دورية أكاديمية
أعرض في EDS

Systems-level network modeling of Small Cell Lung Cancer subtypes identifies master regulators and destabilizers.

التفاصيل البيبلوغرافية
العنوان: Systems-level network modeling of Small Cell Lung Cancer subtypes identifies master regulators and destabilizers.
المؤلفون: Wooten DJ; Department of Physics, The Pennsylvania State University, University Park, Pennsylvania, United States of America.; Department of Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America., Groves SM; Department of Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America., Tyson DR; Department of Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America., Liu Q; Departments of Biomedical Informatics and Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America., Lim JS; Departments of Pediatrics and Genetics, Stanford University, Stanford, California, United States of America., Albert R; Department of Physics, The Pennsylvania State University, University Park, Pennsylvania, United States of America., Lopez CF; Department of Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America., Sage J; Departments of Pediatrics and Genetics, Stanford University, Stanford, California, United States of America., Quaranta V; Department of Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
المصدر: PLoS computational biology [PLoS Comput Biol] 2019 Oct 31; Vol. 15 (10), pp. e1007343. Date of Electronic Publication: 2019 Oct 31 (Print Publication: 2019).
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: Public Library of Science Country of Publication: United States NLM ID: 101238922 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7358 (Electronic) Linking ISSN: 1553734X NLM ISO Abbreviation: PLoS Comput Biol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: San Francisco, CA : Public Library of Science, [2005]-
مواضيع طبية MeSH: Small Cell Lung Carcinoma/*classification , Small Cell Lung Carcinoma/*metabolism, Algorithms ; Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Bayes Theorem ; Cell Line, Tumor ; Cluster Analysis ; Databases, Genetic ; Drug Resistance, Neoplasm ; Gene Expression ; Gene Expression Regulation, Neoplastic/genetics ; Gene Ontology ; Gene Regulatory Networks/genetics ; Humans ; Mice ; Models, Theoretical ; Systems Analysis ; Transcription Factors/metabolism
مستخلص: Adopting a systems approach, we devise a general workflow to define actionable subtypes in human cancers. Applied to small cell lung cancer (SCLC), the workflow identifies four subtypes based on global gene expression patterns and ontologies. Three correspond to known subtypes (SCLC-A, SCLC-N, and SCLC-Y), while the fourth is a previously undescribed ASCL1+ neuroendocrine variant (NEv2, or SCLC-A2). Tumor deconvolution with subtype gene signatures shows that all of the subtypes are detectable in varying proportions in human and mouse tumors. To understand how multiple stable subtypes can arise within a tumor, we infer a network of transcription factors and develop BooleaBayes, a minimally-constrained Boolean rule-fitting approach. In silico perturbations of the network identify master regulators and destabilizers of its attractors. Specific to NEv2, BooleaBayes predicts ELF3 and NR0B1 as master regulators of the subtype, and TCF3 as a master destabilizer. Since the four subtypes exhibit differential drug sensitivity, with NEv2 consistently least sensitive, these findings may lead to actionable therapeutic strategies that consider SCLC intratumoral heterogeneity. Our systems-level approach should generalize to other cancer types.
Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: J.S. receives research funding from StemCentrx/Abbvie, Revolution Medicines, and from Pfizer, and owns stock in Forty Seven Inc.
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معلومات مُعتمدة: U01 CA215845 United States CA NCI NIH HHS; U54 CA217450 United States CA NCI NIH HHS; R50 CA243783 United States CA NCI NIH HHS; R01 CA201513 United States CA NCI NIH HHS; R35 CA231997 United States CA NCI NIH HHS; T32 CA009592 United States CA NCI NIH HHS
المشرفين على المادة: 0 (Basic Helix-Loop-Helix Transcription Factors)
0 (Transcription Factors)
تواريخ الأحداث: Date Created: 20191101 Date Completed: 20200203 Latest Revision: 20231019
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC6860456
DOI: 10.1371/journal.pcbi.1007343
PMID: 31671086
قاعدة البيانات: MEDLINE
الوصف
تدمد:1553-7358
DOI:10.1371/journal.pcbi.1007343