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Notch as an Immunologic Basis of Cancer Disparities.

ABSTRACT: Inter-individual differences due to racial/ethnic backgrounds may alter host immunity responsible for the cancer immunosurveillance and elimination, leading to disparate cancer incidence and relapse. One basis of disparity in tumor incidence, progression or therapeutic outcomes could lie in the components of Notch intercellular communication system, which provide instructive signals for a variety of pathways regulating cell commitment and differentiation including context-dependent lymphocyte polarization in tumor microenvironment. Notch signaling in hematopoietic cells is perturbed by tumor growth for its advantage, and there are indications that differences in Notch components could underlie poor cancer prognosis in certain populations. Here, we discuss the oncogenic and immunologic aspects of Notch, which should inform on cancer health disparities and therapeutic outcomes.

SUBMITTER: LaLiah Thomas P

PROVIDER: S-EPMC8278364 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Notch as an Immunologic Basis of Cancer Disparities.

LaLiah Thomas Portia P Shanker Anil A

Cancer health disparities 20190819

Inter-individual differences due to racial/ethnic backgrounds may alter host immunity responsible for the cancer immunosurveillance and elimination, leading to disparate cancer incidence and relapse. One basis of disparity in tumor incidence, progression or therapeutic outcomes could lie in the components of Notch intercellular communication system, which provide instructive signals for a variety of pathways regulating cell commitment and differentiation including context-dependent lymphocyte po ...[more]

PMID: 34268483

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Project description:COVID-19 has shown a substantial variation in the rate and severity by which it impacts different demographic groups. Specifically, it has shown a predilection towards obese patients as well as as well as other vulnerable groups including predilection of males over females, old age over young age and black races over Caucasian ones.. Single cell sequencing studies have highlighted the role of cell polarity and the co-expression of proteases, such as Furin, along with ACE2 in the genesis of coronavirus disease rather than exclusively link tissue involvement with ACE2 levels thought previously. It has also forged a connection between the genetic and immune cellular mechanisms underlying COVID infection and the inflammatory state of obese patients, offering a more accurate explanation as to why obese patients are at increased risk of poor COVID outcomes. These commonalities encompass macrophage phenotype switching, genetic expression switching, and overexpression of the pro-inflammatory cytokines, depletion of the regulatory cytokines, in situ T cell proliferation, and T cell exhaustion. These findings demonstrate the necessity of single cell sequencing as a rapid means to identify and treat those who are most likely to need hospital admission and intensive care, in the hopes of precision medicine. Furthermore, this study underlines the use of immune modulators such as Leptin sensitizers, rather than immune suppressors as anti-inflammation therapies to switch the inflammatory response from a drastic immunological type 1 response to a beneficial type 2 effective one. Highlights • ScRNA-seq focuses on the analysis of individual cells, instead of bulk cell populations, and can lead to a more insightful characterization of local microenvironments.• ScRNA-seq unleashed that tissue tropism in COVID-19 is not solely determinant by ACE2 distribution but rather by Furin.• ScRNA-seq in COVID-19 revealed two distinct types of immunologic reactions, deleterious type 1 characterized by inefficient antigen presentation, decreased memory B cells, imbalance between M1 and M2 macrophages and T cell exhaustion, and beneficial type 2 reaction which exactly the reverse of the type 1.• The immunotype 1 reaction is intriguingly similar to the immune landscape seen in obese individuals when leptin resistance sets in.• This might indicate that the use of leptin sensitizers to induce an immunologic switch from immunotype 1 to immunotype 2 can greatly improve the outcome of COVID-19 cases.• ScRNA-seq was also able to unveil the disparity between aggressive and milder strains of SARS-CoV-2, which are mainly related to their affinity to cellular activation by Furin.• The applications of ScRNA-seq may help to anticipate cases at higher risk of severe COVID-19 at their earliest encounter.

Project description:ObjectivesFor prostate cancer (PCa), hundreds of risk variants have been identified. It remains unknown whether the polygenic risk score (PRS) that combines the effects of these variants is also a sufficiently informative metric with relevance to the molecular mechanisms of carcinogenesis in prostate. We aimed to understand the biological basis of PRS and racial disparities in the cancer.MethodsWe performed a comprehensive analysis of the data generated (deposited in) by several genomic and/or transcriptomic projects (databases), including the GTEx, TCGA, 1000 Genomes, GEO and dbGap. PRS was constructed from 260 PCa risk variants that were identified by a recent trans-ancestry meta-analysis and contained in the GTEx dataset. The dosages of risk variants and the multi-ancestry effects on PCa incidence estimated by the meta-analysis were used in calculating individual PRS values.ResultsThe following novel results were obtained from our analyses. (1) In normal prostate samples from healthy European Americans (EAs), the expression levels of 540 genes (termed PRS genes) were associated with the PRS (P < .01). (2) Ubiquitin-proteasome system in high-PRS individuals' prostates was more active than that in low-PRS individuals' prostates. (3) Nine PRS genes play roles in the cancer progression-relevant parts, which are frequently hit by somatic mutations in PCa, of PI3K-Akt/RAS-MAPK/mTOR signaling pathways. (4) The expression profiles of the top significant PRS genes in tumor samples were capable of predicting malignant PCa relapse after prostatectomy. (5) The transcriptomic differences between African American and EA samples were incompatible with the patterns of the aforementioned associations between PRS and gene expression levels.ConclusionsThis study provided unique insights into the relationship between PRS and the molecular mechanisms of carcinogenesis in prostate. The new findings, alongside the moderate but significant heritability of PCa susceptibility contributed by the risk variants, suggest the aptness and inaptness of PRS for explaining PCa and disparities.

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Notch as an Immunologic Basis of Cancer Disparities.

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Notch as an Immunologic Basis of Cancer Disparities.

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