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Epistasis among driver mutations is pervasive and explains relevant features of cancer, such as differential therapy response and convergence towards well-characterized molecular subtypes. Furthermore, a growing body of evidence suggests that tumor development could be hampered by the accumulation of slightly deleterious passenger mutations. In this work, we combined empirical epistasis networks, computer simulations, and mathematical models to explore how synergistic interactions among driver mutations affect cancer progression under the burden of slightly deleterious passengers. We found that epistasis plays a crucial role in tumor development by promoting the transformation of precancerous clones into rapidly growing tumors through a process that is analogous to evolutionary rescue. The triggering of epistasis-driven rescue is strongly dependent on the intensity of epistasis and could be a key rate-limiting step in many tumors, contributing to their unpredictability. As a result, central genes in cancer epistasis networks appear as key intervention targets for cancer therapy.

Colorectal cancer is the third most common form of cancer in developed countries and, despite the improvements achieved in its treatment options, remains as one of the main causes of cancer-related death. In this review, we first focus on colorectal carcinogenesis and on the genetic and epigenetic alterations involved. In addition, noncoding RNAs have been shown to be important regulators of gene expression. We present a general overview of what is known about these molecules and their role and dysregulation in cancer, with a special focus on the biogenesis, characteristics, and function of microRNAs. These molecules are important regulators of carcinogenesis, progression, invasion, angiogenesis, and metastases in cancer, including colorectal cancer. For this reason, miRNAs can be used as potential biomarkers for diagnosis, prognosis, and efficacy of chemotherapeutic treatments, or even as therapeutic agents, or as targets by themselves. Thus, this review highlights the importance of miRNAs in the development, progression, diagnosis, and therapy of colorectal cancer and summarizes current therapeutic approaches for the treatment of colorectal cancer., MICINN, Santander-UCM grant, Depto. de Bioquímica y Biología Molecular, Fac. de Ciencias Químicas, TRUE, pub

The study of genes that evolve under conditional selection can shed light on the genomic underpinnings of adaptation, revealing epistasis and phenotypic plasticity. This protocol describes how to use the Coselens package to compare gene-level selection between two groups of samples. After installing Coselens and preparing the datasets, a typical run on a laptop takes less than 10 min. Coselens is best suited to analyze somatic mutations and data from experimental evolution, for which independently evolved samples are available. For complete details on the use and execution of this protocol, please refer to Iranzo et al. (2022).1.

Cancer driver mutations often display mutual exclusion or co-occurrence, underscoring the key role of epistasis in carcinogenesis. However, estimating the magnitude of epistasis and quantifying its effect on tumor evolution remains a challenge. We develop a method (Coselens) to quantify conditional selection on the excess of nonsynonymous substitutions in cancer genes. Coselens infers the number of drivers per gene in different partitions of a cancer genomics dataset using covariance-based mutation models and determines whether coding mutations in a gene affect selection for drivers in any other gene. Using Coselens, we identify 296 conditionally selected gene pairs across 16 cancer types in the TCGA dataset. Conditional selection affects 25%-50% of driver substitutions in tumors with >2 drivers. Conditionally co-selected genes form modular networks, whose structures challenge the traditional interpretation of within-pathway mutual exclusivity and across-pathway synergy, suggesting a more complex scenario where gene-specific across-pathway epistasis shapes differentiated cancer subtypes.

Los insectos parecen ser particularmente proclives a la convivencia con muy diversas bacterias con quienes establecen relaciones de muy variada índole. En particular, los endosimbiontes primarios se alojan en exclusiva en el interior de células especializadas del insecto denominadas bacteriocitos, se transmiten verticalmente a la descendencia, y establecen una relación de mutua dependencia con el hospedador. Las particularidades de los endosimbiontes primarios han probado ser valiosos modelos en el estudio de las características y consecuencias evolutivas de la transición de un modo de vida libre a uno de dependencia total de un hospedador. El genoma bacteriano sufre diversos cambios tras la transición a un estilo de vida intracelular que desencadenan una masiva inhabilitación y pérdida de genes que desembocan en la constitución de un genoma prácticamente mínimo. A la luz de los datos actuales, adaptación, degeneración y evolución neutral son mecanismos posibles que pueden condicionar esta característica reducción genómica. Entonces, ¿qué fuerzas evolutivas están detrás de las características genómicas observadas en los endosimbiontes de insectos?..., Insects seem to be particularly prone to coexistence with very diverse bacteria with whom they establish very varied relationships. In particular, primary endosymbionts are housed exclusively within specialized insect cells called bacteriocytes, are transmitted vertically to offspring, and establish a mutually dependent relationship with the host. The characteristics of the primary endosymbionts have proven to be valuable models in the study of the evolutionary characteristics and consequences of the transition from a free lifestyle to one that is totally dependent on a host. The bacterial genome undergoes various changes after the transition to an intracellular lifestyle that triggers a massive disabling and loss of genes that lead to the constitution of a practically minimal genome. In the light of current data, adaptation, degeneration and neutral evolution are possible mechanisms that may condition this characteristic genomic reduction. So what evolutionary forces are behind the genomic characteristics observed in insect endosymbionts? ...

