An Arntl2-Driven Secretome Enables Lung Adenocarcinoma Metastatic Self-Sufficiency

• High ARNTL2 is a top predictor of lung adenocarcinoma patient outcome
• Arntl2 is required for metastatic ability in vivo and clonal growth in cell culture
• An Arntl2-driven pro-metastatic secretome controls metastatic self-sufficiency
• Smoc2 is an Arntl2/Clock-dependent pro-metastatic secreted factor

SummaryThe ability of cancer cells to establish lethal metastatic lesions requires the survival and expansion of single cancer cells at distant sites. The factors controlling the clonal growth ability of individual cancer cells remain poorly understood. Here, we show that high expression of the transcription factor ARNTL2 predicts poor lung adenocarcinoma patient outcome. Arntl2 is required for metastatic ability in vivo and clonal growth in cell culture. Arntl2 drives metastatic self-sufficiency by orchestrating the expression of a complex pro-metastatic secretome. We identify Clock as an Arntl2 partner and functionally validate the matricellular protein Smoc2 as a pro-metastatic secreted factor. These findings shed light on the molecular mechanisms that enable single cancer cells to form allochthonous tumors in foreign tissue environments.

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