Molecular mechanisms in colitis-associated colorectal cancer.

Sustained chronic inflammation of the large intestine leads to tissue damage and repair, which is associated with an increased incidence of colitis-associated colorectal cancer (CAC). The genetic makeup of CAC is somewhat similar to sporadic colorectal carcinoma (sCRC), but there are differences in the sequence and timing of alterations in the carcinogenesis process. Several models have been developed to explain the development of CAC, particularly the "field cancerization" model, which proposes that chronic inflammation accelerates mutagenesis and selects for the clonal expansion of phenotypically normal, pro-tumorigenic cells. In contrast, the "Big Bang" model posits that tumorigenic clones with multiple driver gene mutations emerge spontaneously. The details of CAC tumorigenesis-and how they differ from sCRC-are not yet fully understood. In this Review, we discuss recent genetic, epigenetic, and environmental findings related to CAC pathogenesis in the past five years, with a focus on unbiased, high-resolution genetic profiling of non-dysplastic field cancerization in the context of inflammatory bowel disease (IBD).

Etiology of super-enhancer reprogramming and activation in cancer.

Super-enhancers are large, densely concentrated swaths of enhancers that regulate genes critical for cell identity. Tumorigenesis is accompanied by changes in the super-enhancer landscape. These aberrant super-enhancers commonly form to activate proto-oncogenes, or other genes upon which cancer cells depend, that initiate tumorigenesis, promote tumor proliferation, and increase the fitness of cancer cells to survive in the tumor microenvironment. These include well-recognized master regulators of proliferation in the setting of cancer, such as the transcription factor MYC which is under the control of numerous super-enhancers gained in cancer compared to normal tissues. This Review will cover the expanding cell-intrinsic and cell-extrinsic etiology of these super-enhancer changes in cancer, including somatic mutations, copy number variation, fusion events, extrachromosomal DNA, and 3D chromatin architecture, as well as those activated by inflammation, extra-cellular signaling, and the tumor microenvironment.

A local tumor microenvironment acquired super-enhancer induces an oncogenic driver in colorectal carcinoma.

Tumors exhibit enhancer reprogramming compared to normal tissue. The etiology is largely attributed to cell-intrinsic genomic alterations. Here, using freshly resected primary CRC tumors and patient-matched adjacent normal colon, we find divergent epigenetic landscapes between CRC tumors and cell lines. Intriguingly, this phenomenon extends to highly recurrent aberrant super-enhancers gained in CRC over normal. We find one such super-enhancer activated in epithelial cancer cells due to surrounding inflammation in the tumor microenvironment. We restore this super-enhancer and its expressed gene, PDZK1IP1, following treatment with cytokines or xenotransplantation into nude mice, thus demonstrating cell-extrinsic etiology. We demonstrate mechanistically that PDZK1IP1 enhances the reductive capacity CRC cancer cells via the pentose phosphate pathway. We show this activation enables efficient growth under oxidative conditions, challenging the previous notion that PDZK1IP1 acts as a tumor suppressor in CRC. Collectively, these observations highlight the significance of epigenomic profiling on primary specimens.

Leflunomide triggers synthetic lethality in PTEN-deficient prostate cancer.

BACKGROUND: The loss of PTEN function presents in up to 50% of late-stage prostate cancers, and is therefore a potential target for therapeutics. PTEN-deficient cells depend on de novo pyrimidine synthesis, a feature that can present a vulnerability. METHODS: We utilized in vitro growth assays and in vivo xenograft models to test the effect of de novo pyrimidine synthesis inhibition on prostate cell lines. RESULTS: Here, we demonstrate that PTEN-deficient prostate cancer cell lines are susceptible to inhibition of de novo pyrimidine synthesis by leflunomide. Tumor growth inhibition was observed in vitro and in vivo following leflunomide treatment, and is likely due to an overwhelming accumulation of DNA damage. CONCLUSIONS: Our work highlights that synthetic lethality arises upon the combination of PTEN loss and leflunomide treatment in prostate cancer, and may present a therapeutic opportunity for this patient population.

