CRISPR-Cas13d functional transcriptomics reveals widespread isoform-selective cancer dependencies on lncRNAs
Abstract
Long noncoding RNAs (lncRNAs) are a significant yet largely uncharted component of the cancer transcriptome, with their isoform-specific functions remaining poorly understood. In this study, we employed RNA-targeting CRISPR-Cas13d to uncover and characterize hundreds of tumor-essential (te)-lncRNA isoforms with clinical relevance. Focusing on multiple myeloma (MM), we targeted the lncRNA transcriptome expressed in tumor cells from MM patients and revealed both MM-specific and pan-cancer dependencies across diverse cancer cell lines, which we further validated in animal models. Additionally, we mapped the subcellular localization of these te-lncRNAs, identifying over 30 cytosolic isoforms that proved essential when targeted by cytosol-localized Cas13d. Notably, a specific isoform of SNHG6, enriched in the endoplasmic reticulum, interacts with heat shock proteins to maintain cellular proteostasis. We also integrated functional and clinical data into the publicly accessible LongDEP Portal, providing a valuable resource for the research community. Our study offers a comprehensive characterization of te-lncRNAs, underscoring their oncogenic roles and therapeutic potential.
Article Details
Authors (22)
Eugenio Morelli
INOC - Istituto Nazionale Oncologico Candiolo, Candiolo, Italy
Anil Aktas Samur
Dana Farber Cancer Institution, Boston, Massachusetts, United States
Domenico Maisano
Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States
Claire Gao
Vanessa Katia Favasuli
Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy
Dimitrios Papaioannou
Giovanni De Nola
3Massachusetts Institute of Technology, David H. Koch Institute for Integrative Cancer Research, Boston, United States
Jonathan E Henninger
Whitehead Institute of Biomedical Research, Cambridge, Massachusetts, United States
Na Liu
Marcello Turi
Candiolo Cancer Institute FPO-IRCCS, Candiolo, Italy
Pietro Folino
1Dana Farber Cancer Institute, Harvard Medical School, Boston, United States
Laure Vreux
Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States
Michela Cumerlato
Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, United States
Liang Chen
Iannis Aifantis
Mariateresa Fulciniti
Dana Farber Cancer Institute, Boston, Massachusetts, United States
Kenneth C. Anderson
Abigail KR Lytton-Jean
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
Annamaria Gulla
Istituto nazionale Oncologico Candiolo INOC, Candiolo, Italy
Richard Young
Whitehead Institute, Cambridge, Massachusetts, United States
Mehmet K. Samur
Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts, United States
Nikhil C. Munshi