Lineage Plasticity: The New Cancer Hallmark on the Block

Abstract

Plasticity refers to the ability of cells to adopt a spectrum of states or phenotypes. In cancer, it is a critical contributor to tumor initiation, progression, invasiveness, and therapy resistance, and it has recently been recognized as an emerging cancer hallmark. Plasticity can occur as a result of cell-intrinsic factors (e.g., genetic, transcriptional, or epigenetic fluctuations), or through cell-extrinsic cues (e.g., signaling from components of the tumor microenvironment or selective pressure from therapy). Over the past decade, technological advances, analysis of patient samples, and studies in mouse model systems have led to a deeper understanding of how such plastic states come about. In this review, we discuss: (i) the definition of plasticity; (ii) methods to measure and quantify plasticity; (iii) the clinical relevance of plasticity; and (iv) therapeutic hypotheses to modulate plasticity in the clinic.

Figure 1.

Molecular features that influence plasticity. The genetic architecture of a tumor cell may constrain the spectrum of cell states a cell can adopt (blue outline). Within this spectrum, cells may exist in dense neighborhoods defined in a multidimensional feature space (cell states). Tumor cell intrinsic (e.g. transcription factors, epigenetic state, among others) and extrinsic factors (e.g. growth factors, immune response, metabolomic environment, mechanical forces, among others) influence the rate of transition between cell states. The rates of transition between two states are one possible metric for the level of plasticity exhibited by a cell. Both intrinsic and extrinsic factors may influence each other, and both may also be influenced by other tumor extrinsic perturbations such as treatment.

Figure 2.

Therapeutic hypotheses for addressing plasticity for patient benefit. To overcome plasticity and treatment-resistant states, we must identify combinations of current therapies with novel drugs that either: 1) prevent emergence of treatment-resistant states; 2) promote plasticity towards treatment-sensitive states; or 3) address dependencies or synthetic lethalities in treatment-resistant states. Such novel drugs need to be assessed for their pharmacodynamic activity in modulating cell states, and if effective, they have the potential in combination with current therapies to increase tumor cell killing, address tumor cell-intrinsic heterogeneity and prevent the emergence of treatment resistance to improve progression free survival, and possibly overall survival, of patients.