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Big Bang and context-driven collapse

Nature Genetics volume 47, pages 196–197 (2015)Cite this article

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Heterogeneity is the single most important factor driving cancer progression and treatment failure, yet little is understood about how and when this heterogeneity arises. A new study shows that colorectal cancers acquire their dominant mutations early in development and that subsequent mutations, even if they confer greater fitness, are unlikely to sweep through the tumor.

Heterogeneity in cancer is an observed fact, both genetically and phenotypically1. Cell-to-cell variation is seen in all aspects of cancer, from early development to invasion and subsequent metastasis. This heterogeneity is also at the heart of why many cancer treatments fail, as it facilitates the emergence of drug resistance. The complex spatial and temporal process by which tumors initiate, grow and evolve is a major focus of the oncology community2 and one that requires the integration of multiple disciplines3. On page 209 of this issue, Christina Curtis, Darryl Shibata and colleagues4 illustrate perfectly the power of an integrated approach through their intriguing hypothesis that colorectal tumors grow by means of a mutational 'Big Bang'. This model is in contrast to the traditional 'clonal selection' view, where sequential mutations lead to fitter clones that sweep through the population5. The Big Bang model emphasizes the importance of early mutations, occurring when tumors are relatively small (104–105 cells) and environmentally proficient. Key mutations at this early stage result in growth mechanisms that are primarily tumor cell centric rather than environmentally constrained. Sottoriva et al.4 do not claim that all cancers will follow this evolutionary trajectory, just a subset—specifically, those whose initial rapid growth occurs in the absence of spatial constraints. In these cases, the early proliferative clone underlies the majority of tumor growth, such that cells with subsequent (and hence private) mutations, even those resulting in greater fitness, will never have time to 'catch up' and sweep through the tumor. Another prediction of this work is that variegated patterns of non-localized private mutations in a Big Bang tumor indicate the presence of abnormally motile cells early in the tumor's development. Tumors with these mutation patterns, which are described as “born to be bad,” have increased risk of both invasive growth and metastatic spread.

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Figure 1: Clonal heterogeneity is a product of spatiotemporal evolution.

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  1. Mark Robertson-Tessi and Alexander R. A. Anderson are in the Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.,

    Mark Robertson-Tessi & Alexander R A Anderson

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  1. Mark Robertson-Tessi
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Correspondence to Mark Robertson-Tessi or Alexander R A Anderson.

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Robertson-Tessi, M., Anderson, A. Big Bang and context-driven collapse. Nat Genet 47, 196–197 (2015). https://doi.org/10.1038/ng.3231

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