Archetype tasks link intratumoral heterogeneity to plasticity and cancer hallmarks in small cell lung cancer.
RNA velocity
dynamical systems
gene regulatory networks
heterogeneity
phenotypic plasticity
single cell
small cell lung cancer
Journal
Cell systems
ISSN: 2405-4720
Titre abrégé: Cell Syst
Pays: United States
ID NLM: 101656080
Informations de publication
Date de publication:
21 09 2022
21 09 2022
Historique:
received:
04
09
2021
revised:
10
05
2022
accepted:
25
07
2022
pubmed:
19
8
2022
medline:
28
9
2022
entrez:
18
8
2022
Statut:
ppublish
Résumé
Small cell lung cancer (SCLC) tumors comprise heterogeneous mixtures of cell states, categorized into neuroendocrine (NE) and non-neuroendocrine (non-NE) transcriptional subtypes. NE to non-NE state transitions, fueled by plasticity, likely underlie adaptability to treatment and dismal survival rates. Here, we apply an archetypal analysis to model plasticity by recasting SCLC phenotypic heterogeneity through multi-task evolutionary theory. Cell line and tumor transcriptomics data fit well in a five-dimensional convex polytope whose vertices optimize tasks reminiscent of pulmonary NE cells, the SCLC normal counterparts. These tasks, supported by knowledge and experimental data, include proliferation, slithering, metabolism, secretion, and injury repair, reflecting cancer hallmarks. SCLC subtypes, either at the population or single-cell level, can be positioned in archetypal space by bulk or single-cell transcriptomics, respectively, and characterized as task specialists or multi-task generalists by the distance from archetype vertex signatures. In the archetype space, modeling single-cell plasticity as a Markovian process along an underlying state manifold indicates that task trade-offs, in response to microenvironmental perturbations or treatment, may drive cell plasticity. Stifling phenotypic transitions and plasticity may provide new targets for much-needed translational advances in SCLC. A record of this paper's Transparent Peer Review process is included in the supplemental information.
Identifiants
pubmed: 35981544
pii: S2405-4712(22)00313-1
doi: 10.1016/j.cels.2022.07.006
pmc: PMC9615940
mid: NIHMS1840435
pii:
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
690-710.e17Subventions
Organisme : NCI NIH HHS
ID : U01 CA224276
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA213274
Pays : United States
Organisme : NCI NIH HHS
ID : K12 CA090625
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK106228
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA231844
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA243783
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA233259
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA236733
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK103831
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA215845
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA251147
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA215798
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA217450
Pays : United States
Organisme : NCI NIH HHS
ID : K00 CA234920
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022. Published by Elsevier Inc.
Déclaration de conflit d'intérêts
Declaration of interests C.M.L. is a consultant/advisory board member for Pfizer, Novartis, Astra Zeneca, Genoptix, Sequenom, Ariad, Takeda, Blueprints Medicine, Cepheid, Foundation Medicine, Roche, Achilles Therapeutics, Genentech, Syros, Amgen, EMD Serono, and Eli Lilly and reports receiving commercial research grants from Xcovery, Astra Zeneca, and Novartis. W.T.I. is a consultant/advisory board member for Genentech, Jazz Pharma, G1 Therapeutics, Mirati, OncLive, Clinical Care Options, Chardan, Outcomes Insights, Cello Health, and Curio Science. T.G.O. is a consultant/advisory board member for Known Medicine. J.S. receives research funding from Pfizer. V.Q. is an Academic co-Founder and equity holder for Parthenon Therapeutics, Inc. and Duet BioSystems, Inc.
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