From genetic mosaicism to tumorigenesis through indirect genetic effects.

Genetic mosaicism has long been linked to aging, and several hypotheses have been proposed to explain the potential connections between mosaicism and susceptibility to cancer. It has been proposed that mosaicism may disrupt tissue homeostasis by affecting intercellular communications and releasing microenvironmental constraints within tissues. The underlying mechanisms driving these tissue-level influences remain unidentified, however. Here, we present an evolutionary perspective on the interplay between mosaicism and cancer, suggesting that the tissue-level impacts of genetic mosaicism can be attributed to Indirect Genetic Effects (IGEs). IGEs can increase the level of cellular stochasticity and phenotypic instability among adjacent cells, thereby elevating the risk of cancer development within the tissue. Moreover, as cells experience phenotypic changes in response to challenging microenvironmental conditions, these changes can initiate a cascade of nongenetic alterations, referred to as Indirect non-Genetic Effects (InGEs), which in turn catalyze IGEs among surrounding cells. We argue that incorporating both InGEs and IGEs into our understanding of the process of oncogenic transformation could trigger a major paradigm shift in cancer research with far-reaching implications for practical applications.

Genomic and metabolic instability during long-term fermentation of an industrial Saccharomyces cerevisiae strain engineered for C5 sugar utilization.

The genetic stability and metabolic robustness of production strains is one of the key criteria for the production of bio-based products by microbial fermentation on an industrial scale. These criteria were here explored in an industrial ethanol-producer strain of Saccharomyces cerevisiae able to co-ferment D-xylose and L-arabinose with glucose through the chromosomal integration of several copies of pivotal genes for the use of these pentose (C5) sugars. Using batch sequential cultures in a controlled bioreactor that mimics long-term fermentation in an industrial setting, this strain was found to exhibit significant fluctuations in D-xylose and L-arabinose consumption as early as the 50th generation and beyond. These fluctuations seem not related to the few low-consumption C5 sugar clones that appeared throughout the sequential batch cultures at a frequency lower than 1.5% and that were due to the reduction in the number of copies of transgenes coding for C5 sugar assimilation enzymes. Also, subpopulations enriched with low or high RAD52 expression, whose expression level was reported to be proportional to homologous recombination rate did not exhibit defect in C5-sugar assimilation, arguing that other mechanisms may be responsible for copy number variation of transgenes. Overall, this work highlighted the existence of genetic and metabolic instabilities in an industrial yeast which, although modest in our conditions, could be more deleterious in harsher industrial conditions, leading to reduced production performance.

The impact of food availability on tumorigenesis is evolutionarily conserved.

The inability to control cell proliferation results in the formation of tumors in many multicellular lineages. Nonetheless, little is known about the extent of conservation of the biological traits and ecological factors that promote or inhibit tumorigenesis across the metazoan tree. Particularly, changes in food availability have been linked to increased cancer incidence in humans, as an outcome of evolutionary mismatch. Here, we apply evolutionary oncology principles to test whether food availability, regardless of the multicellular lineage considered, has an impact on tumorigenesis. We used two phylogenetically unrelated model systems, the cnidarian Hydra oligactis and the fish Danio rerio, to investigate the impact of resource availability on tumor occurrence and progression. Individuals from healthy and tumor-prone lines were placed on four diets that differed in feeding frequency and quantity. For both models, frequent overfeeding favored tumor emergence, while lean diets appeared more protective. In terms of tumor progression, high food availability promoted it, whereas low resources controlled it, but without having a curative effect. We discuss our results in light of current ideas about the possible conservation of basic processes governing cancer in metazoans (including ancestral life history trade-offs at the cell level) and in the framework of evolutionary medicine.

Emerging relevance of cell wall components from non-conventional yeasts as functional ingredients for the food and feed industry.

Non-conventional yeast species, or non-Saccharomyces yeasts, are increasingly recognized for their involvement in fermented foods. Many of them exhibit probiotic characteristics that are mainly due to direct contacts with other cell types through various molecular components of their cell wall. The biochemical composition and/or the molecular structure of the cell wall components are currently considered the primary determinant of their probiotic properties. Here we first present the techniques that are used to extract and analyze the cell wall components of food industry-related non-Saccharomyces yeasts. We then review the current understanding of the cell wall composition and structure of each polysaccharide from these yeasts. Finally, the data exploring the potential beneficial role of their cell wall components, which could be a source of innovative functional ingredients, are discussed. Such research would allow the development of high value-added products and provide the food industry with novel inputs beyond the well-established S. cerevisiae.

