Multi-organ Site Metastatic Reactivation Mediated by Non-canonical Discoidin Domain Receptor 1 Signaling

Cell. 2016 Jun 30;166(1):47-62. doi: 10.1016/j.cell.2016.06.009.


Genetic screening identifies the atypical tetraspanin TM4SF1 as a strong mediator of metastatic reactivation of breast cancer. Intriguingly, TM4SF1 couples the collagen receptor tyrosine kinase DDR1 to the cortical adaptor syntenin 2 and, hence, to PKCα. The latter kinase phosphorylates and activates JAK2, leading to the activation of STAT3. This non-canonical mechanism of signaling induces the expression of SOX2 and NANOG; sustains the manifestation of cancer stem cell traits; and drives metastatic reactivation in the lung, bone, and brain. Bioinformatic analyses and pathological studies corroborate the clinical relevance of these findings. We conclude that non-canonical DDR1 signaling enables breast cancer cells to exploit the ubiquitous interstitial matrix component collagen I to undergo metastatic reactivation in multiple target organs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Surface / metabolism
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Discoidin Domain Receptor 1 / chemistry
  • Discoidin Domain Receptor 1 / metabolism*
  • Humans
  • Lung Neoplasms / secondary
  • Mice
  • Neoplasm Metastasis*
  • Neoplasm Proteins / metabolism
  • Neoplastic Stem Cells / pathology
  • Signal Transduction*


  • Antigens, Surface
  • Neoplasm Proteins
  • TM4SF1 protein, human
  • DDR1 protein, human
  • Discoidin Domain Receptor 1