Exploring Cancer’s Evolutionary Landscape. Speciation and the Emergence of Hopeful Monsters

The very concept of cancer is illuminated by the phenomenon of convergent evolution. Tumors, despite arising from distinct tissues and even different organisms, tend to converge upon a common set of phenotypic traits, widely recognized as the “hallmarks of cancer” (Hanahan, 2022). This recurrent pattern strongly suggests that natural selection plays a pivotal role in shaping these convergent traits (Fortunato et al., 2017).

Charles Darwin’s groundbreaking work, On the Origin of Species, introduced natural selection as the mechanism responsible for the gradual accumulation of differences observed throughout the natural histories of organisms. Supported by extensive paleontological evidence and later integrated with the principles of molecular genetics, this perspective gave rise to the modern evolutionary synthesis. This framework envisions evolution as a slow, incremental process, reminiscent of the iconic (if somewhat oversimplified) progression from ape to man as depicted by Rudolph Zallinger.

Influenced by this gradualist view, it is often assumed that cancer evolution proceeds in a slow and steady manner. However, emerging evidence indicates that the evolutionary dynamics of cancer do not always adhere to a uniform pace. While periods of neutral growth may be evident, selection becomes critical at key stages of clonal expansion to enable neoplastic cells to outcompete their normal counterparts (Cross et al., 2016). In other words, cancer evolution may not strictly follow the predictable patterns of gradual change or neutral drift.

It is important to distinguish between two concepts that are sometimes conflated: punctuated equilibrium and saltation theory. Saltation theory suggests that entirely new species can emerge abruptly through sudden, large-scale mutations. In contrast, punctuated equilibrium describes significant phenotypic shifts that arise from gradual genetic evolution within isolated populations. Richard Goldschmidt famously coined the term “hopeful monsters” to describe these abrupt, radical mutations that, in rare instances, might yield highly optimized forms. Nonetheless, the majority of such drastic genetic rearrangements tend to be maladaptive (Graham & Sottoriva, 2017).

Applying the concept of punctuated equilibrium to cancer suggests that tumor evolution may follow variable, non-linear trajectories, often marked by chaotic bursts of change. This non-gradualism has important implications for clinical prediction models and therapeutic strategies. Sudden evolutionary leaps could result in faster-than-anticipated changes in tumor behavior, challenging models that assume linear mutation rates and predominantly single nucleotide variants. Incorporating models that explicitly account for periods of stasis and rapid change can therefore offer more comprehensive insights into cancer dynamics (Cross et al., 2016).

To illustrate these ideas, imagine an adaptive landscape where the initial population is represented by a purple species, with the size of each circle corresponding to population size. Once this population stabilizes at a local minimum, it may diverge into two subspecies, each evolving toward distinct local peaks. Under a strict gradualist scenario, further speciation via sympatric mechanisms would be unlikely, with geographic isolation (i.e., allopatric speciation) being necessary for colonizing a new evolutionary stable strategy (ESS). However, in the context of cancer, evolution is not confined to such gradual shifts. Punctuated chromosomal alterations can give rise to “hopeful monsters” (depicted in blue) that rapidly establish themselves at a novel ESS.

The G-function model provides a useful framework by assuming a micro-mutation approach, one that limits the range of strategies accessible to natural selection. In their seminal work, Vincent and Brown (2005) discuss the role of hopeful monsters in exploring new regions of the strategy space. Although they adhere to a paradigm in which invading strategies are confined to a small neighborhood around existing values in keeping with genetic constraints, their framework effectively demonstrates both sympatric speciation and the emergence of a hopeful monster within a constrained evolutionary landscape.

While current G-function models of cancer rely on relatively simple adaptive landscapes to observe speciation events, there is considerable potential for refinement. By incorporating a more detailed characterization of the tumor microenvironment and accounting for the effects of multiple drugs, future models could more accurately capture the complexities of speciation, macroevolution, and the sudden emergence of hopeful monsters in cancer.

References

Cross, W. C. H., Graham, T. A., & Wright, N. A. (2016). New paradigms in clonal evolution: punctuated equilibrium in cancer. In Journal of Pathology (Vol. 240, Issue 2, pp. 126–136). John Wiley and Sons Ltd. https://doi.org/10.1002/path.4757

Fortunato, A., Boddy, A., Mallo, D., Aktipis, A., Maley, C. C., & Pepper, J. W. (2017). Natural selection in cancer biology: From molecular snowflakes to trait hallmarks. Cold Spring Harbor Perspectives in Medicine, 7(2). https://doi.org/10.1101/cshperspect.a029652

Graham, T. A., & Sottoriva, A. (2017). Measuring cancer evolution from the genome. In Journal of Pathology (Vol. 241, Issue 2, pp. 183–191). John Wiley and Sons Ltd. https://doi.org/10.1002/path.4821

Hanahan, D. (2022). Hallmarks of Cancer: New Dimensions. In Cancer Discovery (Vol. 12, Issue 1, pp. 31–46). American Association for Cancer Research Inc. https://doi.org/10.1158/2159-8290.CD-21-1059

Vincent, T. L., & Brown, J. S. (2005). Evolutionary Game Theory, Natural Selection, and Darwinian Dynamics. Cambridge University Press. https://doi.org/DOI: 10.1017/CBO9780511542633