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.

Intratumor heterogeneity is a major clinical problem because tumor cell subtypes display variable sensitivity to therapeutics and may play different roles in progression. We previously characterized 2 cell populations in human breast tumors with distinct properties: CD44 + CD24 -cells that have stem cell-like characteristics, and CD44 -CD24 + cells that resemble more differentiated breast cancer cells. Here we identified 15 genes required for cell growth or proliferation in CD44 + CD24 -human breast cancer cells in a large-scale loss-of-function screen and found that inhibition of several of these (IL6, PTGIS, HAS1, CXCL3, and PFKFB3) reduced Stat3 activation. We found that the IL-6/JAK2/Stat3 pathway was preferentially active in CD44 + CD24 -breast cancer cells compared with other tumor cell types, and inhibition of JAK2 decreased their number and blocked growth of xenografts. Our results highlight the differences between distinct breast cancer cell types and identify targets such as JAK2 and Stat3 that may lead to more specific and effective breast cancer therapies.