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

Cell Genom. 2022 Aug 22;2(9):100171. doi: 10.1016/j.xgen.2022.100171. eCollection 2022 Sep 14.

Authors

Roberta Esposito^{1

2

3}, Taisia Polidori^{1

2

4}, Dominik F Meise^{1

2}, Carlos Pulido-Quetglas^{1

2

4}, Panagiotis Chouvardas^{1

2}, Stefan Forster^{1

2}, Paulina Schaerer^{1

2}, Andrea Kobel^{1

2}, Juliette Schlatter^{1

2}, Erik Kerkhof^{1

2}, Michaela Roemmele^{1

2}, Emily S Rice⁵, Lina Zhu^{6

7

8}, Andrés Lanzós^{1

2

4}, Hugo A Guillen-Ramirez^{1

2

9

10}, Giulia Basile^{1

2}, Irene Carrozzo^{1

2}, Adrienne Vancura^{1

2}, Sebastian Ullrich¹¹, Alvaro Andrades^{12

13

14}, Dylan Harvey⁹, Pedro P Medina^{12

13

14}, Patrick C Ma¹⁵, Simon Haefliger^{1

2}, Xin Wang⁶, Ivan Martinez⁵, Adrian F Ochsenbein^{1

2}, Carsten Riether^{1

2}, Rory Johnson^{1

2

9

10}

Affiliations

¹ Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3010 Switzerland.
² Department for BioMedical Research, University of Bern, Bern 3008, Switzerland.
³ Institute of Genetics and Biophysics "Adriano Buzzati-Traverso" CNR, Naples 80131, Italy.
⁴ Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern 3012, Switzerland.
⁵ Department of Microbiology, Immunology, and Cell Biology, Morgantown, WV, USA.
⁶ Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
⁷ Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong.
⁸ Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute, City University of Hong Kong, Shenzhen 518057, China.
⁹ School of Biology and Environmental Science, University College Dublin, Dublin D04 V1W8, Ireland.
¹⁰ Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin D04 V1W8, Ireland.
¹¹ Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology (BIST), Barcelona, Catalonia 08003, Spain.
¹² GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain.
¹³ Instituto de Investigación Biosanitaria, Granada 18014, Spain.
¹⁴ Department of Biochemistry and Molecular Biology I, University of Granada, Granada 18071, Spain.
¹⁵ Penn State Cancer Institute, Hershey, PA 17033, USA.

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.

Keywords: CRISPR; NSCLC; RNA therapeutics; antisense oligonucleotides; cancer; lncRNA; long noncoding RNA; non-small cell lung cancer.