Graphene-Induced Pore Formation on Cell Membranes.

Examining interactions between nanomaterials and cell membranes can expose underlying mechanisms of nanomaterial cytotoxicity and guide the design of safer nanomedical technologies. Recently, graphene has been shown to exhibit potential toxicity to cells; however, the molecular processes driving its lethal properties have yet to be fully characterized. We here demonstrate that graphene nanosheets (both pristine and oxidized) can produce holes (pores) in the membranes of A549 and Raw264.7 cells, substantially reducing cell viability. Electron micrographs offer clear evidence of pores created on cell membranes. Our molecular dynamics simulations reveal that multiple graphene nanosheets can cooperate to extract large numbers of phospholipids from the membrane bilayer. Strong dispersion interactions between graphene and lipid-tail carbons result in greatly depleted lipid density within confined regions of the membrane, ultimately leading to the formation of water-permeable pores. This cooperative lipid extraction mechanism for membrane perforation represents another distinct process that contributes to the molecular basis of graphene cytotoxicity.

Variation in Arabidopsis flowering time associated with cis-regulatory variation in CONSTANS.

The onset of flowering, the change from vegetative to reproductive development, is a major life history transition in flowering plants. Recent work suggests that mutations in cis-regulatory mutations should play critical roles in the evolution of this (as well as other) important adaptive traits, but thus far there has been little evidence that directly links regulatory mutations to evolutionary change at the species level. While several genes have previously been shown to affect natural variation in flowering time in Arabidopsis thaliana, most either show protein-coding changes and/or are found at low frequency (<5%). Here we identify and characterize natural variation in the cis-regulatory sequence in the transcription factor CONSTANS that underlies flowering time diversity in Arabidopsis. Mutation in this regulatory motif evolved recently and has spread to high frequency in Arabidopsis natural accessions, suggesting a role for these cis-regulatory changes in adaptive variation of flowering time.

Integration of responses within and across Arabidopsis natural accessions uncovers loci controlling root systems architecture.

Phenotypic plasticity is presumed to be involved in adaptive change toward species diversification. We thus examined how candidate genes underlying natural variation across populations might also mediate plasticity within an individual. Our implementation of an integrative "plasticity space" approach revealed that the root plasticity of a single Arabidopsis accession exposed to distinct environments broadly recapitulates the natural variation "space." Genome-wide association mapping identified the known gene PHOSPHATE 1 (PHO1) and other genes such as Root System Architecture 1 (RSA1) associated with differences in root allometry, a highly plastic trait capturing the distribution of lateral roots along the primary axis. The response of mutants in the Columbia-0 background suggests their involvement in signaling key modulators of root development including auxin, abscisic acid, and nitrate. Moreover, genotype-by-environment interactions for the PHO1 and RSA1 genes in Columbia-0 phenocopy the root allometry of other natural variants. This finding supports a role for plasticity responses in phenotypic evolution in natural environments.

Developmental reaction norms for water stressed seedlings of succulent cacti.

Succulent cacti are remarkable plants with capabilities to withstand long periods of drought. However, their adult success is contingent on the early seedling stages, when plants are highly susceptible to the environment. To better understand their early coping strategies in a challenging environment, two developmental aspects (anatomy and morphology) in Polaskia chichipe and Echinocactus platyacanthus were studied in the context of developmental reaction norms under drought conditions. The morphology was evaluated using landmark based morphometrics and Principal Component Analysis, which gave three main trends of the variation in each species. The anatomy was quantified as number and area of xylem vessels. The quantitative relationship between morphology and anatomy in early stages of development, as a response to drought was revealed in these two species. Qualitatively, collapsible cells and collapsible parenchyma tissue were observed in seedlings of both species, more often in those subjected to water stress. These tissues were located inside the epidermis, resembling a web of collapsible-cell groups surrounding turgid cells, vascular bundles, and spanned across the pith. Occasionally the groups formed a continuum stretching from the epidermis towards the vasculature. Integrating the morphology and the anatomy in a developmental context as a response to environmental conditions provides a better understanding of the organism's dynamics, adaptation, and plasticity.