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Toward a CRISPR-based mouse model of Vhl-deficient clear cell kidney cancer: Initial experience and lessons learned

  1. Author:
    Stransky, Laura A
    Gao, Wenhua
    Schmidt,Laura [ORCID]
    Bi, Kevin
    Ricketts, Christopher J
    Ramesh, Vijyendra
    James,Amy
    Difilippantonio,Simone
    Ileva,Lilia
    Kalen,Joseph
    Karim,Baktiar [ORCID]
    Jeon, Albert
    Morgan,Tamara
    Warner,Andrew
    Turan, Sevilay
    Unite,Joanne
    Tran,Bao
    Choudhari,Sulbha
    Zhao,Yongmei
    Linn, Douglas E
    Yun, Changhong
    Dhandapani, Sripriya
    Parab, Vaishali
    Pinheiro, Elaine M
    Morris,Nicole
    He, Lixia
    Vigeant, Sean M
    Pignon, Jean-Christophe
    Sticco-Ivins, Maura
    Signoretti, Sabina
    Van Allen, Eliezer M
    Linehan, W Marston [ORCID]
    Kaelin, William G [ORCID]

  2. Author Address

    Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215., Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892., Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702., Division of Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115., Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115., Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142., Animal Research Technical Support, Frederick National Laboratory for Cancer Research, Frederick, MD 21702., Small Animal Imaging Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702., Molecular Histopathology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD 21702., National Cancer Institute Center for Cancer Research, Sequencing Facility, Frederick National Laboratory for Cancer Research, Frederick, MD 21701., Advanced Biomedical and Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21701., Quantitative Biosciences, Merck & Co., Inc., Boston, MA 02115., Pharmacokinetics, Merck & Co., Inc., Boston, MA 02115., Pharmacokinetics, Merck & Co., Inc., South San Francisco, CA 94080., Discovery Oncology Merck & Co., Inc., Boston, MA 02115., Laboratory of Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702., Harvard Medical School, Boston, MA 02115., Department of Pathology, Brigham and Women 39;s Hospital, Boston, MA 02115., Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02115., HHMI, Chevy Chase, MD 20815.,
    1. Year: 2024
    2. Date: Oct 08
    3. Epub Date: 2024 10 04
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 121
    2. 41
    3. Pages: e2408549121
  4. Type of Article: Article
  5. Article Number: e2408549121
  1. Abstract:

    CRISPR is revolutionizing the ability to do somatic gene editing in mice for the purpose of creating new cancer models. Inactivation of the VHL tumor suppressor gene is the signature initiating event in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). Such tumors are usually driven by the excessive HIF2 activity that arises when the VHL gene product, pVHL, is defective. Given the pressing need for a robust immunocompetent mouse model of human ccRCC, we directly injected adenovirus-associated viruses (AAVs) encoding sgRNAs against VHL and other known/suspected ccRCC tumor suppressor genes into the kidneys of C57BL/6 mice under conditions where Cas9 was under the control of one of two different kidney-specific promoters (Cdh16 or Pax8) to induce kidney tumors. An AAV targeting Vhl, Pbrm1, Keap1, and Tsc1 reproducibly caused macroscopic ccRCCs that partially resembled human ccRCC tumors with respect to transcriptome and cell of origin and responded to a ccRCC standard-of-care agent, axitinib. Unfortunately, these tumors, like those produced by earlier genetically engineered mouse ccRCCs, are HIF2 independent.

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External Sources

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  2. DOI: 10.1073/pnas.2408549121
  3. PMID: 39365820

Library Notes

  1. Fiscal Year: FY2024-2025
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