Why is Clonal Evolution Still a Sterile Theory?

May 2, 2022

Despite major revelations in the science of cancer, a classic theory of how it develops—clonal evolution—has remained a perplexing vestige of ‘sterile’ cancer biology. 

Arguing against the sterility of tumors, the last decade of research has revealed metabolically active, immunoreactive, intracellular, cancer type-specific communities of bacteria, viruses, and fungi living within most human cancer types1. These microbes may move during metastasis2 and help cancer cells metastasize more effectively3. They affect virtually all classes of cancer therapies, and trace amounts of their DNA have been identified in blood from cancer patients, suggesting a novel class of microbial cancer diagnostics4. Quite clearly, human cancers are not sterile, and their microbes comprise an entirely new cancer “hallmark”5.

Clonal evolution theory was originally developed on the idea that genetic and non-genetic changes over time in cells explain the trajectory of every cancer, from its origination with a single cell to its own death, or death of the patient6. In particular, clonal evolution has been a very valuable theory for explaining how therapeutic resistance occurs, especially in mutated cancers that are pharmacologically targeted for that specific mutation6. Yet the theory has so far excluded cancer-associated microbes and their impact on carcinogenesis.

In a new article published in BioEssays, “Cancer’s second genome: Microbial cancer diagnostics and redefining clonal evolution as a multispecies process,” Micronoma Co-founder and Chief Analytics Officer, Greg Sepich-Poore, Ph.D., fellow Co-founder Rob Knight, Ph.D., and others, argue that clonal evolution theory can no longer ignore microbes in its accounting if it wants to remain a valid theory.

“Current clonal evolution theory does not account for situations when microbes affect the response or resistance to cancer therapy, whether those microbes are in the tumors themselves or in the gut,” Sepich-Poore said. This point is only amplified when those microbes (e.g., bacteria) are intracellularly located, for they can modify most aspects of how a cancer cell functions.

When one looks at the literature, essentially all of the aspects of a cancer cell that clonal evolution cares about are deeply affected by microbes: Genomic mutations7, transcriptional regulation8, proteomes9, metabolomes10, epigenomes11, epitranscriptomes12, and even actin mechanical structure3. In other words, the cancer cell fitness, or how well a cancer cell is adapted for survival, is intricately tied to tumor-related microbes. But they remain unaccounted for.

To address these gaps in clonal evolution theory, Sepich-Poore and colleagues realized it needed to first become a “multispecies theory,” wherein models of cancer clonal evolution must simultaneously account for co-evolution of microbes themselves.

The major reason for this multispecies revision is that tumor-resident microbes contain distinct genetic cargo from their cancer cell counterparts. This means that intratumoral microbes may face disjoint selection pressures, for example, when treating a patient with an antibiotic. Conversely, treating the patient with a mutation-specific drug would specifically target mutated cancer cells, not their microbes. Moreover, these disjoint selection pressures imply that microbes cannot simply be added as a ‘new layer’ of information in clonal evolution models, for selection pressures—like therapeutics—may dramatically influence cancer cell fitness by acting only on non-cancer entities (e.g., treating pancreatic cancer with a selective antifungal drug).

Sepich-Poore and others thus make the case that a multispecies theory in which cancer cells and microbes comprise independent but interacting clones (see Figure 1) would enable better clonal evolution modeling of cancer development and resistance to therapy.

As a key example of this proposal, consider that more than 300 species of bacteria contain an enzyme that can directly degrade gemcitabine10, a common chemotherapy given to patients with pancreatic and lung cancers, among others. When located in tumors, these bacteria can cause therapeutic resistance of gemcitabine without any influence from the cancer cells themselves10. A multispecies clonal evolution theory would correctly account for how this therapeutic resistance may develop in a patient, whereas its former version would not, and would also suggest how a physician could potentially overcome that resistance.

This BioEssays paper provides a useful theory for the burgeoning cancer microbiome field, in a time in which high-impact papers are aplenty but testable theories are sparse. It also advocates for cancer researchers and cancer-focused companies to not discount the role of microbes in diagnosing and treating cancer. We remain excited to see how the proposed multispecies clonal evolution theory will be tested and fine-tuned in the days and years to come.

To read more, check out our blog post on the addition of polymorphic microbiomes to the vaunted list of Cancer Hallmarks.

References:

  1. Sepich-Poore, G.D. et al. (2021). The microbiome and human cancer. https://doi.org/10.1126/science.abc4552
  2. Bullman et al. (2017). Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science. https://doi.org/10.1126/science.aal5240
  3. Fu, A. et al. (2022). Tumor-resident intracellular microbiota promotes metastatic colonization in breast cancer. Cell. https://doi.org/10.1016/j.cell.2022.02.027
  4. Poore, G. D. et al. (2020). Microbiome analyses of blood and tissues suggest cancer diagnostic approach. Nature. https://doi.org/10.1038/s41586-020-2095-1
  5. Hanahan, D. (2022). Hallmarks of Cancer: New Dimensions. Cancer Discovery. https://doi.org/10.1158/2159-8290.CD-21-1059
  6. McGranahan & Swanton, 2017. Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. Cell. https://doi.org/10.1016/j.cell.2017.01.018
  7. Pleguezuelos-Manzano et al. (2020). Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli. Nature. https://doi.org/10.1038/s41586-020-2080-8
  8. Casasanta et al. (2020). Fusobacterium nucleatum host-cell binding and invasion induces IL-8 and CXCL1 secretion that drives colorectal cancer cell migration. Science Signaling. https://doi.org/10.1126/scisignal.aba9157
  9. Kalaora et al. (2021). Identification of bacteria-derived HLA-bound peptides in melanoma. Nature. https://doi.org/10.1038/s41586-021-03368-8
  10. L.T. et al. (2017). Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science. https://doi.org/10.1126/science.aah5043
  11. Despins et al. (2021). Modulation of the Host Cell Transcriptome and Epigenome by Fusobacterium nucleatum. mBio. https://doi.org/10.1128/mBio.02062-21
  12. Chen et al. (2022). Fusobacterium nucleatum reduces METTL3-mediated m6A modification and contributes to colorectal cancer metastasis. Nature Communications. https://doi.org/10.1038/s41467-022-28913-5

Figure 1: Disjoint clonal evolution, wherein bacteria and cancer cells evolve in parallel before intersecting to create new multispecies clones, several of which have new functional capacities and improved fitness.