| Autor: |
Johanna Zerbib, Marica Rosaria Ippolito, Yonatan Eliezer, Giuseppina De Feudis, Eli Reuveni, Anouk Savir Kadmon, Sara Martin, Sonia Viganò, Gil Leor, James Berstler, Julia Muenzner, Michael Mülleder, Emma M. Campagnolo, Eldad D. Shulman, Tiangen Chang, Carmela Rubolino, Kathrin Laue, Yael Cohen-Sharir, Simone Scorzoni, Silvia Taglietti, Alice Ratti, Chani Stossel, Talia Golan, Francesco Nicassio, Eytan Ruppin, Markus Ralser, Francisca Vazquez, Uri Ben-David, Stefano Santaguida |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Nature Communications, Vol 15, Iss 1, Pp 1-20 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-024-52176-x |
| Popis: |
Abstract 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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