Colon cancer cells colonize the lung from established liver metastases through p38 MAPK signalling and PTHLH

Nat Cell Biol. 2014 Jul;16(7):685-94. doi: 10.1038/ncb2977. Epub 2014 Jun 1.


The mechanisms that allow colon cancer cells to form liver and lung metastases, and whether KRAS mutation influences where and when metastasis occurs, are unknown. We provide clinical and molecular evidence showing that different MAPK signalling pathways are implicated in this process. Whereas ERK2 activation provides colon cancer cells with the ability to seed and colonize the liver, reduced p38 MAPK signalling endows cancer cells with the ability to form lung metastasis from previously established liver lesions. Downregulation of p38 MAPK signalling results in increased expression of the cytokine PTHLH, which contributes to colon cancer cell extravasation to the lung by inducing caspase-independent death in endothelial cells of the lung microvasculature. The concerted acquisition of metastatic traits in the colon cancer cells together with the sequential colonization of liver and lung highlights the importance of metastatic lesions as a platform for further dissemination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Colonic Neoplasms / pathology*
  • Colonic Neoplasms / physiopathology
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Humans
  • Liver Neoplasms / secondary*
  • Lung Neoplasms / secondary*
  • Mice
  • Mutation
  • Neoplasm Metastasis*
  • Parathyroid Hormone-Related Protein / genetics
  • Parathyroid Hormone-Related Protein / metabolism*
  • Signal Transduction*
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*
  • ras Proteins / genetics
  • ras Proteins / metabolism


  • Parathyroid Hormone-Related Protein
  • p38 Mitogen-Activated Protein Kinases
  • ras Proteins