Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis

Chen Hua Chuang, Peyton G. Greenside, Zoë N. Rogers, Jennifer J. Brady, Dian Yang, Rosanna K. Ma, Deborah R. Caswell, Shin Heng Chiou, Aidan F. Winters, Barbara M. Grüner, Gokul Ramaswami, Andrew L. Spencley, Kimberly E. Kopecky, Leanne C. Sayles, E. Alejandro Sweet-Cordero, Jin Billy Li, Anshul Kundaje, Monte M. Winslow

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Lung cancer is the leading cause of cancer deaths worldwide, with the majority of mortality resulting from metastatic spread. However, the molecular mechanism by which cancer cells acquire the ability to disseminate from primary tumors, seed distant organs, and grow into tissue-destructive metastases remains incompletely understood. We combined tumor barcoding in a mouse model of human lung adenocarcinoma with unbiased genomic approaches to identify a transcriptional program that confers metastatic ability and predicts patient survival. Small-scale in vivo screening identified several genes, including Cd109, that encode novel pro-metastatic factors. We uncovered signaling mediated by Janus kinases (Jaks) and the transcription factor Stat3 as a critical, pharmacologically targetable effector of CD109-driven lung cancer metastasis. In summary, by coupling the systematic genomic analysis of purified cancer cells in distinct malignant states from mouse models with extensive human validation, we uncovered several key regulators of metastatic ability, including an actionable pro-metastatic CD109-Jak-Stat3 axis.

Original languageEnglish (US)
Pages (from-to)291-300
Number of pages10
JournalNature medicine
Volume23
Issue number3
DOIs
StatePublished - Mar 1 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint

Dive into the research topics of 'Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis'. Together they form a unique fingerprint.

Cite this