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 journalArticlepeer-review

9 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 languageEnglish (US)
Article number100171
JournalCell Genomics
Volume2
Issue number9
DOIs
StatePublished - Sep 14 2022

All Science Journal Classification (ASJC) codes

  • Genetics
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

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