The Ins and Outs of Endosteal Niche Disruption in the Bone Marrow: Relevance for Myeloma Oncogenesis.

Multiple Myeloma (MM) and its preexisting stage, termed Monoclonal Gammopathy of Undetermined Significance (MGUS), have long been considered mainly as genomic diseases. However, the bone changes observed in both conditions have led to a reassessment of the role of the bone microenvironment, mainly the endosteal niche in their genesis. Here, we consider the disruption of the endosteal niche in the bone marrow, that is, the shift of the endosteal niche from an osteoblastic to an osteoclastic profile produced by bone senescence and inflammaging, as the key element. Thus, this disrupted endosteal niche is proposed to represent the permissive microenvironment necessary not only for the emergence of MM from MGUS but also for the emergence and maintenance of MGUS. Moreover, the excess of osteoclasts would favor the presentation of antigens (Ag) into the endosteal niche because osteoclasts are Ag-presenting cells. As such, they could significantly stimulate the presentation of some specific Ag and the clonal expansion of the stimulated cells as well as favor the expansion of such selected clones because osteoclasts are immunosuppressive. We also discuss this scenario in the Gaucher disease, in which the high incidence of MGUS and MM makes it a good model both at the bone level and the immunological level. Finally, we envisage that this endosteal niche disruption would increase the stochasticity (epigenetic and genetic instability) in the selected clones, according to our Tissue Disruption-induced cell Stochasticity (TiDiS) theory.

The paradox of cooperation among selfish cancer cells.

It is traditionally assumed that during cancer development, tumor cells abort their initially cooperative behavior (i.e., cheat) in favor of evolutionary strategies designed solely to enhance their own fitness (i.e., a "selfish" life style) at the expense of that of the multicellular organism. However, the growth and progress of solid tumors can also involve cooperation among these presumed selfish cells (which, by definition, should be noncooperative) and with stromal cells. The ultimate and proximate reasons behind this paradox are not fully understood. Here, in the light of current theories on the evolution of cooperation, we discuss the possible evolutionary mechanisms that could explain the apparent cooperative behaviors among selfish malignant cells. In addition to the most classical explanations for cooperation in cancer and in general (by-product mutualism, kin selection, direct reciprocity, indirect reciprocity, network reciprocity, group selection), we propose the idea that "greenbeard" effects are relevant to explaining some cooperative behaviors in cancer. Also, we discuss the possibility that malignant cooperative cells express or co-opt cooperative traits normally expressed by healthy cells. We provide examples where considerations of these processes could help understand tumorigenesis and metastasis and argue that this framework provides novel insights into cancer biology and potential strategies for cancer prevention and treatment.

Tuning the expression of the bacterial relBE toxin-antitoxin system in Saccharomyces cerevisiae allows characterizing the subsequent growth inhibition.

The bacterial toxin-antitoxin systems are each composed of a toxin, which severely inhibits bacterial cells growth, and a specific neutralizing antitoxin. Some toxin-antitoxin systems are functional when expressed in the yeast Saccharomyces cerevisiae. For instance, the expression of the relE toxin gene leads to a strong growth defect in yeast, whereas the expression of the relB antitoxin gene restores growth. Nevertheless, there is no available data regarding the required expression levels of each component of the relBE system leading to these growth phenotypes, neither their effects on cell viability. Here we used a double inducible plasmid-based system to independently modulate the relative amounts of relB and relE, and performed growth and gene expression analyses. These results allow us to correlate growth phenotypes to the expression levels of the toxin and the antitoxin, and to determine the levels necessary to observe either a strong growth inhibition or a normal growth. We also showed that the relE expression produces cell cycle progression defect without affecting cell viability. These results provide a detailed characterization of the functioning of the relBE system in S. cerevisiae, and open applicative perspectives of yeast growth control by bacterial toxin-antitoxin systems.

From developmental to atavistic bet-hedging: How cancer cells pervert the exploitation of random single-cell phenotypic fluctuations.

Stochastic gene expression plays a leading developmental role through its contribution to cell differentiation. It is also proposed to promote phenotypic diversification in malignant cells. However, it remains unclear if these two forms of cellular bet-hedging are identical or rather display distinct features. Here we argue that bet-hedging phenomena in cancer cells are more similar to those occurring in unicellular organisms than to those of normal metazoan cells. We further propose that the atavistic bet-hedging strategies in cancer originate from a hijacking of the normal developmental bet-hedging of metazoans. Finally, we discuss the constraints that may shape the atavistic bet-hedging strategies of cancer cells.

A bone paradigm challenging the standard model of myeloma oncogenesis.

