In addition to the receptor TGF also regulates the DDR

In addition to the receptor, TGF-β1 also regulates the DDR1 ligand meaning the type I collagen and the enzyme involved in its maturation (LOXL2). We previously demonstrated that an increase of type I collagen concentration is associated with the presence of more linear invadosomes in lipid metabolism (Juin et al., 2012). In vivo, type I collagen is cross-linked, this modification increases the diameter and the stiffness of the fibrils (Parry et al., 1978). Matrix stiffness is now a well-known parameter implicated in tumor invasion (Levental et al., 2009). Indeed, the matrix stiffness modulates cell adhesion, migration and invasion (Kai et al., 2016). Several studies described the importance of matrix rigidity in invadosome formation and/or activity (Collin et al., 2008, Collin et al., 2006, Linder and Wiesner, 2015, Parekh and Weaver, 2015). Modulating the type I collagen fibril cross-linking using chemical compounds or LOXL2 as a physiological cross-linker, we demonstrated that an increase of collagen cross-linking is associated with an increase of the cell capacity to form linear invadosomes. Thus, DDR1 could be considered as a mechanosensor for the type I collagen fibril stiffness. However, the signaling of this mechanosensing is not elucidated. As mentioned before, DDR1 belongs to the RTK family; however, we demonstrated that the kinase activity of DDR1 is not necessary for linear invadosome formation and activity (Juin et al., 2014). Now, it will be necessary to determine how DDR1 signal as a mechansensor for type I collagen fibrils. In conclusion, our results demonstrated that TGF-β1 promotes linear invadosome formation in hepatocellular carcinoma cells, through the regulation of collagen I, its receptor and its cross-linker (Fig. 6). The key role of TGF-β1 in HCC development allow us to suggest that linear invadosomes and their receptor DDR1 could be an interesting target to stop HCC progression.
Acknowledgements
Introduction Discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase (RTK) superfamily and is distinguished by a discoidin-homology region in its extracellular portion. Uniquely, DDR1 is not a receptor for soluble growth factors but for native, triple-helical collagens, in particular type I to type IV collagens [28], [35], [38]. DDR1 is expressed in a number of tissues, including the mammary gland epithelium [40]. The knockout of DDR1 showed an essential role in postnatal mammary gland development and in the formation of lactogenic tissue. In DDR1-null females, pubertal mammary gland outgrowth is delayed and matrix deposition enhanced [40]. At parturition, knockout females failed to nourish their litter due to the absence of alveolar opening and milk protein secretion. Transplantation experiments of knockout mammary tissue into the cleared fat pad of a wild type recipient revealed that the defect in DDR1-null mice is cell-autonomous [9]. While the absence of lactation is the most striking defect in DDR1-knockout mice, we also documented aberrant formation of the renal basement membrane and reduced signaling capacity of knockout mesangial cells [8], [11]. Additionally, smooth-muscle cells isolated from DDR1-null mice show reduced migration and chemotaxis compared to control cells [12], [13].