Abstract
CD109 drives lung adenocarcinoma metastasis in a JAK–STAT-dependent manner.
Major finding: CD109 drives lung adenocarcinoma metastasis in a JAK–STAT-dependent manner.
Approach: Primary tumors and metastases from a genetic mouse model of lung cancer were transcriptionally profiled.
Impact: Inhibition of JAK or CD109 may be a potential therapeutic strategy to prevent metastasis.
Most of the efforts to identify drivers of metastatic ability have relied upon the molecular analyses of cancer cell lines or bulk samples from human tumors and metastases. To transcriptionally characterize neoplastic cells at different stages of malignant progression, Chuang and colleagues used a genetically engineered mouse model in which KrasG12D/+; p53−/− lung adenocarcinomas were initiated with a barcoded library of lentiviral vectors. Through the analysis of the stably integrated barcoded vector they could identify which primary tumors had given rise to metastases and which had not. Gene expression profiling on purified neoplastic cells revealed that primary tumors that had not metastasized were transcriptionally distinct from metastases. Further, patients with primary tumors that exhibited a metastasis signature comprised of the most differentially expressed genes between metastases and nonmetastatic tumors from the mouse model had worse overall survival. Consistent with these findings, knockdown of several candidate prometastatic genes did not significantly affect the growth of primary tumors but significantly reduced metastasis to the lung and liver; in particular, knockdown of the cell-surface antigen CD109, which was the strongest predictor of survival for patients with lung adenocarcinoma, almost completely blocked the formation of metastasis from subcutaneous tumors or after intravenous transplantation of cancer cells. Knockdown and overexpression of Cd109 resulted in decreased and increased active phosphorylated STAT3, respectively, and CD109 expression correlated with STAT3 phosphorylation across human lung cancer cell lines. Similarly, Stat3 knockdown resulted in reduced metastasis to the lung and liver, rescuing STAT3 activity restored metastatic ability of Cd109-knockdown cells, and pharmacologic inhibition of Jak family kinases, which function upstream of STAT3, inhibited metastasis formation. Together, these results identify key drivers of metastasis and suggest that inhibition of the CD109–JAK–STAT3 is a potential antimetastasis strategy.