Abstract
The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen. Using an inducible expression system in human HT1080 fibrosarcoma cells, we investigated the role of DDR1b and DDR2 on primary tumour growth and experimental lung metastases. Neither DDR1b nor DDR2 expression altered tumour growth at the primary site. However, implantation of DDR1b- or DDR2-expressing HT1080 cells with collagen I significantly accelerated tumour growth rate, an effect that could not be observed with collagen I in the absence of DDR induction. Interestingly, DDR1b, but not DDR2, completely hindered the ability of HT1080 cells to form lung colonies after intravenous inoculation, suggesting a differential role for DDR1b in primary tumour growth and lung colonization. Analyses of tumour extracts revealed specific alterations in Hippo pathway core components, as a function of DDR and collagen expression, that were associated with stimulation of tumour growth by DDRs and collagen I. Collectively, these findings identified divergent effects of DDRs on primary tumour growth and experimental lung metastasis in the HT1080 xenograft model and highlight the critical role of fibrillar collagen and DDRs in supporting the growth of tumours thriving within a collagen-rich stroma.
Highlights
The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen
We report that DDR1b, but not DDR2, expression potently suppressed the ability of HT1080 cells to form lung colonies after intravenous inoculation
Collagen matrices can restrict tumour cell proliferation[129,130,131,132,133,134,135,136]. Consistent with this view[128], we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma[48], breast cancer[76,78], and lung cancer cells[74,75]
Summary
The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen. Using an inducible expression system in human HT1080 fibrosarcoma cells, we investigated the role of DDR1b and DDR2 on primary tumour growth and experimental lung metastases. In spite of the accumulating evidence and considering that both DDRs can be expressed by the same tumour type, a comparison of DDRs’ action in tumour growth and metastases within the same cellular background has not been conducted To address this limitation and to gain more insight into the roles of DDRs in malignancy, we set to investigate the contribution of DDR1b and DDR2 to the tumorigenic and lung colonizing abilities of human fibrosarcoma HT1080 cells. These malignant cells display a consistent ability to form rapidly proliferating tumours when inoculated subcutaneously (s.c.) into immunodeficient mice. DDRs elicit divergent effects on tumour cell malignancy in a context-dependent manner
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