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

Roberta Esposito; Taisia Polidori; Dominik F. Meise; Carlos Pulido-Quetglas; Panagiotis Chouvardas; Stefan Forster; Paulina Schaerer; Andrea Kobel; Juliette Schlatter; Erik Kerkhof; Michaela Roemmele; Emily S. Rice; Lina Zhu; Andrés Lanzós; Hugo A. Guillen-Ramirez; Giulia Basile; Irene Carrozzo; Adrienne Vancura; Sebastian Ullrich; Alvaro Andrades; Dylan Harvey; Pedro P. Medina; Patrick C. Ma; Simon Haefliger; Xin Wang; Ivan Martinez; Adrian F. Ochsenbein; Carsten Riether; Rory Johnson

doi:10.1016/j.xgen.2022.100171

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

Roberta Esposito, Taisia Polidori, Dominik F. Meise, Carlos Pulido-Quetglas, Panagiotis Chouvardas, Stefan Forster, Paulina Schaerer, Andrea Kobel, Juliette Schlatter, Erik Kerkhof, Michaela Roemmele, Emily S. Rice, Lina Zhu, Andrés Lanzós, Hugo A. Guillen-Ramirez, Giulia Basile, Irene Carrozzo, Adrienne Vancura, Sebastian Ullrich, Alvaro AndradesDylan Harvey, Pedro P. Medina, Patrick C. Ma, Simon Haefliger, Xin Wang, Ivan Martinez, Adrian F. Ochsenbein, Carsten Riether, Rory Johnson

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

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.

Original language	English (US)
Article number	100171
Journal	Cell Genomics
Volume	2
Issue number	9
DOIs	https://doi.org/10.1016/j.xgen.2022.100171
State	Published - Sep 14 2022

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology (miscellaneous)
Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.xgen.2022.100171

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Esposito, R., Polidori, T., Meise, D. F., Pulido-Quetglas, C., Chouvardas, P., Forster, S., Schaerer, P., Kobel, A., Schlatter, J., Kerkhof, E., Roemmele, M., Rice, E. S., Zhu, L., Lanzós, A., Guillen-Ramirez, H. A., Basile, G., Carrozzo, I., Vancura, A., Ullrich, S., ... Johnson, R. (2022). Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities. Cell Genomics, 2(9), Article 100171. https://doi.org/10.1016/j.xgen.2022.100171

@article{e5e52471599b437b853593d928dbfca0,

title = "Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities",

abstract = "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.",

author = "Roberta Esposito and Taisia Polidori and Meise, {Dominik F.} and Carlos Pulido-Quetglas and Panagiotis Chouvardas and Stefan Forster and Paulina Schaerer and Andrea Kobel and Juliette Schlatter and Erik Kerkhof and Michaela Roemmele and Rice, {Emily S.} and Lina Zhu and Andr{\'e}s Lanz{\'o}s and Guillen-Ramirez, {Hugo A.} and Giulia Basile and Irene Carrozzo and Adrienne Vancura and Sebastian Ullrich and Alvaro Andrades and Dylan Harvey and Medina, {Pedro P.} and Ma, {Patrick C.} and Simon Haefliger and Xin Wang and Ivan Martinez and Ochsenbein, {Adrian F.} and Carsten Riether and Rory Johnson",

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = sep,

day = "14",

doi = "10.1016/j.xgen.2022.100171",

language = "English (US)",

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Esposito, R, Polidori, T, Meise, DF, Pulido-Quetglas, C, Chouvardas, P, Forster, S, Schaerer, P, Kobel, A, Schlatter, J, Kerkhof, E, Roemmele, M, Rice, ES, Zhu, L, Lanzós, A, Guillen-Ramirez, HA, Basile, G, Carrozzo, I, Vancura, A, Ullrich, S, Andrades, A, Harvey, D, Medina, PP, Ma, PC, Haefliger, S, Wang, X, Martinez, I, Ochsenbein, AF, Riether, C & Johnson, R 2022, 'Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities', Cell Genomics, vol. 2, no. 9, 100171. https://doi.org/10.1016/j.xgen.2022.100171

TY - JOUR

T1 - Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities

AU - Esposito, Roberta

AU - Polidori, Taisia

AU - Meise, Dominik F.

AU - Pulido-Quetglas, Carlos

AU - Chouvardas, Panagiotis

AU - Forster, Stefan

AU - Schaerer, Paulina

AU - Kobel, Andrea

AU - Schlatter, Juliette

AU - Kerkhof, Erik

AU - Roemmele, Michaela

AU - Rice, Emily S.

AU - Zhu, Lina

AU - Lanzós, Andrés

AU - Guillen-Ramirez, Hugo A.

AU - Basile, Giulia

AU - Carrozzo, Irene

AU - Vancura, Adrienne

AU - Ullrich, Sebastian

AU - Andrades, Alvaro

AU - Harvey, Dylan

AU - Medina, Pedro P.

AU - Ma, Patrick C.

AU - Haefliger, Simon

AU - Wang, Xin

AU - Martinez, Ivan

AU - Ochsenbein, Adrian F.

AU - Riether, Carsten

AU - Johnson, Rory

PY - 2022/9/14

Y1 - 2022/9/14

N2 - 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.

AB - 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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JO - Cell Genomics

JF - Cell Genomics

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ER -

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

Abstract

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