The tryptophan-metabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) is frequently overexpressed in epithelial-derived malignancies, where it plays a recognized role in promoting tumor immune ...tolerance. We previously demonstrated that the IDO1-kynurenine pathway (KP) also directly supports colorectal cancer growth by promoting activation of β-catenin and driving neoplastic growth in mice lacking intact adaptive immunity. In this study, we sought to delineate the specific role of epithelial IDO1 in colon tumorigenesis and define how IDO1 and KP metabolites interact with pivotal neoplastic signaling pathways of the colon epithelium. We generated a novel intestinal epithelial-specific IDO1 knockout mouse and utilized established colorectal cancer cell lines containing β-catenin-stabilizing mutations, human colorectal cancer samples, and human-derived epithelial organoids (colonoids and tumoroids). Mice with intestinal epithelial-specific knockout of IDO1 developed fewer and smaller tumors than wild-type littermates in a model of inflammation-driven colon tumorigenesis. Moreover, their tumors exhibited reduced nuclear β-catenin and neoplastic proliferation but increased apoptosis. Mechanistically, KP metabolites (except kynurenic acid) rapidly activated PI3K-Akt signaling in the neoplastic epithelium to promote nuclear translocation of β-catenin, cellular proliferation, and resistance to apoptosis. Together, these data define a novel cell-autonomous function and mechanism by which IDO1 activity promotes colorectal cancer progression. These findings may have implications for the rational design of new clinical trials that exploit a synergy of IDO1 inhibitors with conventional cancer therapies for which Akt activation provides resistance such as radiation.
This study identifies a new mechanistic link between IDO1 activity and PI3K/AKT signaling, both of which are important pathways involved in cancer growth and resistance to cancer therapy.
As an increasingly important resource in ecological research, citizen scientists have proven dynamic and cost‐effective in the supply of data for use within habitat suitability models. With ...predictions critical to the provision of effective conservation measures in cryptic marine species, this study delivers baseline ecological data for the Critically Endangered angelshark (Squatina squatina), exploring: (i) seasonal, sex‐differentiated distributions; (ii) environmental distribution predictors; and (iii) examining bias‐corrected, imperfect citizen science data for use in coastal habitat suitability models with cryptic species.
Citizen science presence data, comprising over 60,000 hours of sampling effort, were used alongside carefully selected open‐source predictor variables, with maxent generating seasonal male and female habitat suitability models for angelsharks in the Canary Islands. A biased prior method was used, alongside two model validation measures to ensure reliability.
Citizen science data used within maxent suggest that angelshark habitat suitability is low in coastal areas during warmer months, with fewer occurrences despite a negligible change in sampling effort. The prime importance of bathymetry may indicate the importance of depth for reproductive activity and possible diel vertical migration, whereas aspect may act as a proxy for sheltered habitats away from open ocean. Substrate as a predictor of female habitats in spring and summer could imply that soft sediment is sought for birthing areas, assisting in the identification of areas critical to reproductive activity and thus locations that may benefit from spatial protections.
Model outputs to inform recovery plan development and ecotourism are identified as plausible safeguards of population recovery, whereas the comparison of biased and bias‐corrected models highlights some variance between methodologies, with bias‐corrected models producing greater areas of habitat suitability. Accordingly, an adaptive framework is provided for the implementation of citizen science data within the modelling of cryptic coastal species distribution.
Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer death in the United States. Cytotoxic therapies cause significant adverse effects for most ...patients and do not offer cure in many advanced cases of CRC. Immunotherapy is a promising new approach to harness the body's own immune system and inflammatory response to attack and clear the cancer. Tryptophan metabolism along the kynurenine pathway (KP) is a particularly promising target for immunotherapy. Indoleamine 2,3-dioxygenase 1 (IDO1) is the most well studied of the enzymes that initiate this pathway and it is commonly overexpressed in CRC. Herein, we provide an in-depth review of how tryptophan metabolism and KP metabolites shape factors important to CRC pathogenesis including the host mucosal immune system, pivotal transcriptional pathways of neoplastic growth, and luminal microbiota. This pathway's role in other gastrointestinal (GI) malignancies such as gastric, pancreatic, esophageal, and GI stromal tumors is also discussed. Finally, we highlight how currently available small molecule inhibitors and emerging methods for therapeutic targeting of IDO1 might be applied to colon, rectal, and colitis–associated cancer.
