Cell-ECM interactions control DDR

Fundamental to an improvement of cancer cure rates is a better understanding of the underlying molecular mechanisms driving resistance to standard treatments such as radioand chemotherapy. A powerful and promising approach to sensitize cancer cells to therapy is represented by Paul Ehrlich ́s old and still up-to-date concept of the “magic bullet”. Reviewing the complexity of the “hallmarks of cancer” provides clarity about the needs to employ pathophysiological models for our examinations and consider multi-targeting concepts [1]. For identifying novel potential cancer targets, we need to unravel the molecular biology of how cancer cells develop, manifest and interact with their microenvironment. These actions are not only promoted by intrinsic genetic and epigenetic alterations but also through a tightly regulated interplay between cancer cells and stromal components documented as key determinants of various hallmarks, including resistance to cell death, sustainability of proliferative signals, and activation of invasion and metastasis. Among this large plethora of autocrine and paracrine interactions, integrin-mediated adhesion to the extracellular matrix (ECM) is one of the most influencing characteristics eliciting cancer cell therapy resistance. Integrins are transmembrane receptors consisting of one alpha and one beta subunit [2]. Overall, 18 α and 8 β subunits form 24 different integrin cell adhesion receptors. Their dual functionality, ECM binding for structure and for signaling, and their location at subcellular sites pinpoint them as highly interesting molecules. Structurally, a linkage of ECM/integrin/actin cytoskeleton/nuclear membrane/chromatin connects the outside with the inside of the cell [3]. Signaling-wise, outside-in and inside-out communication by integrins significantly contributes to the regulation of cell survival, proliferation, migration or apoptosis. However what turns integrins into potent cancer targets? First, integrins are overexpressed in different tumor entities relative to the corresponding healthy tissue. Secondly, integrins are critically involved in the prosurvival, promigratory and therapy resistance mechanisms, and third, integrins are surface receptors that are easily druggable and utilizable for imaging. Different preclinical studies convincingly show that inhibition of integrin receptors sensitizes tumor cells to chemoand radiotherapy [4,5]. As is often the case, clinical trials were unable to recapitulate these findings due to insufficient integrin inhibition. Thus, a new strategy proposed by us and others is to inhibit all β1 integrin associated integrin receptors. As β1 integrins form by far the biggest group of integrin receptors, β1 integrin targeting enables the deactivation of a wide variety of integrins at once. In our case, we used the monoclonal inhibitory anti-β1 integrin antibody AIIB2 in head and neck squamous cell carcinomas (HNSCC). We previously showed that β1 integrins signal via the focal adhesions kinase (FAK)/ Cortactin/c-Jun N-terminal kinase 1 (JNK1) signaling axis for increased survival after radiation [4]. Hence, we asked whether there is a connection between β1 integrin signaling and DNA repair. Despite one report on suppression of Bleomycin-induced DNA damage by integrin signaling [6], there was a lack of knowledge about integrin signaling and repair of Editorial