Sociobiology meets oncology: unraveling altruistic cooperation in cancer cells and its implications.

Altruism, an act of benefiting others at a cost to the self, challenges our understanding of evolution. This Perspective delves into the importance of altruism in cancer cells and its implications for therapy. Against the backdrop of existing knowledge on various social organisms found in nature, we explore the mechanisms underlying the manifestation of altruism within breast tumors, revealing a complex interplay of seemingly counteracting cancer signaling pathways and processes that orchestrate the delicate balance between cost and benefit underlying altruistic cooperation.

Tumor Heterogeneity Shapes Survival Dynamics in Drug-Treated Cells, Revealing Size-Drifting Subpopulations.

The goal of this project was to demonstrate that subpopulations of cells in tumors can uniquely fluctuate in size in response to environmental conditions created during drug treatment, thereby acting as a dynamic "rheostat" to create a favorable tumor environment for growth. The cancer modeling used for these studies was subpopulations of melanoma cells existing in cultured and tumor systems that differed in aldehyde dehydrogenase (ALDH) activity. However, similar observations were found in other cancer types in addition to melanoma, making them applicable broadly across cancer.

Dynamic altruistic cooperation within breast tumors.

Background: Social behaviors such as altruism, where one self-sacrifices for collective benefits, critically influence an organism's survival and responses to the environment. Such behaviors are widely exemplified in nature but have been underexplored in cancer cells which are conventionally seen as selfish competitive players. This multidisciplinary study explores altruism and its mechanism in breast cancer cells and its contribution to chemoresistance.

Soft selection reduces loss of heterozygosity in asexual reproduction.

The adaptive value of sexual reproduction is still debated in evolutionary theory. It has been proposed that the advantage of sexual reproduction over asexual reproduction is to promote genetic diversity, to prevent the accumulation of harmful mutations or to preserve heterozygosity. Since these hypothetical advantages depend on the type of asexual reproduction, understanding how selection affects the taxonomic distribution of each type could help us discriminate between existing hypotheses.

Polyploidy as an Adaptation against Loss of Heterozygosity in Cancer.

Polyploidy is common in cancer cells and has implications for tumor progression and resistance to therapies, but it is unclear whether it is an adaptation of the tumor or the non-adaptive effect of genomic instability. I discuss the possibility that polyploidy reduces the deleterious effects of loss of heterozygosity, which arises as a consequence of mitotic recombination, and which in diploid cells leads instead to the rapid loss of complementation of recessive deleterious mutations. I use computational predictions of loss of heterozygosity to show that a population of diploid cells dividing by mitosis with recombination can be easily invaded by mutant polyploid cells or cells that divide by endomitosis, which reduces loss of complementation, or by mutant cells that occasionally fuse, which restores heterozygosity.

Delivery of Therapeutic miR-148b Mimic via Poly(β Amino Ester) Polyplexes for Post-transcriptional Gene Regulation and Apoptosis of A549 Cells.

In this study, we utilized selectively modified, biodegradable polymer-based polyplexes to deliver custom, exogenous miR-148b mimics to induce apoptosis in human lung cancer (A549) cells. The gene regulatory effects of the payload miRNA mimics (miR-148b-3p) were first evaluated through bioinformatic analyses to uncover specific gene targets involved in critical carcinogenic pathways. Hyperbranched poly(β amino ester) polyplexes (hPBAE) loaded with custom miR-148b mimics were then developed for targeted therapy.

Evidence from automixis with inverted meiosis for the maintenance of sex by loss of complementation.

The adaptive value of sexual reproduction is still debated. A short-term disadvantage of asexual reproduction is loss of heterozygosity, which leads to the unmasking of recessive deleterious mutations. The cost of this loss of complementation is predicted to be higher than the twofold cost of meiosis for most types of asexual reproduction.

Collapse of Intra-Tumor Cooperation Induced by Engineered Defector Cells.

Anti-cancer therapies promote clonal selection of resistant cells that evade treatment. Effective therapy must be stable against the evolution of resistance. A potential strategy based on concepts from evolutionary game theory is to impair intra-tumor cooperation using genetically modified cells in which genes coding for essential growth factors have been knocked out.

A test of the photoprotection hypothesis for the evolution of autumn colours: Chlorophyll resorption, not anthocyanin production, is correlated with nitrogen translocation.

A prominent hypothesis for the adaptive value of anthocyanin production in the autumn leaves of trees and shrubs is that anthocyanins protect leaves from photooxidative stress at low temperatures, allowing a better resorption of nutrients-in particular, nitrogen-before leaf fall. While there is evidence that anthocyanins enable photoprotection, it is not clear whether this translates to improved nitrogen translocation and how this can explain inter-specific variation in autumn colours. A recent comparative analysis showed no correlation between temperature and anthocyanin production across species but did not analyse nitrogen content and nitrogen resorption efficiency.

A synthetic defective interfering SARS-CoV-2.

Viruses thrive by exploiting the cells they infect, but in order to replicate and infect other cells they must produce viral proteins. As a result, viruses are also susceptible to exploitation by defective versions of themselves that do not produce such proteins. A defective viral genome with deletions in protein-coding genes could still replicate in cells coinfected with full-length viruses.

A comparative analysis of the photoprotection hypothesis for the evolution of autumn colours.

