Chromosome 8p engineering reveals increased metastatic potential targetable by patient-specific synthetic lethality in liver cancer

Thorben Huth, Emely C. Dreher, Steffen Lemke, Sarah Fritzsche, Raisatun N. Sugiyanto, Darko Castven, David Ibberson, Carsten Sticht, Eva Eiteneuer, Anna Jauch, Stefan Pusch, Thomas Albrecht, Benjamin Goeppert, Julián Candia, Xin Wei Wang, Junfang Ji, Jens U. Marquardt, Sven Nahnsen, Peter Schirmacher, Stephanie Roessler*

*Korrespondierende/r Autor/-in für diese Arbeit

Abstract

Large-scale chromosomal aberrations are prevalent in human cancer, but their function remains poorly understood. We established chromosome-engineered hepatocellular carcinoma cell lines using CRISPR-Cas9 genome editing. A 33-mega-base pair region on chromosome 8p (chr8p) was heterozygously deleted, mimicking a frequently observed chromosomal deletion. Using this isogenic model system, we delineated the functional consequences of chr8p loss and its impact on metastatic behavior and patient survival. We found that metastasisassociated genes on chr8p act in concert to induce an aggressive and invasive phenotype characteristic for chr8p-deleted tumors. Genome-wide CRISPR-Cas9 viability screening in isogenic chr8p-deleted cells served as a powerful tool to find previously unidentified synthetic lethal targets and vulnerabilities accompanying patient-specific chromosomal alterations. Using this target identification strategy, we showed that chr8p deletion sensitizes tumor cells to targeting of the reactive oxygen sanitizing enzyme Nudix hydrolase 17. Thus, chromosomal engineering allowed for the identification of novel synthetic lethalities specific to chr8p loss of heterozygosity.

OriginalspracheEnglisch
Aufsatznummereadh1442
ZeitschriftScience Advances
Jahrgang9
Ausgabenummer51
DOIs
PublikationsstatusVeröffentlicht - 12.2023

Strategische Forschungsbereiche und Zentren

  • Profilbereich: Lübeck Integrated Oncology Network (LION)
  • Zentren: Universitäres Cancer Center Schleswig-Holstein (UCCSH)

DFG-Fachsystematik

  • 205-14 Hämatologie, Onkologie
  • 201-05 Allgemeine Genetik und funktionelle Genomforschung

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