Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage
Aneuploidy is a hallmark of human cancer, yet the molecular mechanisms to cope with aneuploidy-induced cellular stresses remain largely unknown. Here, we induce chromosome mis-segregation in non-transformed RPE1-hTERT cells and derive multiple stable clones with various degrees of aneuploidy. We perform a systematic genomic, transcriptomic and proteomic profiling of 6 isogenic clones, using whole-exome DNA, mRNA and miRNA sequencing, as well as proteomics. Concomitantly, we functionally interrogate their cellular vulnerabilities, using genome-wide CRISPR/Cas9 and large-scale drug screens. Aneuploid clones activate the DNA damage response and are more resistant to further DNA damage induction. Aneuploid cells also exhibit elevated RAF/MEK/ERK pathway activity and are more sensitive to clinically-relevant drugs targeting this pathway, and in particular to CRAF inhibition. Importantly, CRAF and MEK inhibition sensitize aneuploid cells to DNA damage-inducing chemotherapies and to PARP inhibitors. We validate these results in human cancer cell lines. Moreover, resistance of cancer patients to olaparib is associated with high levels of RAF/MEK/ERK signaling, specifically in highly-aneuploid tumors. Overall, our study provides a comprehensive resource for genetically-matched karyotypically-stable cells of various aneuploidy states, and reveals a therapeutically-relevant cellular dependency of aneuploid cells.
Authors
- Johanna Zerbib
- Giuseppina De Feudis (ORCID: https://orcid.org/0000-0002-5948-878X)
- Carmela Rubolino
- Sonia Viganò (ORCID: https://orcid.org/0000-0003-0437-0087)
- Marica Rosaria Ippolito (ORCID: https://orcid.org/0000-0001-7310-1871)
- Uri Ben‐David (ORCID: https://orcid.org/0000-0001-7098-2378)
- Eldad David Shulman (ORCID: https://orcid.org/0000-0002-1859-8819)
- Stefano Santaguida (ORCID: https://orcid.org/0000-0002-1501-6190)
- Francisca Vázquez (ORCID: https://orcid.org/0000-0002-2857-4685)
- Julia Muenzner (ORCID: https://orcid.org/0000-0002-5402-5890)
- Yael Cohen‐Sharir
- Sara L. Martin (ORCID: https://orcid.org/0000-0003-2055-6498)
- Francesco Nicassio (ORCID: https://orcid.org/0000-0002-5954-5318)
- Kathrin Laue
- Eytan Ruppin (ORCID: https://orcid.org/0000-0002-7862-3940)
- Anouk Savir Kadmon
- Eli Reuveni (ORCID: https://orcid.org/0009-0000-2899-0593)
- Michael Mülleder (ORCID: https://orcid.org/0000-0001-9792-3861)
- Tiangen Chang (ORCID: https://orcid.org/0000-0003-1485-1992)
- Markus Ralser (ORCID: https://orcid.org/0000-0001-9535-7413)
- Gil Leor (ORCID: https://orcid.org/0000-0003-2225-5744)
- Chani Stossel (ORCID: https://orcid.org/0000-0002-4158-5549)
- Talia Golan (ORCID: https://orcid.org/0000-0001-5939-7012)
- Yonatan Eliezer (ORCID: https://orcid.org/0009-0002-0515-7579)
- Silvia Taglietti (ORCID: https://orcid.org/0009-0007-8837-1648)
- James Berstler (ORCID: https://orcid.org/0000-0003-2545-7405)
- Simone Scorzoni (ORCID: https://orcid.org/0000-0003-2046-2678)
- Emma M. Campagnolo (ORCID: https://orcid.org/0009-0009-0031-5241)
- Adele Ratti
Institutions
- Broad Institute (US)
- National Institutes of Health (US)
- Tel Aviv University (IL)
- University of Milan (IT)
- Sheba Medical Center (IL)
- University of Oxford (GB)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- National Cancer Institute (US)
- Max Planck Institute for Molecular Genetics (DE)
- Center for Cancer Research (US)
- Center for Genomic Science (IT)
- European Institute of Oncology (IT)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-09
- DOI
- https://doi.org/10.1038/s41467-024-52176-x
- Citations
- 28
- Primary Topic
- MicroRNA in disease regulation
- Type
- article
- Field-Weighted Citation Impact
- 7.41