Noncanonical DDR1 Signaling Drives Multisite Metastatic Reactivation

Breast cancer metastatic relapse is thought to be due to the reactivation of dormant disseminated breast cancer cells and their interaction with the local extracellular matrix (ECM) microenvironments. To elucidate the mechanism underlying metastatic reactivation of latent breast cancer cells, Gao, Chakraborty, and colleagues evaluated the tetraspanin transmembrane 4 L six family member 1 (TM4SF1), which they had previously identified in a mouse genetic screen as a potential mediator of metastatic reactivation. Exogenous expression of TM4SF1 in dormant breast cancer cells resulted in metastatic colonization of the lung and induced the exhibition of cancer stem cell traits. Evaluation of ECM components revealed that TM4SF1-mediated metastatic colonization in vivo and induction of stem cell traits occurred in response to collagen I, and that collagen I promoted the association of TM4SF1 with the collagen receptor discoidin domain tyrosine kinase receptor 1 (DDR1) and the formation of TM4SF1–DDR1 clusters. Collagen I induced the simultaneous association of TM4SF1 with DDR1 and the syntenin 2–protein kinase C alpha (PKCA) complex to facilitate the interaction of DDR1 with PKCA and induce the activation of total PKC. Activated PKCA subsequently phosphorylated JAK2 to drive noncanonical DDR1 signaling via activated JAK2/STAT3. Consistent with these findings, stable depletion of DDR1 or inhibition of PKCA, or JAK2/STAT3 signaling decreased collagen I–induced tumor sphere formation and expression of genes related to cancer stemness. Histopathologic analysis of metastatic murine breast cancer cells revealed the presence of invasive breast tumor cells and micrometastases surrounded by collagen and showed that the majority of metastases in contact with collagen were proliferative, whereas the majority of single tumor cells not in contact with collagen were quiescent. In patients with metastatic breast cancer, TM4SF1 expression was predictive for metastatic relapse and pSTAT3 expression was elevated in metastases. These findings describe how the interaction of dormant disseminated tumor cells with the ECM microenvironment promotes cancer stem cell behavior and metastatic reactivation.

Gao H, Chakraborty G, Zhang Z, Akalay I, Gadiya M, Gao Y, et al. Multi-organ site metastatic reactivation mediated by non-canonical discoidin domain receptor 1 signaling. Cell 2016;166:47–62.