Cancer cells even within the same tumor can display startling differences for many features including migratory/invasive potential and sensitivity to therapeutic agents. This intratumor heterogeneity is a major obstacle toward understanding and treatment of cancers. In solid tumors differences in the local microenvironment, in part due to variability in blood supply and topologic differences in the distribution of leukocytes, can lead to high degree of spatial heterogeneity and also select for cancer cells with different properties. While our ability to define intratumor clonal heterogeneity has grown immensely in the past few years due to technologic advances enabling whole genome sequencing studies even at the single cell level, our understanding of the functional relevance of this heterogeneity has been lagging behind. Similarly, our definition of cancer drivers has been based on the relative frequency of the cells within tumors and based on their cell-autonomous function, thus, by definition neglecting the potential relevance of minor clones and non-cell-autonomous (e.g., paracrine and juxtracrine) effects.

In experimental models there is increasing evidence for cooperation among cancer cell clones with different properties, but identifying and characterizing such interactions in clinical samples has been challenging. At the same time, emerging data suggest that intratumor clonal heterogeneity is maintained by non-cell-autonomous drivers and many of these never achieve clonal dominance due to lack of selective advantage. Thus, it is likely that non-cell-autonomous driver clones exist in human tumors and the effects of the microenvironment are mostly non-cell-autonomous as well. Because interactions among clones of cancer cells and between cancer cells and the tumor microenvironment have a major impact on overall therapeutic outcomes, understanding these interactions is necessary for the design of more effective treatment strategies for heterogeneous tumors.

Citation Format: Polyak K. Non-cell-autonomous drivers of tumor growth and progression [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES1-1.