Multi-organ site metastatic reactivation mediated by non-canonical discoidin domain receptor 1 signaling

• Autores: Hua Gao, Goutam Chakraborty, Zhanguo Zhang
• Localización: Cell, ISSN 0092-8674, Vol. 166, Nº. 1, 2016, págs. 47-62
• Idioma: inglés
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• Resumen

  • 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.