The extracellular matrix critically controls cancer cell behavior by inducing several signaling pathways through cell membrane receptors. Besides conferring structural properties to tissues around the tumor, the extracellular matrix is able to regulate cell proliferation, survival, migration and invasion. Among these receptors, the integrins family constitutes a major class of receptors that mediate cell interactions with extracellular matrix components. Twenty years ago, a new class of extracellular matrix receptors has been discovered. These tyrosine kinase receptors are the two discoidin domain receptors DDR1 and DDR2. DDR1 was first identified in the Dictyostelium discoideum and was shown to mediate cell aggregation. DDR2 shares highly conserved sequences with DDR1. Both receptors are activated upon binding to collagen, one of the most abundant proteins in extracellular matrix. While DDR2 can only be activated by fibrillar collagen, particularly types I and III, DDR1 is mostly activated by type I and IV collagens. In contrast with classical growth factor tyrosine kinase receptors which display a rapid and transient activation, DDR1 and DDR2 are unique in that they exhibit delayed and sustained receptor phosphorylation upon binding to collagen. Recent studies have reported differential expression and mutations of DDR1 and DDR2 in several cancer types and indicate clearly that these receptors have to be taken into account as new players in the different aspects of tumor progression, from non-malignant to highly malignant and invasive stages. This review will discuss the current knowledge on the role DDR1 and DDR2 in malignant transformation, cell proliferation, epithelial to mesenchymal transition, migratory and invasive processes, and finally the modulation of the response to chemotherapy. These new insights suggest that DDR1 and DDR2 are new potential targets in cancer therapy.

Chemotherapeutic drug efflux via the P-glycoprotein (P-gp) transporter encoded by the MDR1/ABCB1 gene is a significant cause of drug resistance in numerous malignancies, including acute leukemias, especially in older patients with acute myeloid leukemia (AML). Therefore, the P-gp modulators that block P-gp-mediated drug efflux have been developed, and used in combination with standard chemotherapy. In this paper, the capacity of zosuquidar, a specific P-gp modulator, to reverse chemoresistance was examined in both leukemia cell lines and primary AML blasts.

Melanoma is the most common cause of death in skin cancer due to its high metastatic potential. While targeted therapies have improved the care of patients with metastatic melanoma harboring the BRAFV600E mutation, these treatments are associated with a high frequency of resistance. Resistance factors are related to cellular adaptation as well as to changes in the tumor microenvironment. At the cellular level, resistance involves mutations, overexpression, activation, or inhibition of effectors involved in cell signaling pathways such as MAPK, PI3K/AKT, MITF, and epigenetic factors (miRNAs). In addition, several components of the melanoma microenvironment, such as soluble factors, collagen, and stromal cells also play a crucial role in this resistance. In fact, extracellular matrix remodeling impacts the physical and chemical properties with changes in the stiffness and acidity, respectively of the microenvironment. The cellular and immune components of the stroma are also affected, including immune cells and CAF. The aim of this manuscript is to review the mechanisms responsible for resistance to targeted therapies in BRAFV600E-mutated metastatic melanoma.

AVE9633 is a new immunoconjugate comprising a humanized monoclonal antibody, anti-CD33 antigen, linked through a disulfide bond to the maytansine derivative DM4, a cytotoxic agent and potent tubulin inhibitor. It is undergoing a phase I clinical trial. Chemoresistance to anti-mitotic agents has been shown to be related, in part, to overexpression of ABC proteins. The aim of the present study was to investigate the potential roles of P-gp, MRP1 and BCRP in cytotoxicity in AVE9633-induced acute myeloid leukaemia (AML).

Type I collagen is the major adhesive component in breast interstitial stroma which represent the first stromal barrier against tumor invasion. We have previously shown that type I collagen activates DDR1 which plays a key role in cell growth suppression and BIK-induced apoptosis in non-invasive luminal-like breast carcinoma cells. We have also shown that MT1-MMP is able to rescue these cells and protect them against apoptosis suggesting a degradation of type I collagen and/or DDR1 cleavage by MT1-MMP. Decreased DDR1 expression has been associated with the epithelial to mesenchymal transition process in breast cancer. In the present work, we propose to study the role of MT1-MMP in the protection of basal-like MDA-MB-231 carcinoma against BIK associated apoptosis. We aimed to investigate whether MT1-MMP depletion is able to restore apoptosis, and to verify if such depletion is able to restore full length DDR1 expression and phosphorylation. Sh-RNA strategy against MT1-MMP mRNA was able to restore relatively full length DDR1 expression and phosphorylation. This was accompanied by a decrease in cell growth and an overexpression of BIK. This suggested that MT1-MMP expression in these cells probably protects these cells against tumor suppression and apoptosis via DDR1 cleavage. Since DDR1 was moderately expressed in MDA-MB-231 cells, we then investigated whether overexpression of DDR1 could increase cell growth suppression and apoptosis. Data showed that overexpression of DDR1 increased cell growth and increased BIK expression, suggesting that moderate expression level of full length DDR1 in basal-like breast carcinoma provides them with a capacity to resist to cell growth suppression and collagen-induced apoptosis. Finally, overexpression of DDR1 and MT1-MMP depletion in MDA-MB-231 cells increased in a synergistic way collagen-induced cell growth suppression and apoptosis. Taken together, our data suggest that during the acquisition of mesenchymal features, the low level of DDR1 expression should be considered as an important biomarker in the prognosis of basal-like breast carcinoma, conferring a high rate of cell growth and protection against collagen-induced apoptosis.