Chromosome 8p engineering reveals increased metastatic potential targetable by patient-specific synthetic lethality in liver cancer-Reference-Cited by-同舟云学术

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

Published:2023-12-22 Issue:51 Volume:9 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Huth Thorben¹^ORCID,Dreher Emely C.¹,Lemke Steffen²³⁴⁵^ORCID,Fritzsche Sarah¹,Sugiyanto Raisatun N.¹^ORCID,Castven Darko⁶^ORCID,Ibberson David⁷,Sticht Carsten⁸^ORCID,Eiteneuer Eva¹,Jauch Anna⁹,Pusch Stefan¹⁰¹¹^ORCID,Albrecht Thomas¹^ORCID,Goeppert Benjamin¹¹²¹³^ORCID,Candia Julián¹⁴^ORCID,Wang Xin Wei¹⁵^ORCID,Ji Junfang¹⁶,Marquardt Jens U.⁶,Nahnsen Sven²⁵¹⁷¹⁸,Schirmacher Peter¹^ORCID,Roessler Stephanie¹^ORCID

Affiliation:

1. Heidelberg University, Medical Faculty, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.

2. Quantitative Biology Center (QBiC), University of Tübingen, 72076 Tübingen, Germany.

3. Department of Peptide-based Immunotherapy, University and University Hospital Tübingen, 72076 Tübingen, Germany.

4. Institute for Cell Biology, Department of Immunology, University of Tübingen, 72076 Tübingen, Germany.

5. Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, 72076 Tübingen, Germany.

6. Department of Medicine I, University Medical Center Schleswig Holstein, 23538 Lübeck, Germany.

7. Deep Sequencing Core Facility, CellNetworks Excellence Cluster, Heidelberg University, 69120 Heidelberg, Germany.

8. NGS Core Facility, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.

9. Institute of Human Genetics, Heidelberg University, 69120 Heidelberg, Germany.

10. Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.

11. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

12. Institute of Tissue Medicine and Pathology, University of Bern, 3008 Bern, Switzerland.

13. Institute of Pathology and Neuropathology, RKH Klinikum Ludwigsburg, 71640 Ludwigsburg, Germany.

14. Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.

15. Laboratory of Human Carcinogenesis and Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

16. The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.

17. Biomedical Data Science, Department of Computer Science, University of Tübingen, 72076 Tübingen, Germany.

18. The M3 Research Center, University of Tübingen, 72076 Tübingen, Germany.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adh1442

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