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Chromosome 8p engineering reveals increased metastatic potential targetable by patient-specific synthetic lethality in liver cancer.
Huth, Thorben; Dreher, Emely C; Lemke, Steffen; Fritzsche, Sarah; Sugiyanto, Raisatun N; Castven, Darko; Ibberson, David; Sticht, Carsten; Eiteneuer, Eva; Jauch, Anna; Pusch, Stefan; Albrecht, Thomas; Goeppert, Benjamin; Candia, Julián; Wang, Xin Wei; Ji, Junfang; Marquardt, Jens U; Nahnsen, Sven; Schirmacher, Peter; Roessler, Stephanie.
Afiliação
  • Huth T; Heidelberg University, Medical Faculty, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
  • Dreher EC; Heidelberg University, Medical Faculty, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
  • Lemke S; Quantitative Biology Center (QBiC), University of Tübingen, 72076 Tübingen, Germany.
  • Fritzsche S; Department of Peptide-based Immunotherapy, University and University Hospital Tübingen, 72076 Tübingen, Germany.
  • Sugiyanto RN; Institute for Cell Biology, Department of Immunology, University of Tübingen, 72076 Tübingen, Germany.
  • Castven D; Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, 72076 Tübingen, Germany.
  • Ibberson D; Heidelberg University, Medical Faculty, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
  • Sticht C; Heidelberg University, Medical Faculty, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
  • Eiteneuer E; Department of Medicine I, University Medical Center Schleswig Holstein, 23538 Lübeck, Germany.
  • Jauch A; Deep Sequencing Core Facility, CellNetworks Excellence Cluster, Heidelberg University, 69120 Heidelberg, Germany.
  • Pusch S; NGS Core Facility, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
  • Albrecht T; Heidelberg University, Medical Faculty, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
  • Goeppert B; Institute of Human Genetics, Heidelberg University, 69120 Heidelberg, Germany.
  • Candia J; Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
  • Wang XW; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • Ji J; Heidelberg University, Medical Faculty, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
  • Marquardt JU; Heidelberg University, Medical Faculty, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
  • Nahnsen S; Institute of Tissue Medicine and Pathology, University of Bern, 3008 Bern, Switzerland.
  • Schirmacher P; Institute of Pathology and Neuropathology, RKH Klinikum Ludwigsburg, 71640 Ludwigsburg, Germany.
  • Roessler S; Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Sci Adv ; 9(51): eadh1442, 2023 Dec 22.
Article em En | MEDLINE | ID: mdl-38134284
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 metastasis-associated 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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Mutações Sintéticas Letais / Neoplasias Hepáticas Limite: Humans Idioma: En Revista: Sci Adv Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Mutações Sintéticas Letais / Neoplasias Hepáticas Limite: Humans Idioma: En Revista: Sci Adv Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Alemanha