Convergent Evolution, Evolving Evolvability, and the Origins of Lethal Cancer

Abstract

Advances in curative treatment to remove the primary tumor have increased survival of localized cancers for most solid tumor types, yet cancers that have spread are typically incurable and account for >90% of cancer-related deaths. Metastatic disease remains incurable because, somehow, tumors evolve resistance to all known compounds, including therapies. In all of these incurable patients, de novo lethal cancer evolves capacities for both metastasis and resistance. Therefore, cancers in different patients appear to follow the same eco-evolutionary path that independently manifests in affected patients. This convergent outcome, that always includes the ability to metastasize and exhibit resistance, demands an explanation beyond the slow and steady accrual of stochastic mutations. The common denominator may be that cancer starts as a speciation event when a unicellular protist breaks away from its multicellular host and initiates a cancer clade within the patient. As the cancer cells speciate and diversify further, some evolve the capacity to evolve: evolvability. Evolvability becomes a heritable trait that influences the available variation of other phenotypes that can then be acted upon by natural selection. Evolving evolvability may be an adaptation for cancer cells. By generating and maintaining considerable heritable variation, the cancer clade can, with high certainty, serendipitously produce cells resistant to therapy and cells capable of metastasizing. Understanding that cancer cells can swiftly evolve responses to novel and varied stressors create opportunities for adaptive therapy, double-bind therapies, and extinction therapies; all involving strategic decision making that steers and anticipates the convergent coevolutionary responses of the cancers.

Figure 1.. The convergent evolution of lethal cancer.

Each year worldwide, 20 million people are diagnosed with cancer. Approximately 10 million of those patients are cured of their disease by local therapy. The other 10 million patients develop lethal and incurable disease. Each of these 10 million cancers in different patients lead to the same convergent phenotype: metastatic potential and therapy resistance.

Figure 2.. The diversification of species.

The tree of life diagram shows the major extant branches of life across a geologic time scale of millions of years. Major clades (distinctly colored) are related by a last common ancestor. Species are represented by branch lines within these clades. Dashed lines indicate major points of speciation (e.g., the Cambrian Explosion approximately 543 Ma) and extinction, emphasizing the changes in diversity throughout the history of life. (Figure modified from and used with permission: © Leonard Eisenberg, 2008, 2017, All Rights Reserved. https://www.evogeneao.com.)

Figure 3.. The diversification of cancer species within a monophyletic clade.

The cancer clade arises from a common ancestor: the single-cell cancer protist. After this initial speciation event, the species rapidly diversifies into multiple species, thus generating a monophyletic cancer clade. The various species within this clade will experience changing ecological pressures during cancer progression and treatment, resulting in additional speciation and extinction events. Ultimately, the cancer clade only goes extinct upon the death of the patient: the elimination of its requisite biosphere. (Figure modified from and used with permission: © Leonard Eisenberg, 2008, 2017, All Rights Reserved. https://www.evogeneao.com.)

Figure 4.. Evolution of evolvability in species of the cancer clade.

All cancer species arise from a single unicellular cancer protist followed by rapid hyperspeciation. In this diagram, each line/branch represent a genetically distinct cancer species, all related to the same common ancestor. Within each species, there may emerge multiple different strains, each with different epigenetic variation and carrier mutation status that arise in response to varied ecological circumstances (inset). There is strong selection for evolvability as successful cancer cell species are likely those that respond to selection pressures in the tumor microenvironment. Tumor heterogeneity promotes an adaptive radiation of the cancer cells into distinct species that occupy the different ecological niches. Thus, even as nonevolvable species are eliminated by therapy, those species that evolved an evolvable phenotype survive to seed a metastasis and mediate therapy resistance (in this diagram, the pink species). The selection for this evolvable phenotype – and therefore the lethal phenotype – is initiated early in cancer progression, prior to any exposure to therapy. (Illustrations: Tim Phelps © 2019 JHU AAM; Department of Art as Applied to Medicine; The Johns Hopkins University School of Medicine)