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

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

Author information

1
Metastasis Research Institute, Breast Cancer Center, Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University, Shanghai 200092, China; Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Cell Biology Program and Center for Metastasis Research, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: gaoh@tongji.edu.cn.
2
Cell Biology Program and Center for Metastasis Research, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Cell Biology Program and Center for Metastasis Research, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Sloan Kettering Division, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA.
4
Metastasis Research Institute, Breast Cancer Center, Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University, Shanghai 200092, China; Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
5
Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Collaborative Innovation Center for Brain Science, Tongji University, Shanghai 200092, China.
6
Department of Pathology, Memorial Hospital, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
7
Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
8
Cell Biology Program and Center for Metastasis Research, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Cancer Biology and David H. Koch Center for Applied Research of Genitourinary Cancers, UT MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address: fggiancotti@mdanderson.org.

Abstract

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.

PMID:
27368100
PMCID:
PMC4980842
DOI:
10.1016/j.cell.2016.06.009
[Indexed for MEDLINE]
Free PMC Article

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