Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the fourth leading cause of cancer death in the world, accounting for about 1.4 million new cases and almost 700.000 deaths in 2012. Although the advent of targeted therapies has increased life expectancy of selected patient subsets, cancer cells become progressively resistant to conventional and targeted treatments, leaving essentially no therapeutic options for advanced stage/metastatic patients. Current knowledge on therapy-resistant cancer cells is scarce, thus hindering an effective targeting of this population. Cells endowed with increased properties of self-renewal, survival and migration called cancer stem cells (CSCs) have been demonstrated to fuel tumor progression, metastatization and relapse. A subset of CSCs is characterized by a non-cycling state which, together with a peculiar metabolic landscape, confers them resistance to chemotherapy and targeted therapies. Quiescent therapy-resistant CSCs (Q-CSCs) represent an armored reservoir of stem cells within the tumor that can be targeted through innovative approaches based on a deep knowledge of their molecular and biological features. By using a proliferation-sensitive dye, we isolated and characterized a rare subpopulation of quiescent cells from colorectal tumors which, upon gene expression, proteomic and functional studies, revealed combined features of stemness, drug resistance and epithelial-to-mesenchymal transition (EMT). Based on this solid framework constructed in previous years of work on Q-CSCs we aim to select drugs showing in vitro activity against Q-CSCs that will be translated to in vivo preclinical model including CSC-derived xenografts with fluorescent reporter for quiescent cells.
