Figure 2: Oncogenic targets and cell states.

This schematic represents the coexistence of distinct, yet isogenic malignant cell states within a tumor, each one presenting an equally distinct repertoire of non-oncogene dependencies. To avoid cluttering, tumor microenvironment-related cell states are not shown, even though they are involved in critical paracrine interactions with tumor cells. (A) Schematic representation of isogenic tumor cells presenting with distinct transcriptional states and epigenetic profiles. These include: (i) a low-proliferative (i.e., quiescent) meta-stable stem-like progenitor cell state capable of self-renewal and asymmetric differentiation (ii) two stable, differentiated cell states, persisting for long time periods, associated with either an epithelial (proliferative) or a mesenchymal (quiescent) cell phenotype, and (iii) an additional neuroendocrine (quiescent) stable state that can only be achieved by drug-induced transdifferentiation. The size of the arrows illustrates the likelihood of transition from one cell state to another. Stem-like progenitors can differentiate into either epithelial or mesenchymal cells, which can plastically reprogram between these states, albeit at different rates, for instance as a result of epithelial mesenchymal transformation processes. The neuroendocrine state is not pathophysiologically accessible but can be reached via drug-mediated transdifferentiation from the epithelial cell state. (B) Schematic representation of the canalization entropy landscape that underlies the possible cell states. Cells tend to move from a higher to a lower entropy state with a probability that is inversely proportional to the entropic barrier that separates them DE1 (i.e., height of the peak separating two adjacent valleys) and directly proportional to their differential entropy DE2 (i.e. differential depth of two adjacent valleys). For instance, an epithelial state cell can reprogram to a mesenchymal state cell because the entropic barrier between the two is low (plasticity) but the forward direction is more likely than the reverse one because the entropy of the mesenchymal state is lower. (C) Schematic representation of the tumor composition changes following drug treatment or spontaneous progression. For simplicity, only four transitions are illustrated, including: (i) Metastatic progression, associated with an increased ratio of mesenchymal to epithelial cells but no change in the fraction of stem-like progenitors, (ii) Chemotherapy treatment, resulting in ablation of the proliferative epithelial state and increase of the stem-like progenitor and mesenchymal quiescent states, (iii) Targeted Therapy A, inducing reduction of the stem-like progenitor and mesenchymal quiescent states and increase of the epithelial proliferative state, and (iv) Targeted Therapy B, resulting in the emergence of a novel neuroendocrine state resulting from drug-induced transdifferentiation.