Colorectal cancer is a major cause of mortality worldwide. Chemotherapy and radiation remain standard treatment for locally advanced disease, with current immune-targeting therapies applying to only ...a small subset of patients. Expression of the immuno-oncology target indoleamine 2,3 dioxygenase 1 (IDO1) is associated with poor colorectal cancer clinical outcomes but is understudied as a potential treatment target. In this study, we examined the interaction between the IDO1 pathway and radiotherapy in colorectal cancer. We used human and mouse colorectal cancer cell lines, organoids, mouse syngeneic colorectal cancer tumor graft models, and colorectal cancer tissues from patients who received radiotherapy. IDO1 activity was blocked using the clinical IDO1 inhibitor epacadostat and by genetic disruption. We found that radiation induced IDO1 overexpression in colorectal cancer through type I and II IFN signaling. IDO1 enzymatic activity directly influenced colorectal cancer radiation sensitivity. IDO1 inhibition sensitized colorectal cancer to radiation-induced cell death, whereas the IDO1 metabolite kynurenine promoted radioprotection. IDO1 inhibition also potentiated Th1 cytokines and myeloid cell-modulating factors in the tumor microenvironment and promoted an abscopal effect on tumors outside the radiation field. Conversely, IDO1 blockade protected the normal small intestinal epithelium from radiation toxicity and accelerated recovery from radiation-induced weight loss, indicating a role in limiting side effects. These data demonstrated that IDO1 inhibition potentiates radiotherapy effectiveness in colorectal cancer. The findings also provide rationale and mechanistic insight for the study of IDO1 inhibitors as adjuvant therapy to radiation in patients with locally advanced sporadic and colitis-associated colorectal cancer.
ABSTRACT The discovery of rings around extrasolar planets ("exorings") is one of the next breakthroughs in exoplanetary research. Previous studies have explored the feasibility of detecting exorings ...with present and future photometric sensitivities by seeking anomalous deviations in the residuals of a standard transit light curve fit, at the level of ppm for Kronian rings. In this work, we explore two much larger observational consequences of exorings: (1) the significant increase in transit depth that may lead to the misclassification of ringed planetary candidates as false-positives and/or the underestimation of planetary density; and (2) the so-called "photo-ring" effect, a new asterodensity profiling effect, revealed by a comparison of the light curve derived stellar density to that measured with independent methods (e.g., asteroseismology). While these methods do not provide an unambiguous detection of exorings, we show that the large amplitude of these effects, combined with their relatively simple analytic description, makes them highly suited to large-scale surveys to identify candidate ringed planets worthy of more detailed investigation. Moreover, these methods lend themselves to ensemble analyses seeking to uncover evidence of a population of ringed planets. We describe the method in detail, develop the basic underlying formalism, and test it in the parameter space of rings and transit configuration. We discuss the prospects of using this method for the first systematic search of exoplanetary rings in the Kepler database and provide a basic computational code for implementing it.
Inflammation, injury, and infection up-regulate expression of the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in the intestinal epithelium. We studied the effects of ...cell-specific IDO1 expression in the epithelium at baseline and during intestinal inflammation in mice.
We generated transgenic mice that overexpress fluorescence-tagged IDO1 in the intestinal epithelium under control of the villin promoter (IDO1-TG). We generated intestinal epithelial spheroids from mice with full-length Ido1 (controls), disruption of Ido1 (knockout mice), and IDO1-TG and analyzed them for stem cell and differentiation markers by real-time polymerase chain reaction, immunoblotting, and immunofluorescence. Some mice were gavaged with enteropathogenic Escherichia coli (E2348/69) to induce infectious ileitis, and ileum contents were quantified by polymerase chain reaction. Separate sets of mice were given dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid to induce colitis; intestinal tissues were analyzed by histology. We utilized published data sets GSE75214 and GDS2642 of RNA expression data from ilea of healthy individuals undergoing screening colonoscopies (controls) and patients with Crohn’s disease.
Histologic analysis of small intestine tissues from IDO1-TG mice revealed increases in secretory cells. Enteroids derived from IDO1-TG intestine had increased markers of stem, goblet, Paneth, enteroendocrine, and tuft cells, compared with control enteroids, with a concomitant decrease in markers of absorptive cells. IDO1 interacted non-enzymatically with the aryl hydrocarbon receptor to inhibit activation of NOTCH1. Intestinal mucus layers from IDO1-TG mice were 2-fold thicker than mucus layers from control mice, with increased proportions of Akkermansia muciniphila and Mucispirillum schaedleri. Compared to controls, IDO1-TG mice demonstrated an 85% reduction in ileal bacteria (P = .03) when challenged with enteropathogenic E coli, and were protected from immune infiltration, crypt dropout, and ulcers following administration of dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid. In ilea of Crohn’s disease patients, increased expression of IDO1 correlated with increased levels of MUC2, LYZ1, and aryl hydrocarbon receptor, but reduced levels of SLC2A5.
In mice, expression of IDO1 in the intestinal epithelial promotes secretory cell differentiation and mucus production; levels of IDO1 are positively correlated with secretory cell markers in ilea of healthy individuals and Crohn’s disease patients. We propose that IDO1 contributes to intestinal homeostasis.
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