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  • DDR although normally expressed in cells with mesenchymal fe


    DDR2, although normally expressed in 3576 with mesenchymal features, has also been reported to enhance EMT. In A549 lung cancer cells, TGFβ1 increases the expression of type I collagen and DDR2. Knocking-down COL1A1 or DDR2 with siRNA is sufficient to inhibit EMT and cell migration induced by TGFβ1 [101]. Additionally, in breast cancer, the activation of DDR2 stimulates ERK2 activity in a Src-dependent manner [102]. ERK2 activation results in Snail phosphorylation and nuclear accumulation. Moreover, DDR2 expression is found in most human invasive ductal breast carcinomas and is associated with nuclear Snail and the absence of E-cadherin expression [102,103].
    Therapeutic prospects So far we have reviewed the function of cadherin switching during tumor progression, and the mechanism of collagen-induced cadherin switching. Many types of cancers are characterized by an abundant deposition of collagen within the tumor microenvironment. Therefore, targeting collagen-DDR-driven signaling pathways is a potential therapeutic strategy for these cancers. Several small-molecule inhibitors that were originally developed to target the activity of the breakpoint cluster region-Abelson kinase (Bcr-Abl), such as imatinib, dasatinib, nilotinib, and bafetinib, also potently inhibit DDR1/2 activity [104]. Dasatinib in particular has demonstrated promising therapeutic efficacy in lung cancer cells harboring gain-of-function mutations of DDR2; moreover, it also seems to be effective in squamous cell carcinoma patients with a DDR2S768R mutation, with significant shrinkage of the tumors after treatment [105,106]. Recently, a series of DDR inhibitors have been reported. For example, N-isopropyl-4-methyl-3-(2-(pyrazolo-[1,5-a]pyrimidin-6-yl)ethynyl) 7rh benzamide (7rh) is a new potent DDR1 inhibitor derived from pyrazolopyrimidine alkyne [104]. The compound potently inhibits DDR1 with an IC50 value of 6.8 nM and is significantly less active against DDR2 and Bcr-Abl, with IC50 values of 101.4 nM and 355 nM, respectively. Cell-based investigation has demonstrated that 7rh inhibits the activation of DDR1 and downstream signaling in a concentration-dependent manner and potently suppresses the migration, invasion, and tumorigenicity of cancer cells. In addition, 7rh is therapeutically attractive as preliminary pharmacokinetic studies in rats have demonstrated that the compound possesses a promising PK profile with an oral bioavailability of 67.4% and T1/2 of 15.5 h when dosed at 25 mg/kg by oral gavage. Recent studies, including ours, have demonstrated that 7rh is effective in vivo in preclinical models of pancreatic, gastric, and lung cancer [94,107,108]. Besides DDR1, DDR2 has a function in tumor progression that has indicated the need for the identification of potent DDR2 inhibitors. A recent study has reported a promising compound, 5n, which can tightly bind to DDR1 and DDR2 proteins with an IC50 of 9.4 and 20.4 nM, respectively. This drug shows great potential to inhibit 3576 collagen signaling driven by DDR1/2 [109].
    Conclusion During EMT, epithelial cancer cells gain mesenchymal features, which are thought to facilitate therapeutic resistance and metastasis. However, several investigations have suggested EMT is not required for the metastatic spread of pancreatic and breast cancer [[110], [111], [112], [113]]. These studies exploited lineage-tracing systems including fibroblast-specific protein (FSP) and alpha smooth muscle actin (alpha-sma) to study the link between EMT and metastasis. As a hallmark of EMT, cadherin switching has unique biological meaning. Tumor cells switching from E-cadherin to an inappropriate cadherin, such as N-cadherin, show aggressive phenotypes. We suggest that the use of the expression of N-cadherin as a lineage trace could be valuable for this debate.
    Conflicts of interest