Molecular Definition of a Metastatic Lung Cancer State Reveals a Targetable CD109-Janus kinase-Stat Axis

Nat Med. 2017 Mar;23(3):291-300. doi: 10.1038/nm.4285. Epub 2017 Feb 13.

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.

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism
  • Animals
  • Antigens, CD / genetics*
  • Blotting, Western
  • Cell Line, Tumor
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic / genetics*
  • Gene Knockdown Techniques
  • Janus Kinase 1 / genetics
  • Janus Kinase 3 / genetics
  • Janus Kinases / genetics*
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Mice
  • Molecular Targeted Therapy
  • Neoplasm Metastasis / genetics
  • Neoplasm Proteins / genetics*
  • Polymerase Chain Reaction
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins p21(ras) / genetics
  • STAT3 Transcription Factor / genetics*
  • Signal Transduction
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Antigens, CD
  • CD109 protein, mouse
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Tumor Suppressor Protein p53
  • Jak1 protein, mouse
  • Jak3 protein, mouse
  • Janus Kinase 1
  • Janus Kinase 3
  • Janus Kinases
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)