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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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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. |
format | Online Article Text |
id | pubmed-9903773 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
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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