Most human cancers exhibit a high degree of intratumour heterogeneity that arises from heritable and stochastic genetic and epigenetic changes, as well as environmental variations within the tumour. Heterogeneous subpopulations that exist within close proximity and compete for limited resources can engage in complex interactions that affect tumorigenesis, disease progression and therapeutic outcomes.
Phenotypic changes that arise from subclonal interactions in heterogeneous tumours were observed by cancer biologists very early on. However, as studies mostly focused on cell-autonomous oncogenes and tumour suppressors, investigations into clonal interactions went under the radar for almost three decades. With the increasing recognition of intratumour heterogeneity fuelled by advances in technology, dissecting the mechanistic basis of clonal interactions is now gaining more attention.
In addition to the more traditional models that explore clonal interactions strictly from the competitive angle, newer studies are investigating cooperative interactions among subclones that could give rise to novel characteristics and that potentially increase the growth and progression of the tumour.
In the absence of proper tools to directly study clonal interactions in patient samples, studies in D. melanogaster, rodents and xenograft systems (using both established cell lines and patient-derived cells) are providing us with mechanistic insights into interclonal crosstalk.
Theoretical and mathematical modelling are being used to simulate clonal dynamics under variable circumstances. Although currently far from perfect, these in silico cancer models have already been useful for the design of optimized cancer therapies for the more effective eradication of tumours.
Cooperation can be metabolically costly but evolution and survival are more efficient, especially in a changing environment, when diversity and heterogeneity are high. Insights from patient tumours have revealed the presence of multiple independent neoplastic driver subclones that could re-establish tumour heterogeneity after therapy and lead to disease relapse. Furthermore, there is increasing evidence of transient clonal cooperation between neoplastic and benign subclones, which can also lead to tumour recurrence.
In order to tackle the ever-evolving populations of tumour cells more effectively and to devise more lasting cures in patients, we must use ecological approaches that take advantage of cooperative tumour-promoting interactions and strategically eliminate them instead of targeting each individual subpopulation.
Although it is widely accepted that most cancers exhibit some degree of intratumour heterogeneity, we are far from understanding the dynamics that operate among subpopulations within tumours. There is growing evidence that cancer cells behave as communities, and increasing attention is now being directed towards the cooperative behaviour of subclones that can influence disease progression. As expected, these interactions can add a greater layer of complexity to therapeutic interventions in heterogeneous tumours, often leading to a poor prognosis. In this Review, we highlight studies that demonstrate such interactions in cancer and postulate ways to overcome them with better-designed therapeutic strategies.
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The authors thank A. Marusyk and M. Janiszewska for their critical reading of the manuscript and for stimulating discussions. Tumour heterogeneity research in the authors' laboratory is supported by US Army Congressionally Directed Research BC131217P1 (K.P.), and the Breast Cancer Research Foundation (K.P.).
Sponsored research agreement and consultancy with Novartis Oncology (K.P.). D.P.T. declares no competing interests.
Groups of cells that each originate from a common ancestor and share the same set of genetic and epigenetic alterations. Any new subset of changes occurring within clones gives rise to subclones.
- Clonal interference
A phenomenon in which multiple clones of higher than average fitness coexist in the same population and interfere with each other. It results from negative interactions that eventually reach equilibrium. Clonal interference is thought to slow down evolution.
- 'Free-rider' or 'cheater' subclones
These are cancer cell populations that take advantage of resources produced by other cancer cell populations within the tumour to proliferate and survive without any obvious reciprocation to their neighbours.
- Eye-imaginal discs
A zone of cells in the Drosophila melanogaster larvae that give rise to the structures of compound eyes in the adult fly.
- Phenotype switching
The ability of cells to change their phenotype in response to the environment. It is usually a result of changes in epigenetic modifications within the cell and is reversible.
- Recovery periods and drug holidays
As most therapeutic regimens have some accompanying side effects, patients are usually taken off the treatment for short intervals to allow for recovery from systemic toxicity. Sometimes drug holidays are also scheduled to increase the efficacy of the treatment.
- Cellular diversity scoring
Widely used in ecology, diversity scoring is a process of quantifying heterogeneity in an environment by taking into account the number and abundance of its inhabiting species. In tumours, the cellular diversity score is a number that represents the extent of unique sub-clonal populations that contribute to the intratumour heterogeneity.
- Common gooders
Populations of cells that can act as non-cell-autonomous drivers of tumour growth through the secretion of diffusible factors that can have positive paracrine influences on neighbouring populations.
- Public goods
A term from the field of economics that denotes resources that are consumed by the entire society rather than an individual. In the tumour milieu, public goods can be exemplified by diffusible growth factors, nutrients and oxygen.
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Tabassum, D., Polyak, K. Tumorigenesis: it takes a village. Nat Rev Cancer 15, 473–483 (2015). https://doi.org/10.1038/nrc3971
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