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Integration of mathematical modeling, ecological analyses of patient biopsies, and neoantigen heterogeneity suggests recruitment of immunosuppressive cells is key to initializing transformation from adenoma to carcinoma in human colorectal cancer.

Claudin-low tumors are a rare aggressive subtype of breast cancers. In this study, the authors use a multiomics approach to demonstrate that these tumors are heterogeneous and comprise three main subgroups that emerge from different evolutionary processes.

Abstract Cancer is a potentially lethal disease, in which patients with nearly identical genetic backgrounds can develop a similar pathology through distinct combinations of genetic alterations. We aimed to reconstruct the evolutionary process underlying tumour initiation, using the combination of convergence and discrepancies observed across 2,742 cancer genomes from nine tumour types. We developed a framework using the repeatability of cancer development to score the local malignant adaptation (LMA) of genetic clones, as their potential to malignantly progress and invade their environment of origin. Using this framework, we found that premalignant skin and colorectal lesions appeared specifically adapted to their local environment, yet insufficiently for full cancerous transformation. We found that metastatic clones were more adapted to the site of origin than to the invaded tissue, suggesting that genetics may be more important for local progression than for the invasion of distant organs. In addition, we used network analyses to investigate evolutionary properties at the system‐level, highlighting that different dynamics of malignant progression can be modelled by such a framework in tumour‐type‐specific fashion. We find that occurrence‐based methods can be used to specifically recapitulate the process of cancer initiation and progression, as well as to evaluate the adaptation of genetic clones to given environments. The repeatability observed in the evolution of most tumour types could therefore be harnessed to better predict the trajectories likely to be taken by tumours and preneoplastic lesions in the future.

Summary: Despite advances in single-cell and molecular techniques, it is still unclear how to best quantify phenotypic heterogeneity in cancer cells that evolved beyond normal, known classifications. We present an approach to phenotypically characterize cells based on their activities rather than static classifications. We validated the detectability of specific activities (epithelial-mesenchymal transition, glycolysis) in single cells, using targeted RT-qPCR analyses and in vitro inductions. We analyzed 50 established activity signatures as a basis for phenotypic description in public data and computed cell-cell distances in 28,513 cells from 85 patients and 8 public datasets. Despite not relying on any classification, our measure correlated with standard diversity indices in populations of known structure. We identified bottlenecks as phenotypic diversity reduced upon colorectal cancer initiation. This suggests that focusing on what cancer cells do rather than what they are can quantify phenotypic diversity in universal fashion, to better understand and predict intra-tumor heterogeneity dynamics.

Clonal dynamics of Barrett’s esophagus (BE) leading to cancer are poorly understood. Here, they report BE segments are clonal, have frequent mutations at the gastro-esophageal junction, genomic instability precedes genome doubling/clonal expansion, and a correlation between inter- and intra-biopsy genetic diversity.

Abstract As it is altered by ionizing radiation, the vascular network is considered as a prime target in limiting normal tissue damage and improving tumor control in radiation therapy. Irradiation activates endothelial cells which then participate in the recruitment of circulating cells, especially by overexpressing cell adhesion molecules, but also by other as yet unknown mechanisms. Since protein glycosylation is an important determinant of cell adhesion, we hypothesized that radiation could alter the glycosylation pattern of endothelial cells and thereby impact adhesion of circulating cells. Herein, we show that ionizing radiation increases high mannose-type N-glycans and decreases glycosaminoglycans. These changes stimulate interactions measured under flow conditions between irradiated endothelial cells and monocytes. Targeted transcriptomic approaches in vitro in endothelial cells and in vivo in a radiation enteropathy mouse model confirm that genes involved in N- and O-glycosylation are modulated by radiation, and in silico analyses give insight into the mechanism by which radiation modifies glycosylation. The endothelium glycome may therefore be considered as a key therapeutic target for modulating the chronic inflammatory response observed in healthy tissues or for participating in tumor control by radiation therapy.

Abstract Intra-tumour genetic heterogeneity (ITH) fosters drug resistance and is a critical hurdle to clinical treatment. ITH can be well-measured using multi-region sampling but this is costly and challenging to implement. There is therefore a need for tools to estimate ITH in individual samples, using standard genomic data such as SNP-arrays, that could be implemented routinely. We designed two novel scores S and R, respectively based on the Shannon diversity index and Ripley’s L statistic of spatial homogeneity, to quantify ITH in single SNP-array samples. We created in-silico and in-vitro mixtures of tumour clones, in which diversity was known for benchmarking purposes. We found significant but highly-variable associations of our scores with diversity in-silico (p

The repeatability observed across cancers arising in the same tissue can help understand the evolutionary process of tumour initiation. We recently developed a framework to quantify the local malignant adaptation of genetic clones in tissue-specific environments. In this Commentary, we argue that such a 1-dimensional model can be improved by separating its 2 components to obtain a dual scale: local adaptation, dictating proliferation rates in the local environment, and malignant adaptation, influencing the likelihood that a clone becomes cancerous and invasive. Such a change could strengthen our understanding of the population dynamics underlying cancer initiation and assess different evolutionary scenarios.

Barrett’s oesophagus is thought to be a precursor lesion for oesophageal cancer, and predicting the benign lesions that progress to cancer is clinically important. Here, the authors use FISH to study the clonal evolution of Barrett’s oesophagus and show that genetic diversity and somatic mutations are present early in the benign disease.

The p53 family of genes and their protein products, namely, p53, p63 and p73, have over one billion years of evolutionary history. Advances in computational biology and genomics are enabling studies of the complexities of the molecular evolution of p53 protein family to decipher the underpinnings of key biological conditions spanning from cancer through to various metabolic and developmental disorders and facilitate the design of personalised medicines. However, a complete understanding of the inherent nature of the thermodynamic and structural stability of the p53 protein family is still lacking. This is due, to a degree, to the lack of comprehensive structural information for a large number of homologous proteins and to an incomplete knowledge of the intrinsic factors responsible for their stability and how these might influence function. Here we investigate the thermal stability, secondary structure and folding properties of the DNA-binding domains (DBDs) of a range of proteins from the p53 family using biophysical methods. While the N- and the C-terminal domains of the p53 family show sequence diversity and are normally targets for post-translational modifications and alternative splicing, the central DBD is highly conserved. Together with data obtained from Molecular Dynamics simulations in solution and with structure based homology modelling, our results provide further insights into the molecular properties of evolutionary related p53 proteins. We identify some marked structural differences within the p53 family, which could account for the divergence in biological functions as well as the subtleties manifested in the oligomerization properties of this family.

The University laboratories are places where teaching, extension and research activities are develop, which harmful substances are manipulated and hazardous waste are generated, the lack of information about this makes them an inadequate provision causing human health and environmental risks. This research proposes the implementation of environmental education as an alternative for waste management and safety in the University of Magdalena laboratories. Applying a series of polls showed the effectiveness with efficiency or assertively rises at 30% cognitive level during the process. It recommends to obtain better results is necessary evaluate the ethic component.