Lineage Plasticity in Cancer Progression and Treatment

Abstract

Historically, it has been widely presumed that differentiated cells are determined during development and become irreversibly committed to their designated fates. In certain circumstances, however, differentiated cells can display plasticity by changing their identity, either by dedifferentiation to a progenitor-like state or by transdifferentiation to an alternative differentiated cell type. Such cellular plasticity can be triggered by physiological or oncogenic stress, or it can be experimentally induced through cellular reprogramming. Notably, physiological stresses that promote plasticity, such as severe tissue damage, inflammation, or senescence, also represent hallmarks of cancer. Furthermore, key drivers of cellular plasticity include 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.

Keywords: cancer progression; differentiation; drug resistance; lineage plasticity; reprogramming; transdifferentiation.

Figure 1

Waddington’s (1957) landscape of differentiation, depicting the process of differentiation of a stem cell into distinct cell types, visualized as a ball rolling down a hill. Pathways of dedifferentiation, transdifferentiation (both direct and indirect), and reprogramming are indicated. Adapted from Waddington (1957, p. 29, figure 4) with permission from Taylor & Francis.

Figure 2

The intrinsic and extrinsic factors that can promote cell plasticity in homeostasis and cancer.