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
PKC. 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.