The adaptive value of autumn colours-the seasonal production of red anthocyanins observed in many species of trees and shrubs-is still debated. According to the photoprotection hypothesis, anthocyanins protect leaves from photo-inhibition and photo-oxidation at low temperatures, enabling the tree to reabsorb nutrients more efficiently before leaf fall. Hence, the hypothesis predicts that autumn colours are more likely to evolve in species growing in colder environments.

Inverted meiosis and the evolution of sex by loss of complementation.

Inverted meiosis, in which sister chromatids segregate before homologous chromosomes, is a common aberration of conventional meiosis (in which sister chromatids segregate after homologous chromosomes) and is routinely observed in certain species. This raises an evolutionary mystery: what is the adaptive advantage of the more common, conventional order of segregation in meiosis? I use a population genetic model to show that asexual mutants arising from inverted meiosis are relatively immune from the deleterious effects of loss of complementation (heterozygosity), unlike the asexual mutants arising from conventional meiosis, in which loss of complementation can outweigh the two-fold cost of meiosis. Hence, asexual reproduction can replace sexual reproduction with inverted meiosis, but not with conventional meiosis.

Maintenance of variation in mutualism by screening.

Models of partner choice leading to mutualism raise a conceptual problem: directional selection for high-quality partners should ultimately erode variation in partner quality. How do we explain the persistence of variation in partner quality observed in nature? The problem arises in all models of partner choice, including screening models, in which a host induces potential symbionts of different quality to screen themselves by assigning them different costs and rewards. Using a screening model in which costs and rewards are sometimes assigned incorrectly, I show that a stable polymorphism can arise because rewards are higher when partners vary in quality than when there is only one type of partner.

Cooperation among cancer cells: applying game theory to cancer.

Cell cooperation promotes many of the hallmarks of cancer via the secretion of diffusible factors that can affect cancer cells or stromal cells in the tumour microenvironment. This cooperation cannot be explained simply as the collective action of cells for the benefit of the tumour because non-cooperative subclones can constantly invade and free-ride on the diffusible factors produced by the cooperative cells. A full understanding of cooperation among the cells of a tumour requires methods and concepts from evolutionary game theory, which has been used successfully in other areas of biology to understand similar problems but has been underutilized in cancer research.

Evolutionary Dynamics of Tumor-Stroma Interactions in Multiple Myeloma.

Cancer cells and stromal cells cooperate by exchanging diffusible factors that sustain tumor growth, a form of frequency-dependent selection that can be studied in the framework of evolutionary game theory. In the case of multiple myeloma, three types of cells (malignant plasma cells, osteoblasts and osteoclasts) exchange growth factors with different effects, and tumor-stroma interactions have been analysed using a model of cooperation with pairwise interactions. Here we show that a model in which growth factors have autocrine and paracrine effects on multiple cells, a more realistic assumption for tumor-stroma interactions, leads to different results, with implications for disease progression and treatment.

Evolution of optimal Hill coefficients in nonlinear public goods games.

In evolutionary game theory, the effect of public goods like diffusible molecules has been modelled using linear, concave, sigmoid and step functions. The observation that biological systems are often sigmoid input-output functions, as described by the Hill equation, suggests that a sigmoid function is more realistic. The Michaelis-Menten model of enzyme kinetics, however, predicts a concave function, and while mechanistic explanations of sigmoid kinetics exist, we lack an adaptive explanation: what is the evolutionary advantage of a sigmoid benefit function? We analyse public goods games in which the shape of the benefit function can evolve, in order to determine the optimal and evolutionarily stable Hill coefficients.

Cooperation among cancer cells as public goods games on Voronoi networks.

Cancer cells produce growth factors that diffuse and sustain tumour proliferation, a form of cooperation that can be studied using mathematical models of public goods in the framework of evolutionary game theory. Cell populations, however, form heterogeneous networks that cannot be described by regular lattices or scale-free networks, the types of graphs generally used in the study of cooperation. To describe the dynamics of growth factor production in populations of cancer cells, I study public goods games on Voronoi networks, using a range of non-linear benefits that account for the known properties of growth factors, and different types of diffusion gradients.

Heterogeneity for IGF-II production maintained by public goods dynamics in neuroendocrine pancreatic cancer.

The extensive intratumor heterogeneity revealed by sequencing cancer genomes is an essential determinant of tumor progression, diagnosis, and treatment. What maintains heterogeneity remains an open question because competition within a tumor leads to a strong selection for the fittest subclone. Cancer cells also cooperate by sharing molecules with paracrine effects, such as growth factors, and heterogeneity can be maintained if subclones depend on each other for survival.

Stable heterogeneity for the production of diffusible factors in cell populations.

The production of diffusible molecules that promote survival and growth is common in bacterial and eukaryotic cell populations, and can be considered a form of cooperation between cells. While evolutionary game theory shows that producers and non-producers can coexist in well-mixed populations, there is no consensus on the possibility of a stable polymorphism in spatially structured populations where the effect of the diffusible molecule extends beyond one-step neighbours. I study the dynamics of biological public goods using an evolutionary game on a lattice, taking into account two assumptions that have not been considered simultaneously in existing models: that the benefit of the diffusible molecule is a non-linear function of its concentration, and that the molecule diffuses according to a decreasing gradient.