Discoidin Domain Receptors, DDR1b and DDR2, Promote Tumour Growth within Collagen but DDR1b Suppresses Experimental Lung Metastasis in HT1080 Xenografts

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. The DDRs constitute a unique subfamily of receptor tyrosine kinases (RTKs) that signal in response to collagens, and therefore they represent the only RTKs that are directly activated upon contact of cells with their collagenous matrix 1-6. The DDR subfamily comprises two kinases: DDR1 and DDR2 1,2,7. The DDR1 subfamily includes six isoforms generated by alternative splicing, while there is only one form of DDR2. Among the DDR1 isoforms, DDR1a, DDR1b, and DDR1c are full length, highly homologous receptors, with the only structural difference being the presence of 37 additional residues, including two additional tyrosine residues, within the intracellular region of DDR1b and DDR1c, suggesting that these species may activate different downstream signalling pathways 1. DDR1d and DDR1e are truncated, kinase-deficient receptors of unknown function 8. DDR1f contains a full kinase domain but lacks most of the extracellular domains 9. Structurally, the DDRs are type I transmembrane

Transcriptome analysis of heterogeneity in mouse model of metastatic breast cancer

“…Cluster A was enriched in regulatory pathways associated with cell adhesion, correlating with the expression of DDR1, HOXA7, MMP2, THBS1, TNFRSF14, and TGFB2. (Wasinski et al, 2020;Xu et al, 2005) Cluster A was also enriched in pathways associated with cellular locomotion, corroborated by the expression of SERPINE1, PDGFA, ITGAV, and ITGB1BP1. (Heldin, 2013;Morandi et al, 2016) Both sets of upregulated genes were observed in CD44 high /EpCAM high lung-derived cells, but not MFP-derived or CD44 low /EpCAM high lung-derived cells.…”

Silencing SAPCD2 Represses Proliferation and Lung Metastasis of Fibrosarcoma by Activating Hippo Signaling Pathway

“…As a tumor-suppressive pathway, inactivation of Hippo signaling has been extensively reported to be involved in the progression and metastasis of numerous types of cancer (41,42), including fibrosarcoma (43)(44)(45). On the one hand, core components of the Hippo pathway MST1/2 and LATS1/2 were downregulated, and this downregulation was involved in the inactivation of Hippo signaling (46,47); on the other hand, upregulation of the Hippo pathway transcription coactivators YAP and TAZ further exacerbated inactivation of the Hippo signaling, promoting the development and progression of cancers (48).…”

Influences of TP53 and the anti-aging DDR1 receptor in controlling Raf/MEK/ERK and PI3K/Akt expression and chemotherapeutic drug sensitivity in prostate cancer cell lines

“…While suppression of DDR1 has also been observed to reduce the invasive properties of other cancer cell lines such as melanoma, colon and hepatoma cells [44]. Interestingly, DDR1b and DDR2, promoted tumor growth in the presence of collagen while DDR1b suppressed the lung metastasis of HT1080 fibrosarcoma cells in a xenograft model [45]. Elucidating the interactions between TP53 and DDR1 and drug sensitivity could further our understanding of how the invasive properties of various cancer types is influenced by the presence of different types/classes of adult vs old collagen present in the extracellular matrix.…”