Intra-tumour heterogeneity: a looking glass for cancer?

Key Points

  • Primary human tumours consist of cells that differ in clinically important phenotypic features. This phenotypic heterogeneity is a result of the interplay between genetic and non-genetic factors that shape cellular phenotypes.

  • Genomic instability, which is frequently observed in human cancers, in combination with the large numbers of cell divisions required for the formation of macroscopic tumours, leads to inevitable genetic diversity in populations of tumour cells.

  • Somatic evolution that drives tumour progression is characterized by complex dynamics arising from the Darwinian nature of the process. As a result, individual tumours have a unique clonal architecture that is spatially and temporally heterogeneous.

  • The cancer stem cell perspective can explain only some of the non-genetic variability in tumour cell phenotypes. A more comprehensive explanation of non-genetic sources of phenotypic heterogeneity necessitates the consideration of mechanisms that underlie cellular phenotypes.

  • Both deterministic and stochastic determinants of cellular phenotypes can be substantially affected during oncogenic transformation and tumour progression, contributing both to abnormal phenotypes and to an increased degree of phenotypic plasticity.

  • Phenotypic and genetic heterogeneity within tumours impedes clinical diagnostics: owing to topological heterogeneity in the distribution of diagnostically important phenotypes even multiple sampling might not provide adequate information. At the same time, given the link between a high degree of genetic heterogeneity and poor prognosis, a measure of heterogeneity by itself may be useful as a prognostic marker.

  • Phenotypic heterogeneity in tumour cell populations that results from both genetic and non-genetic determinants constitutes a major source of therapeutic resistance. Initial phenotypic heterogeneity and changes in cellular phenotypes resulting from adaptation to response and selection for resistant phenotypes need to be accounted for in order to achieve substantial improvements in therapeutic outcomes.


Populations of tumour cells display remarkable variability in almost every discernable phenotypic trait, including clinically important phenotypes such as ability to seed metastases and to survive therapy. This phenotypic diversity results from the integration of both genetic and non-genetic influences. Recent technological advances have improved the molecular understanding of cancers and the identification of targets for therapeutic interventions. However, it has become exceedingly apparent that the utility of profiles based on the analysis of tumours en masse is limited by intra-tumour genetic and epigenetic heterogeneity, as characteristics of the most abundant cell type might not necessarily predict the properties of mixed populations. In this Review, we discuss both genetic and non-genetic causes of phenotypic heterogeneity of tumour cells, with an emphasis on heritable phenotypes that serve as a substrate for clonal selection. We discuss the implications of intra-tumour heterogeneity in diagnostics and the development of therapeutic resistance.

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Figure 1: Differentiation hierarchies in normal tissues and cancers.
Figure 2: Factors that shape cellular phenotypes: normal tissues versus tumours.
Figure 3: Tumour heterogeneity in metastatic spread.
Figure 4: Tumour heterogeneity in diagnostics.


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We thank members of our laboratory and F. Michor and S. Itzkovitz for their critical reading of our manuscript and for stimulating discussions. Tumour diversity research in the authors' laboratory is supported by US Army Congressionally Directed Research W81XWH-07-1-0294 (K.P.) and BC087579 (A.M.), US National Cancer Institute PO1 CA80111 (K.P.), Susan G. Komen Foundation (K.P.), Breast Cancer Research Foundation (K.P.) and the Cellex Foundation (V.A.).

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Correspondence to Kornelia Polyak.

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Phenotypic plasticity

The ability of cells to change phenotype stochastically or in response to changes in the environment.

Effective population sizes

The numbers of tumour cells capable of passing their genotypes to next generations.

Allelic imbalances

Changes in the copy number of alleles as a result of chromosomal amplification or deletions.

Heat shock protein response

A response to cellular stress involving the activation of molecular chaperones called heat shock proteins (HSPs). HSPs help to maintain cellular homeostasis and to promote survival in the face of stress.


A group of cells that share a common ancestor and that are genetically identical. Whereas all of the cells in the body originate from a single ancestor, every new mutation creates a new clone (a subclone).

Clonal diversity

The diversity of clones within a tumour; results from a branching pattern of evolution. Increased with larger population size, smaller fitness differences, higher mutation rates and heterogeneity of environments.

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Marusyk, A., Almendro, V. & Polyak, K. Intra-tumour heterogeneity: a looking glass for cancer?. Nat Rev Cancer 12, 323–334 (2012).

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