Stem cells are essential for maintaining and repairing regenerative tissues. Moreover, genetic alterations of stem cells and their progeny can lead to the generation of “cancer stem cells” (CSCs) that drive tumorigenesis and metastasis. The most potent HSCs are in a state of deep dormancy. In response to bacterial (LPS) or viral infections (Interferons) or chemotherapy mediated cell loss, dormant HSCs become activated to produce new stem cells and progenitors (Wilson et al., Cell 2008; Essers et al., Nature 2009). Using genome-wide transcriptomics, proteomics and methylome analysis, we have established the molecular landscape of HSCs and immediate progenitors to understand the molecular basis of self-renewal and multipotency, as well as the interactions between stem cells and their niche (Cabezas et al., Cell Stem Cell 2014). Using single cell RNAseq and single cell functional assays we uncover the molecular mechanisms driving dormancy. Stress-induced dormancy exit is associated with down-regulation of RA signaling while all-trans-retinoic-acid inhibits this process by restricting ROS and MYC levels. Mice maintained in a vitamin A-free diet progressively lose HSCs and show a disrupted dormancy re-entry after exposure to inflammatory stress stimuli. These results highlight the impact of dietary vitamin A on the regulation of activation mediated stem cell plasticity (Cabezas-Wallscheid et al., Cell 2017). The regulation of MYC in the majority of hematopoietic cells of the systm is controlled by a super-enhancer located 1.7 megabases downstream of the Myc gene. This Blood ENhancer Cluster’ (BENC) is also required for maintenance of AML-AF9 mediated leukemias in mice and is hijacked in human AML (Bahr et al., Nature 2018). Moreover, we have recently shown that the oncogene MYC can regulate the dormancy of pluripotent cells present within pre-implantation embryos during the state of diapause (Scognamilglio et al., Cell 2016). We assume that MYC may be the key regulator controlling entry and exit from dormancy in normal stem cells as well as in cancer and metastasis stem cells.
Pancreatic ductal adenocarcinoma (PDAC) is clinically still treated as a single disease. Here we present PDX models and cell lines derived thereof representing all three PDAC subtypes: quasi-mesenchymal, classical and exocrine-like. These subtypes show significant differences in overall survival and drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel. Cytochrome P450 3A5 (CYP3A5) metabolizes these compounds in exocrine-like tumors, and pharmacological or shRNA-mediated CYP3A5 inhibition sensitizes tumor cells to these drugs (Noll et al., Nature Medicine 2016). Our findings designate CYP3A5 as predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance.