Epithelial cancers make up the vast majority of cancers and, during the transition from benign adenoma to malignant carcinoma and metastatic dissemination, differentiated epithelial tumor cells acquire a de-differentiated, invasive phenotype accompanied by dramatic changes in cellular morphology, the loss and remodeling of cell-cell and cell-matrix adhesion and the gain of migratory and invasive capabilities. These changes are hallmarks of Epithelial-Mesenchymal-Transition (EMT), a multistage process involving distinct genetic and epigenetic alterations and a high degree of cellular plasticity. Notably, during an EMT cells also acquire profound survival capabilities and are able to overcome cell death by apoptosis-inducing signals or by the loss of substrate adhesion (anoikis), to escape from immunosurveillance in the blood stream and even to resist to chemotherapy. Moreover, cancer cells undergoing an EMT exhibit hallmarks of cancer stem cells, such as increased growth as spheroids, colony formation in clonal growth assays and high tumorigenicity upon transplantation into mice. In conclusion, an EMT may not only provide the morphological changes required for cancer cells to migrate, disseminate and seed metastasis, but also reprograms cancer cells to survive during an EMT and systemic dissemination and, most importantly, to withstand chemotherapy. Thus, an EMT may be a principal mechanism for metastatic cancer cells to escape therapy and to continue to seed metastasis. These findings indicate that EMT is regulated on the level of both morphogenesis and cell survival, and propose a concept that EMT, and with it tumor progression and metastasis and drug resistance, could be therapeutically targeted on at least two different levels.

In the past years, a number of signaling pathways and transcription factors have been identified that seem to be critical for the process of EMT. However, the pathways and regulatory networks that cause the acquisition of drug resistance and increased tumorigenicity and metastatic capabilities of cancer cells remain poorly understood. We will take a number of independent experimental approaches to delineate the molecular pathways shared by and critical for EMT, drug resistance and cancer stemness. In a combination of establishing drug-resistant cell lines, whole transcriptome sequencing, synthetic lethal high-content microscopy screening and gain and loss of function experiments in cultured cells and in transplantation mouse models of breast cancer we will identify and validate the signaling pathways underlying EMT, drug resistance and cancer stemness, three critical features of malignant tumor progression and metastasis.