title: Multi-organ Site Metastatic Reactivation Mediated by Non-canonical Discoidin Domain Receptor 1 Signaling.
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.
authors.affiliation: 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.
authors.forename: Hua
authors.initials: H
authors.lastname: Gao
authors.affiliation: Cell Biology Program and Center for Metastasis Research, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Goutam
authors.initials: G
authors.lastname: Chakraborty
authors.affiliation: Cell Biology Program and Center for Metastasis Research, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Zhanguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Cell Biology Program and Center for Metastasis Research, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Intissar
authors.initials: I
authors.lastname: Akalay
authors.affiliation: 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.
authors.forename: Mayur
authors.initials: M
authors.lastname: Gadiya
authors.affiliation: 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.
authors.forename: Yaquan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Cell Biology Program and Center for Metastasis Research, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Surajit
authors.initials: S
authors.lastname: Sinha
authors.affiliation: 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.
authors.forename: Jian
authors.initials: J
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Cizhong
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Pathology, Memorial Hospital, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Muzaffar
authors.initials: M
authors.lastname: Akram
authors.affiliation: Department of Pathology, Memorial Hospital, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Edi
authors.initials: E
authors.lastname: Brogi
authors.affiliation: Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Birgit
authors.initials: B
authors.lastname: Leitinger
authors.affiliation: 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.
authors.forename: Filippo G
authors.initials: FG
authors.lastname: Giancotti
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D000070819:Discoidin Domain Receptor 1 / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000473:pathology; D015398:Signal Transduction
chemical_list: D000954:Antigens, Surface; D009363:Neoplasm Proteins; C074075:TM4SF1 protein, human; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1