Multiple Myeloma Exemplifies a Model of Cancer Based on Tissue Disruption as the Initiator Event

The standard model of multiple myeloma (MM) oncogenesis is based on the genetic instability of MM cells and presents its evolution as the emergence of clones with more and more aggressive genotypes, giving them surviving and proliferating advantage. The micro-environment has a passive role. In contrast, many works have shown that the progression of MM is also characterized by the selection of clones with extended phenotypes able to destroy bone trabeculae, suggesting a major role for early micro-environmental disruption. We present a model of MM oncogenesis in which genetic instability is the consequence of the disruption of normal interactions between plasma cells and their environment, the bone remodeling compartment. These interactions, which normally ensure the stability of the genotypes and phenotypes of normal plasma cells could be disrupted by many factors as soon as the early steps of the disease (MGUS, pre-MGUS states). Therapeutical implications of the model are presented

Gene Expression Noise Produces Cell-to-Cell Heterogeneity in Eukaryotic Homologous Recombination Rate

Variation in gene expression among genetically identical individual cells (called gene expression noise) directly contributes to phenotypic diversity. Whether such variation can impact genome stability and lead to variation in genotype remains poorly explored. We addressed this question by investigating whether noise in the expression of genes affecting homologous recombination (HR) activity either directly (RAD52) or indirectly (RAD27) confers cell-to-cell heterogeneity in HR rate in Saccharomyces cerevisiae. Using cell sorting to isolate subpopulations with various expression levels, we show that spontaneous HR rate is highly heterogeneous from cell-to-cell in clonal populations depending on the cellular amount of proteins affecting HR activity. Phleomycin-induced HR is even more heterogeneous, showing that RAD27 expression variation strongly affects the rate of recombination from cell-to-cell. Strong variations in HR rate between subpopulations are not correlated to strong changes in cell cycle stage. Moreover, this heterogeneity occurs even when simultaneously sorting cells at equal expression level of another gene involved in DNA damage response (BMH1) that is upregulated by DNA damage, showing that the initiating DNA damage is not responsible for the observed heterogeneity in HR rate. Thus gene expression noise seems mainly responsible for this phenomenon. Finally, HR rate non-linearly scales with Rad27 levels showing that total amount of HR cannot be explained solely by the time- or population-averaged Rad27 expression. Altogether, our data reveal interplay between heterogeneity at the gene expression and genetic levels in the production of phenotypic diversity with evolutionary consequences from microbial to cancer cell populations

The DNA polymerase λ is required for the repair of non-compatible DNA double strand breaks by NHEJ in mammalian cells

DNA polymerase lambda (polλ) is a recently identified DNA polymerase whose cellular function remains elusive. Here we show, that polλ participates at the molecular level in a chromosomal context, in the repair of DNA double strand breaks (DSB) via non-homologous end joining (NHEJ) in mammalian cells. The expression of a catalytically inactive form of polλ (polλDN) decreases the frequency of NHEJ events in response to I-Sce-I-induced DSB whereas inactivated forms of its homologues polβ and polμ do not. Only events requiring DNA end processing before ligation are affected; this defect is associated with large deletions arising in the vicinity of the induced DSB. Furthermore, polλDN-expressing cells exhibit increased sensitization and genomic instability in response to ionizing radiation similar to that of NHEJ-defective cells. Our data support a requirement for polλ in repairing a subset of DSB in genomic DNA, thereby contributing to the maintenance of genetic stability mediated by the NHEJ pathway

Differences in mutational processes and intratumour heterogeneity between organs: the local selective filter hypothesis.

International audienceExtensive diversity (genetic, cytogenetic, epigenetic and phenotypic) exists within and between tumors, but reasons behind these variations, as well as their consistent hierarchical pattern between organs, are poorly understood at the moment. We argue that these phenomena are, at least partially, explanable by the evolutionary ecology of organs’ theory, in the same way that environmental adversity shapes mutation rates and level of polymophism in organisms. Organs in organisms can be considered as specialized ecosystems that are, for ecological and evolutionary reasons, more or less efficient at supressing tumours. When a malignancy does arise in an organ applying strong selection pressure on tumours, its constituent cells are expected to display a large range of possible surviving strategies, from hyper mutator phenotypes relying on bet-hedging to persist (high mutation rates and high diversity), to few poorly variable variants that become invisible to natural defences. In contrast, when tumour suppression is weaker, selective pressure favouring extreme surviving strategies is relaxed, and tumours are moderately variable as a result. We provide a comprehensive overview of this hypothesis

Involvement of DNA polymerase μ in the repair of a specific subset of DNA double-strand breaks in mammalian cells

