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

Abstract

SUMMARY 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.

Emerging Biological Principles of Metastasis

“…In this case, the capacity for multi-organ colonization has been traced to the production of the matrix protein laminin-a4 (LAMA4), which seems to be critical for the initial proliferation of DTCs. Similarly, the collagen receptor DDR1, in collaboration with the TM4SF1 adaptor protein, has recently been identified as a signaling axis that regulates CSCs and thereby enables the outgrowth of otherwise-dormant carcinoma cells in multiple organ sites (Gao et al, 2016). The activation of such programs could account for the apparently synchronous appearance of metastases in various organs – metastatic showers – that are occasionally observed in patients.…”

STAT3/p53 pathway activation disrupts IFN-β–induced dormancy in tumor-repopulating cells

“…As a result, p-STAT3 (S) upregulates p27 expression by binding to the p27 promoter. This selective serine phosphorylation by IFN-β may be caused either by Tyk, as IFN-γ activates Jak1 and Jak2, while IFN-β activates Jak1 and Tyk, or by Jak2, since a previous study shows that phosphorylation of Jak2 leads to the activation of STAT3 in a breast cancer model (55). Thus, IFN-β can use p-STAT3 (S) to further enhance p27 expression, facilitating TRCs to enter dormancy.…”

Discoidin domain receptor 1 kinase activity is required for regulating collagen IV synthesis

“…DDR1 is required for normal tissue development, but the function of DDR1 in adult tissues particularly in diseased tissues is poorly understood [12,13]. DDR1 contributes to cancer [14,15] and promotes inflammation in models of atherosclerosis [10,16] and lung fibrosis [17], but the mechanisms whereby DDR1 contributes to disease progression are not clear.…”