Colorectal cancer is the third most common form of cancer in developed countries and, despite the improvements achieved in its treatment options, remains as one of the main causes of cancer-related death. In this review, we first focus on colorectal carcinogenesis and on the genetic and epigenetic alterations involved. In addition, noncoding RNAs have been shown to be important regulators of gene expression. We present a general overview of what is known about these molecules and their role and dysregulation in cancer, with a special focus on the biogenesis, characteristics, and function of microRNAs. These molecules are important regulators of carcinogenesis, progression, invasion, angiogenesis, and metastases in cancer, including colorectal cancer. For this reason, miRNAs can be used as potential biomarkers for diagnosis, prognosis, and efficacy of chemotherapeutic treatments, or even as therapeutic agents, or as targets by themselves. Thus, this review highlights the importance of miRNAs in the development, progression, diagnosis, and therapy of colorectal cancer and summarizes current therapeutic approaches for the treatment of colorectal cancer., Ministerio de Ciencia, Innovación y Universidades (España), Universidad Complutense de Madrid, Banco de Santander, Sección Deptal. de Bioquímica y Biología Molecular, Fac. de Ciencias Biológicas, TRUE, pub

Bacterial endosymbionts and their insect hosts establish an intimate metabolic relationship. Bacteria offer a variety of essential nutrients to their hosts, whereas insect cells provide the necessary sources of matter and energy to their tiny metabolic allies. These nutritional complementations sustain themselves on a diversity of metabolite exchanges between the cell host and the reduced yet highly specialized bacterial metabolism-which, for instance, overproduces a small set of essential amino acids and vitamins. A well-known case of metabolic complementation is provided by the cedar aphid Cinara cedri that harbors two co-primary endosymbionts, Buchnera aphidicola BCc and Ca. Serratia symbiotica SCc, and in which some metabolic pathways are partitioned between different partners. Here we present a genome-scale metabolic network (GEM) for the bacterial consortium from the cedar aphid iBSCc. The analysis of this GEM allows us the confirmation of cases of metabolic complementation previously described by genome analysis (i.e., tryptophan and biotin biosynthesis) and the redefinition of an event of metabolic pathway sharing between the two endosymbionts, namely the biosynthesis of tetrahydrofolate. In silico knock-out experiments with iBSCc showed that the consortium metabolism is a highly integrated yet fragile network. We also have explored the evolutionary pathways leading to the emergence of metabolic complementation between reduced metabolisms starting from individual, complete networks. Our results suggest that, during the establishment of metabolic complementation in endosymbionts, adaptive evolution is significant in the case of tryptophan biosynthesis, whereas vitamin production pathways seem to adopt suboptimal solutions.

Bacterial endosymbionts and their insect hosts establish an intimate metabolic relationship. Bacteria offer a variety of essential nutrients to their hosts, whereas insect cells provide the necessary sources of matter and energy to their tiny metabolic allies. These nutritional complementations sustain themselves on a diversity of metabolite exchanges between the cell host and the reduced yet highly specialized bacterial metabolism-which, for instance, overproduces a small set of essential amino acids and vitamins. A well-known case of metabolic complementation is provided by the cedar aphid Cinara cedri that harbors two co-primary endosymbionts, Buchnera aphidicola BCc and Ca. Serratia symbiotica SCc, and in which some metabolic pathways are partitioned between different partners. Here we present a genome-scale metabolic network (GEM) for the bacterial consortium from the cedar aphid iBSCc. The analysis of this GEM allows us the confirmation of cases of metabolic complementation previously described by genome analysis (i.e., tryptophan and biotin biosynthesis) and the redefinition of an event of metabolic pathway sharing between the two endosymbionts, namely the biosynthesis of tetrahydrofolate. In silico knock-out experiments with iBSCc showed that the consortium metabolism is a highly integrated yet fragile network. We also have explored the evolutionary pathways leading to the emergence of metabolic complementation between reduced metabolisms starting from individual, complete networks. Our results suggest that, during the establishment of metabolic complementation in endosymbionts, adaptive evolution is significant in the case of tryptophan biosynthesis, whereas vitamin production pathways seem to adopt suboptimal solutions.