated with these different growth patterns. This progress sheds light on the complex and dynamic interplay between MICs and their host ecosystems and point at therapeutically actionable targets to hasten the elimination of disseminated disease. Citation Format: Joan Massagué. Metastasis initiating cells and ecosystems [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA001.