TY - JOUR
T1 - Multi-organ Site Metastatic Reactivation Mediated by Non-canonical Discoidin Domain Receptor 1 Signaling
AU - Gao, Hua
AU - Chakraborty, Goutam
AU - Zhang, Zhanguo
AU - Akalay, Intissar
AU - Gadiya, Mayur
AU - Gao, Yaquan
AU - Sinha, Surajit
AU - Hu, Jian
AU - Jiang, Cizhong
AU - Akram, Muzaffar
AU - Brogi, Edi
AU - Leitinger, Birgit
AU - Giancotti, Filippo G
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/6/30
Y1 - 2016/6/30
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2016.06.009
DO - 10.1016/j.cell.2016.06.009
M3 - Article
C2 - 27368100
AN - SCOPUS:84976870320
SN - 0092-8674
VL - 166
SP - 47
EP - 62
JO - Cell
JF - Cell
IS - 1
ER -