The standard model of multiple myeloma (MM) oncogenesis from monoclonal gammopathy of undetermined significance (MGUS) relies on genetic instability in the normal counterparts of MM cells. However, the importance of both MGUS-associated and MM-induced bone changes has been recently re-appraised, emphasizing the bone microenvironment (BME) as a tissue of significance. In this review, we propose that early BME alterations (bone senescence and inflammation, i.e., bone inflamm'aging) at the pre-MGUS stage could be causal, and not simply permissive, and creative of phenotypic instability and genetic alterations thanks to the concept of tissue disruption-induced cell stochasticity (TiDiS). This article offers a bone scenario challenging the chromosome-and-gene-centric standard model of MM oncogenesis. The high incidence of both MGUS and MM in Gaucher disease supports such a scenario.

The evolution and ecology of benign tumors.

Tumors are usually classified into two main categories - benign or malignant, with much more attention being devoted to the second category given that they are usually associated with more severe health issues (i.e., metastatic cancers). Here, we argue that the mechanistic distinction between benign and malignant tumors has narrowed our understanding of neoplastic processes. This review provides the first comprehensive discussion of benign tumors in the context of their evolution and ecology as well as interactions with their hosts. We compare the genetic and epigenetic profiles, cellular activities, and the involvement of viruses in benign and malignant tumors. We also address the impact of intra-tumoral cell composition and its relationship with the tumoral microenvironment. Lastly, we explore the differences in the distribution of benign and malignant neoplasia across the tree of life and provide examples on how benign tumors can also affect individual fitness and consequently the evolutionary trajectories of populations and species. Overall, our goal is to bring attention to the non-cancerous manifestations of tumors, at different scales, and to stimulate research on the evolutionary ecology of host-tumor interactions on a broader scale. Ultimately, we suggest that a better appreciation of the differences and similarities between benign and malignant tumors is fundamental to our understanding of malignancy both at mechanistic and evolutionary levels.

Bridging Tumorigenesis and Therapy Resistance With a Non-Darwinian and Non-Lamarckian Mechanism of Adaptive Evolution.

Although neo-Darwinian (and less often Lamarckian) dynamics are regularly invoked to interpret cancer's multifarious molecular profiles, they shine little light on how tumorigenesis unfolds and often fail to fully capture the frequency and breadth of resistance mechanisms. This uncertainty frames one of the most problematic gaps between science and practice in modern times. Here, we offer a theory of adaptive cancer evolution, which builds on a molecular mechanism that lies outside neo-Darwinian and Lamarckian schemes. This mechanism coherently integrates non-genetic and genetic changes, ecological and evolutionary time scales, and shifts the spotlight away from positive selection towards purifying selection, genetic drift, and the creative-disruptive power of environmental change. The surprisingly simple use-it or lose-it rationale of the proposed theory can help predict molecular dynamics during tumorigenesis. It also provides simple rules of thumb that should help improve therapeutic approaches in cancer.

Is There One Key Step in the Metastatic Cascade?

The majority of cancer-related deaths are the result of metastases (i.e., dissemination and establishment of tumor cells at distant sites from the origin), which develop through a multi-step process classically termed the metastatic cascade. The respective contributions of each step to the metastatic process are well described but are also currently not completely understood. Is there, for example, a critical phase that disproportionately affects the probability of the development of metastases in individual patients? Here, we address this question using a modified Drake equation, initially formulated by the astrophysicist Frank Drake to estimate the probability of the emergence of intelligent civilizations in the Milky Way. Using simulations based on realistic parameter values obtained from the literature for breast cancer, we examine, under the linear progression hypothesis, the contribution of each component of the metastatic cascade. Simulations demonstrate that the most critical parameter governing the formation of clinical metastases is the survival duration of circulating tumor cells (CTCs).

Does Cancer Biology Rely on Parrondo's Principles?

Many aspects of cancer biology remain puzzling, including the proliferative and survival success of malignant cells in spite of their high genetic and epigenetic instability as well as their ability to express migrating phenotypes and/or enter dormancy despite possible fitness loss. Understanding the potential adaptive value of these phenotypic traits is confounded by the fact that, when considered separately, they seem to be rather detrimental at the cell level, at least in the short term. Here, we argue that cancer's biology and success could frequently be governed by processes underlying Parrondo's paradox, whereby combinations of intrinsically losing strategies may result in winning outcomes. Oncogenic selection would favor Parrondo's dynamics because, given the environmental adversity in which malignant cells emerge and evolve, alternating between various less optimal strategies would represent the sole viable option to counteract the changing and deleterious environments cells are exposed to during tumorigenesis. We suggest that malignant processes could be viewed through this lens, and we discuss how Parrondo's principles are also important when designing therapies against cancer.

