Cancer reactivated by collagen

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Science Signaling  19 Jul 2016:
Vol. 9, Issue 437, pp. ec165
DOI: 10.1126/scisignal.aah5670

Disseminated breast cancer cells often enter a state of dormancy in metastatic niches, and their reactivation causes the emergence of metastatic disease even many years later. The tetraspanin TM4SF1 was previously identified as a molecule that promotes metastatic outgrowth in mice injected with dormant cancer cells. Gao et al. found that TM4SF1 promotes the reactivation of dormant breast cancer cells in the lung, bone, and brain by facilitating signaling in response to cellular contact with type I collagen, a major component of the extracellular matrix (ECM). Bioinformatics analyses showed that high TM4SF1 expression correlated with reduced metastasis-free survival in breast cancer patients and that expression of a TM4SF1-associated gene signature (identified in TM4SF1-transfected cells) was a predictive marker of early relapse. Silencing TM4SF1 in metastatic breast cancer cell lines both decreased the expression of various pluripotency factors, including Sox2, a signal transducer and activator of transcription 3 (STAT3) target gene. When injected into mice, breast cancer cells in which TMS4SF1 was knocked down exhibited less metastatic outgrowth in lung, bone, and brain without impairing tumor cell viability. Staining lung sections from a mouse model of metastatic breast cancer to detect collagen and Ki-67, an indicator of actively dividing cells, indicated that most tumor cells in contact with type I collagen were proliferating, whereas most of those not in contact with type I collagen were not positive for Ki-67, suggesting that these may be quiescent. Treating cultured breast cancer cells with soluble type I collagen but not other ECM components induced wild-type but not TM4SF1-deficient cells to form tumor spheres. Various analyses revealed that TM4SF1 interacted with the extracellular portion of the collagen receptor discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase, and stimulated collagen-induced clustering of DDR1. The TM4SF1-DDR1 complex interacted with the scaffold protein syntenin 2. Silencing TM4SF1 prevented the coimmunoprecipitation of DDR1 and syntenin 2. Time course analyses after treating dormant breast cancer cell line 4TO7 with type I collagen while manipulating the abundance or activity of various proteins revealed that collagen-stimulated DDR1 activates protein kinase Cα (PKCα) through TM4SF1, which recruits PKCα through syntenin 2, and that PKCα subsequently activates Janus kinase 2 (JAK2)–STAT3 signaling. Silencing STAT3, SOX2, or syntenin 2; disrupting syntenin 2 binding to TM4SF1; or silencing but not enzymatically inhibiting DDR1 suppressed the ability of breast cancer cells to form organoids in culture or colonize metastatic niches in mice. Given that the presence of type I collagen stimulates cell migration out of the primary tumor, these new findings reveal another mechanism by which this ECM component promotes metastatic disease.

H. Gao, G. Chakraborty, Z. Zhang, I. Akalay, M. Gadiya, Y. Gao, S. Sinha, J. Hu, C. Jiang, M. Akram, E. Brogi, B. Leitinger, F. G. Giancotti, Multi-organ site metastatic reactivation mediated by non-canonical discoidin domain receptor 1 signaling. Cell 166, 47–62 (2016). [PubMed]

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