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Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities

Long noncoding RNAs (lncRNAs) are widely dysregulated in cancer, yet their functional roles in cancer hallmarks remain unclear. We employ pooled CRISPR deletion to perturb 831 lncRNAs detected in KRAS-mutant non-small cell lung cancer (NSCLC) and measure their contribution to proliferation, chemores...

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Autores principales: Esposito, Roberta, Polidori, Taisia, Meise, Dominik F., Pulido-Quetglas, Carlos, Chouvardas, Panagiotis, Forster, Stefan, Schaerer, Paulina, Kobel, Andrea, Schlatter, Juliette, Kerkhof, Erik, Roemmele, Michaela, Rice, Emily S., Zhu, Lina, Lanzós, Andrés, Guillen-Ramirez, Hugo A., Basile, Giulia, Carrozzo, Irene, Vancura, Adrienne, Ullrich, Sebastian, Andrades, Alvaro, Harvey, Dylan, Medina, Pedro P., Ma, Patrick C., Haefliger, Simon, Wang, Xin, Martinez, Ivan, Ochsenbein, Adrian F., Riether, Carsten, Johnson, Rory
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9903773/
https://www.ncbi.nlm.nih.gov/pubmed/36778670
http://dx.doi.org/10.1016/j.xgen.2022.100171
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author Esposito, Roberta
Polidori, Taisia
Meise, Dominik F.
Pulido-Quetglas, Carlos
Chouvardas, Panagiotis
Forster, Stefan
Schaerer, Paulina
Kobel, Andrea
Schlatter, Juliette
Kerkhof, Erik
Roemmele, Michaela
Rice, Emily S.
Zhu, Lina
Lanzós, Andrés
Guillen-Ramirez, Hugo A.
Basile, Giulia
Carrozzo, Irene
Vancura, Adrienne
Ullrich, Sebastian
Andrades, Alvaro
Harvey, Dylan
Medina, Pedro P.
Ma, Patrick C.
Haefliger, Simon
Wang, Xin
Martinez, Ivan
Ochsenbein, Adrian F.
Riether, Carsten
Johnson, Rory
author_facet Esposito, Roberta
Polidori, Taisia
Meise, Dominik F.
Pulido-Quetglas, Carlos
Chouvardas, Panagiotis
Forster, Stefan
Schaerer, Paulina
Kobel, Andrea
Schlatter, Juliette
Kerkhof, Erik
Roemmele, Michaela
Rice, Emily S.
Zhu, Lina
Lanzós, Andrés
Guillen-Ramirez, Hugo A.
Basile, Giulia
Carrozzo, Irene
Vancura, Adrienne
Ullrich, Sebastian
Andrades, Alvaro
Harvey, Dylan
Medina, Pedro P.
Ma, Patrick C.
Haefliger, Simon
Wang, Xin
Martinez, Ivan
Ochsenbein, Adrian F.
Riether, Carsten
Johnson, Rory
author_sort Esposito, Roberta
collection PubMed
description Long noncoding RNAs (lncRNAs) are widely dysregulated in cancer, yet their functional roles in cancer hallmarks remain unclear. We employ pooled CRISPR deletion to perturb 831 lncRNAs detected in KRAS-mutant non-small cell lung cancer (NSCLC) and measure their contribution to proliferation, chemoresistance, and migration across two cell backgrounds. Integrative analysis of these data outperforms conventional “dropout” screens in identifying cancer genes while prioritizing disease-relevant lncRNAs with pleiotropic and background-independent roles. Altogether, 80 high-confidence oncogenic lncRNAs are active in NSCLC, which tend to be amplified and overexpressed in tumors. A follow-up antisense oligonucleotide (ASO) screen shortlisted two candidates, Cancer Hallmarks in Lung LncRNA 1 (CHiLL1) and GCAWKR, whose knockdown consistently suppressed cancer hallmarks in two- and three-dimension tumor models. Molecular phenotyping reveals that CHiLL1 and GCAWKR control cellular-level phenotypes via distinct transcriptional networks. This work reveals a multi-dimensional functional lncRNA landscape underlying NSCLC that contains potential therapeutic vulnerabilities.
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spelling pubmed-99037732023-02-10 Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities Esposito, Roberta Polidori, Taisia Meise, Dominik F. Pulido-Quetglas, Carlos Chouvardas, Panagiotis Forster, Stefan Schaerer, Paulina Kobel, Andrea Schlatter, Juliette Kerkhof, Erik Roemmele, Michaela Rice, Emily S. Zhu, Lina Lanzós, Andrés Guillen-Ramirez, Hugo A. Basile, Giulia Carrozzo, Irene Vancura, Adrienne Ullrich, Sebastian Andrades, Alvaro Harvey, Dylan Medina, Pedro P. Ma, Patrick C. Haefliger, Simon Wang, Xin Martinez, Ivan Ochsenbein, Adrian F. Riether, Carsten Johnson, Rory Cell Genom Article Long noncoding RNAs (lncRNAs) are widely dysregulated in cancer, yet their functional roles in cancer hallmarks remain unclear. We employ pooled CRISPR deletion to perturb 831 lncRNAs detected in KRAS-mutant non-small cell lung cancer (NSCLC) and measure their contribution to proliferation, chemoresistance, and migration across two cell backgrounds. Integrative analysis of these data outperforms conventional “dropout” screens in identifying cancer genes while prioritizing disease-relevant lncRNAs with pleiotropic and background-independent roles. Altogether, 80 high-confidence oncogenic lncRNAs are active in NSCLC, which tend to be amplified and overexpressed in tumors. A follow-up antisense oligonucleotide (ASO) screen shortlisted two candidates, Cancer Hallmarks in Lung LncRNA 1 (CHiLL1) and GCAWKR, whose knockdown consistently suppressed cancer hallmarks in two- and three-dimension tumor models. Molecular phenotyping reveals that CHiLL1 and GCAWKR control cellular-level phenotypes via distinct transcriptional networks. This work reveals a multi-dimensional functional lncRNA landscape underlying NSCLC that contains potential therapeutic vulnerabilities. Elsevier 2022-08-22 /pmc/articles/PMC9903773/ /pubmed/36778670 http://dx.doi.org/10.1016/j.xgen.2022.100171 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Esposito, Roberta
Polidori, Taisia
Meise, Dominik F.
Pulido-Quetglas, Carlos
Chouvardas, Panagiotis
Forster, Stefan
Schaerer, Paulina
Kobel, Andrea
Schlatter, Juliette
Kerkhof, Erik
Roemmele, Michaela
Rice, Emily S.
Zhu, Lina
Lanzós, Andrés
Guillen-Ramirez, Hugo A.
Basile, Giulia
Carrozzo, Irene
Vancura, Adrienne
Ullrich, Sebastian
Andrades, Alvaro
Harvey, Dylan
Medina, Pedro P.
Ma, Patrick C.
Haefliger, Simon
Wang, Xin
Martinez, Ivan
Ochsenbein, Adrian F.
Riether, Carsten
Johnson, Rory
Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities
title Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities
title_full Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities
title_fullStr Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities
title_full_unstemmed Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities
title_short Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities
title_sort multi-hallmark long noncoding rna maps reveal non-small cell lung cancer vulnerabilities
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9903773/
https://www.ncbi.nlm.nih.gov/pubmed/36778670
http://dx.doi.org/10.1016/j.xgen.2022.100171
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