期刊
DEVELOPMENTAL CELL
卷 56, 期 20, 页码 2808-+出版社
CELL PRESS
DOI: 10.1016/j.devcel.2021.08.018
关键词
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资金
- NIH [R01CA229215, DP2CA186572, F30CA220954, T32GM007739, R01AR062547, R01CA83115, K00CA223016]
- Melanoma Research Alliance
- The Pershing Square Sohn Cancer Research Alliance
- Mark Foundation for Cancer Research
- The Alan and Sandra Gerry Metastasis Research Initiative at the Memorial Sloan Kettering Cancer Center
- The Harry J. Lloyd Foundation
- Starr Cancer Consortium
- Melanoma Research Foundation
- American Association for Anatomy
- Cancer Research UK [C588/A19167, C8216/A6129, C588/A10721, C7535/A6408, C2195/A8466]
- Medical Research Council [MR/V000292/1]
- European Research Council [101001652]
- Swiss National Science Foundation [PP00P3_190077]
- Swiss Cancer League [KLS-4834-08-2019]
- ETH Zurich
- H2O20 Marie Sk1odowska-Curie Actions [847012]
- Swiss National Science Foundation (SNF) [PP00P3_190077] Funding Source: Swiss National Science Foundation (SNF)
- European Research Council (ERC) [101001652] Funding Source: European Research Council (ERC)
- Marie Curie Actions (MSCA) [847012] Funding Source: Marie Curie Actions (MSCA)
Melanomas can have multiple coexisting cell states, including proliferative (PRO) versus invasive (INV) subpopulations that cooperate in the seeding of metastasis. INV cells tightly adhere to each other and form clusters with a rim of PRO cells, facilitating dissemination of less metastatic PRO cells. TFAP2 neural crest transcription factor is identified as a master regulator of clustering and PRO/INV states.
Melanomas can have multiple coexisting cell states, including proliferative (PRO) versus invasive (INV) sub populations that represent a go or growtrade-off; however, how these populations interact is poorly understood. Using a combination of zebrafish modeling and analysis of patient samples, we show that INV and PRO cells form spatially structured heterotypic clusters and cooperate in the seeding of metastasis, maintaining cell state heterogeneity. INV cells adhere tightly to each other and form clusters with a rim of PRO cells. Intravital imaging demonstrated cooperation in which INV cells facilitate dissemination of less metastatic PRO cells. We identified the TFAP2 neural crest transcription factor as a master regulator of clustering and PRO/INV states. Isolation of clusters from patients with metastatic melanoma revealed a subset with heterotypic PRO-INV clusters. Our data suggest a framework for the co-existence of these two divergent cell populations, in which heterotypic clusters promote metastasis via cell-cell cooperation.
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