Interplay between genetic, epigenetic, and gene expression variability: Considering complexity in evolvability.

Genetic variability, epigenetic variability, and gene expression variability (noise) are generally considered independently in their relationship with phenotypic variation. However, they appear to be intrinsically interconnected and influence it in combination. The study of the interplay between genetic and epigenetic variability has the longest history. This article rather considers the introduction of gene expression variability in its relationships with the two others and reviews for the first time experimental evidences over the four relationships connected to gene expression noise. They show how introducing this third source of variability complicates the way of thinking evolvability and the emergence of biological novelty. Finally, cancer cells are proposed to be an ideal model to decipher the dynamic interplay between genetic, epigenetic, and gene expression variability when one of them is either experimentally increased or therapeutically targeted. This interplay is also discussed in an evolutionary perspective in the context of cancer cell drug resistance.

Identifying key questions in the ecology and evolution of cancer.

The application of evolutionary and ecological principles to cancer prevention and treatment, as well as recognizing cancer as a selection force in nature, has gained impetus over the last 50 years. Following the initial theoretical approaches that combined knowledge from interdisciplinary fields, it became clear that using the eco-evolutionary framework is of key importance to understand cancer. We are now at a pivotal point where accumulating evidence starts to steer the future directions of the discipline and allows us to underpin the key challenges that remain to be addressed. Here, we aim to assess current advancements in the field and to suggest future directions for research. First, we summarize cancer research areas that, so far, have assimilated ecological and evolutionary principles into their approaches and illustrate their key importance. Then, we assembled 33 experts and identified 84 key questions, organized around nine major themes, to pave the foundations for research to come. We highlight the urgent need for broadening the portfolio of research directions to stimulate novel approaches at the interface of oncology and ecological and evolutionary sciences. We conclude that progressive and efficient cross-disciplinary collaborations that draw on the expertise of the fields of ecology, evolution and cancer are essential in order to efficiently address current and future questions about cancer.

Group phenotypic composition in cancer.

Although individual cancer cells are generally considered the Darwinian units of selection in malignant populations, they frequently act as members of groups where fitness of the group cannot be reduced to the average fitness of individual group members. A growing body of studies reveals limitations of reductionist approaches to explaining biological and clinical observations. For example, induction of angiogenesis, inhibition of the immune system, and niche engineering through environmental acidification and/or remodeling of extracellular matrix cannot be achieved by single tumor cells and require collective actions of groups of cells. Success or failure of such group activities depends on the phenotypic makeup of the individual group members. Conversely, these group activities affect the fitness of individual members of the group, ultimately affecting the composition of the group. This phenomenon, where phenotypic makeup of individual group members impacts the fitness of both members and groups, has been captured in the term 'group phenotypic composition' (GPC). We provide examples where considerations of GPC could help in understanding the evolution and clinical progression of cancers and argue that use of the GPC framework can facilitate new insights into cancer biology and assist with the development of new therapeutic strategies.

Insights on the Control of Yeast Single-Cell Growth Variability by Members of the Trehalose Phosphate Synthase (TPS) Complex.

Single-cell variability of growth is a biological phenomenon that has attracted growing interest in recent years. Important progress has been made in the knowledge of the origin of cell-to-cell heterogeneity of growth, especially in microbial cells. To better understand the origins of such heterogeneity at the single-cell level, we developed a new methodological pipeline that coupled cytometry-based cell sorting with automatized microscopy and image analysis to score the growth rate of thousands of single cells. This allowed investigating the influence of the initial amount of proteins of interest on the subsequent growth of the microcolony. As a preliminary step to validate this experimental setup, we referred to previous findings in yeast where the expression level of Tsl1, a member of the Trehalose Phosphate Synthase (TPS) complex, negatively correlated with cell division rate. We unfortunately could not find any influence of the initial TSL1 expression level on the growth rate of the microcolonies. We also analyzed the effect of the natural variations of trehalose-6-phosphate synthase (TPS1) expression on cell-to-cell growth heterogeneity, but we did not find any correlation. However, due to the already known altered growth of the tps1Δ mutants, we tested this strain at the single-cell level on a permissive carbon source. This mutant showed an outstanding lack of reproducibility of growth rate distributions as compared to the wild-type strain, with variable proportions of non-growing cells between cultivations and more heterogeneous microcolonies in terms of individual growth rates. Interestingly, this variable behavior at the single-cell level was reminiscent to the high variability that is also stochastically suffered at the population level when cultivating this tps1Δ strain, even when using controlled bioreactors.