Figure 1.

Mechanisms governing CSC plasticity model. Intra-tumor heterogeneity relies on the capacity to shift dynamically and reversibly between CSC and non-CSC/differentiated state. Tumor cell modifications as genetic and epigenetic alterations and microenvironment perturbations as inflammation, injury, and senescence represent the major causes of cancer cells plasticity. Moreover, CSCs exhibit an induced epithelial-to-mesenchymal transition (EMT) program and, particularly, they display an intermediate state of EMT. This process depends on both genetic mutations, epigenetic modifications and transcriptional modulation of cancer cells and signals provided by the tumor microenvironment (i.e., growth factors, cytokines, CAFs or TAMs). Created with BioRender.com.