PNAS. major oncogenic and tumor suppressor pathways and can be exacerbated by drug treatment. Thus, plasticity may help cancer cells evade detection and treatment. We propose that cancer can be considered as a disease of excess plasticity, a notion that has important implications for intervention and treatment. development in the 1960s. Imaginal discs are larval tissues that are primordia for specific structures of the adult fly and that can stably maintain their identity during long-term culture. However, at low frequencies, cultured imaginal discs can alter their fate and form alternative tissue structures, termed transdetermination (Worley et al. 2012). These early studies established the basic principle that determined cells could change their fate and offered hints about the importance of the native tissue microenvironment in BRD4770 maintaining stable cell fate. Dedifferentiation, Transdifferentiation, and Metaplasia We can distinguish two basic categories of plasticity that can occur at the cellular level in normal tissues. Dedifferentiation refers to the transition from a fully determined cell type to a less differentiated state, perhaps corresponding to an endogenous stem/progenitor. Although dedifferentiation is considered a distinguishing feature of tumor cells, it is not common in normal physiological contexts but appears to play a major role in BRD4770 tissue repair in response to injury. For example, in BRD4770 the germline, exogenous stimuli or cell depletion can induce adult cells to dedifferentiate to functional stem cells during tissue regeneration (Brawley & Matunis 2004, Kai & Spradling 2004). In a mammalian context, a loss-of-function mutation of the transcription factor promotes diabetes by inducing the dedifferentiation of cells (Talchai et al. 2012b). In contrast, transdifferentiation represents a change in cellular identity from one differentiated cell type to an alternative differentiated state. Transdifferentiation may result from dedifferentiation to a progenitor state followed by differentiation to a distinct cell type, or it may instead correspond to direct conversion from one cell fate to another through a pathway that does not occur in normal development. For example, in the pancreas, following the near-total ablation of cells, cells can be converted to insulin-producing cells (Thorel et al. 2010). Additionally, deletion of in the gut epithelium results in conversion to insulin-producing -like cells (Talchai et al. 2012a). Although rare in normal physiological contexts, it is becoming increasingly apparent that transdifferentiation plays an important role in cancer and treatment response, as discussed below. The phenomenon of metaplasia refers to tissue plasticity that may not necessarily occur at the cellular level. This term is generally used in circumstances in which multiple cell types within a tissue are replaced with other cell types, although the experimental evidence is not sufficient to ascertain whether such phenotypes reflect cellular plasticity or alternative mechanisms (Slack 2007). Metaplasia is rare in nontumorigenic contexts but can occur in cancer, as exemplified by Barretts esophageal cancer, in which the normal squamous epithelium is replaced with an intestinal-like columnar epithelium (Jankowski et al. 2000). Cellular Reprogramming Among the first experimental demonstrations of cellular plasticity at the molecular level was the classic work of Weintraub and colleagues, who showed that expression of a single gene, (termed OSKM factors) could convert differentiated fibroblasts into induced pluripotent (iPS) cells (Takahashi & Yamanaka 2006, Takahashi et al. 2007). Notably, aberrant expression of each of the OSKM factors has been linked to cancer, which underscores the intimate relationship of plasticity mechanisms and oncogenesis, as discussed below. As with transdifferentiation, experimental approaches ILF3 for reprogramming can be broadly separated into two distinct categories. Direct conversion approaches generate a differentiated cell type from a distinct BRD4770 cell type by transient expression of a cocktail of specification genes. Notably, a cocktail of three genes ((Livet et al. 2007), (Snippert et al. 2010), and (Yu et al. 2017), which allow for a higher-resolution assessment of clonal lineage relationships. Two-color fluorescent protein systems also facilitate methods for mosaic analysis, such as mosaic analysis with double markers, which combine lineage tracing with the ability to.