The repair of DNA double-strand breaks (DSB) requires processing of the broken ends to complete the ligation process. Recently, it has been shown that DNA polymerase μ (polμ) and DNA polymerase λ (polλ) are both involved in such processing during non-homologous end joining in vitro. However, no phenotype was observed in animal models defective for either polμ and/or polλ. Such observations could result from a functional redundancy shared by the X family of DNA polymerases. To avoid such redundancy and to clarify the role of polμ in the end joining process, we generated cells over-expressing the wild type as well as an inactive form of polμ (polμD). We observed that cell sensitivity to ionizing radiation (IR) was increased when either polμ or polμD was over-expressed. However, the genetic instability in response to IR increased only in cells expressing polμD. Moreover, analysis of intrachromosomal repair of the I-SceI-induced DNA DSB, did not reveal any effect of either polμ or polμD expression on the efficiency of ligation of both cohesive and partially complementary ends. Finally, the sequences of the repaired ends were specifically affected when polμ or polμD was over-expressed, supporting the hypothesis that polμ could be involved in the repair of a DSB subset when resolution of junctions requires some gap filling

Le rôle des phénomènes aléatoires dans le cancer

In the reductionist perspective, genetic modifications are considered to initiate cancer. Their appearance is a stochastic phenomenon, but there are some biases linked to DNA sequence or exposure to mutagenic agents for instance. Cancer genome sequencing has shown a high interand intra-tumoral heterogeneity, sometimes questioning the genetic origin of cancer. Other stochastic processes are also studied in cancer, especially epigenetic modifications. They have a major role in diversifying phenotypes among cancer cells in the progression steps, but might also provide an alternative to genetic theories of cancer initiation. Nevertheless, the reductionist framework remains dominant here. Finally, stochastic cell-to-cell variations in gene expression constitute a third class of stochastic phenomena that can be considered as causal factors in cancer. Highlighting the role of high gene expression variability due to disruption of cellular interactions and communications allows avoiding reductionism by considering the interplay between genetic and tissue levels at every step of the disease. No organization level is privileged in this alternative theory.Dans la perspective réductionniste, les modifications génétiques sont conçues comme les éléments initiateurs des cancers. Elles apparaissent de manière aléatoire et les séquençages de génomes cancéreux ont montré une forte hétérogénéité génétique inter- et intratumorale. D’autres phénomènes aléatoires retiennent aussi l’attention,en particulier les modifications épigénétiques de la chromatine. Elles fournissent pour certains une alternative à une théorie seulement génétique du cancer. Enfin les variations aléatoires de l’expression des gènes constituent une troisième classe d’événements aléatoires qui pourraient avoir un rôle causal. L’accent mis sur ce dernier type d’événements permet de sortir du schéma réductionniste en considérant les interactions entre les niveaux génétique et tissulaire

Tissue disruption increases stochastic gene expression thus producing tumors: Cancer initiation without driver mutation

Cancer research produced many paradoxical results in recent years. The reductionist approach now shows its limits. Considering the origin of the disease at the tissue level and increased stochastic gene expression (SGE) as a driving force, while admitting a role for genetic alterations in cancer progression, might solve these contradictions. Undifferentiated cells are characterized by open and accessible chromatin generating global and highly SGE (high expression noise) which is a hallmark of pluripotency, while differentiation is associated with progressive chromatin closing and decreased noise. Cell-cell interactions stabilize phenotypes and homogenize expression patterns from cell-to-cell during development and differentiation, while disruption of these interactions is responsible for increased expression noise that might be the causal event in cancer by producing phenotypic plasticity. It would produce cancer stem cells defined as cells exhibiting increased SGE that are no more controlled by the microenvironment. Following tissue disruption, differentiation and/or quiescence would no longer be maintained because of SGE. Genetic and epigenetic instabilities would necessary appear, increasing the risk of malignant transformation. The classical perspective is reversed: disruption of the tissue equilibrium is the initiator event, and genetic alterations are tumor promoters. The major role of genetic modifications in cancer progression is not denied, but microenvironmental and epigenetic alterations would precede the emergence of cancer. If mutagenic exposure, cancer predisposition or spontaneous mutations have already produced genetic alterations, precancerous cells would become more aggressive more rapidly, increasing the probability that a tumor forms, but only if the correct microenvironment is not maintained

Stochastic gene expression stabilization as a new therapeutic strategy for cancer

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Stochastic gene expression is the driving force of cancer

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Cancer Stem Cells: From Historical Roots to a New Perspective

The relationships between cancer and stemness have a long history that is traced here. From the mid-19th century when the first theory on the embryonic origin of cancer was formulated to works on embryonal carcinoma cells in the mid-20th century, many steps have been crossed leading to the current cancer stem cell theory postulating that tumor growth is supported by a small fraction of the tumoral cells that have stem-like properties. However, in the last fifteen years, many works regularly encourage us to revise the concept of cancer stem cell. This article mentions key results that lead to a new perspective where cancer stem cells are primarily seen as cells exhibiting increased epigenetic plasticity and increased gene expression variability. This perspective suggests new therapeutical interventions consisting in stabilizing gene expression to control cancer cell proliferation and prevent stochastic gene expression variations that could lead to therapeutic resistance