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In vivo CRISPR screening identifies geranylgeranyl diphosphate as a pancreatic cancer tumor growth dependency.
Kubota, Casie S; Myers, Stephanie L; Seppälä, Toni T; Burkhart, Richard A; Espenshade, Peter J.
Afiliación
  • Kubota CS; Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Myers SL; Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Molecular & Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Seppälä TT; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Burkhart RA; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Espenshade PJ; Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Giovanis Institute for Translational Cell Biology, Johns Hopkin
Mol Metab ; 85: 101964, 2024 Jul.
Article en En | MEDLINE | ID: mdl-38823776
ABSTRACT

OBJECTIVE:

Cancer cells must maintain lipid supplies for their proliferation and do so by upregulating lipogenic gene programs. The sterol regulatory element-binding proteins (SREBPs) act as modulators of lipid homeostasis by acting as transcriptional activators of genes required for fatty acid and cholesterol synthesis and uptake. SREBPs have been recognized as chemotherapeutic targets in multiple cancers, however it is not well understood which SREBP target genes are essential for tumorigenesis. In this study, we examined the requirement of SREBP target genes for pancreatic ductal adenocarcinoma (PDAC) tumor growth.

METHODS:

Here we constructed a custom CRISPR knockout library containing known SREBP target genes and performed in vitro 2D culture and in vivo orthotopic xenograft CRISPR screens using a patient-derived PDAC cell line. In vitro, we grew cells in medium supplemented with 10% fetal bovine serum (FBS) or 10% lipoprotein-deficient serum (LPDS) to examine differences in gene essentiality in different lipid environments. In vivo, we injected cells into the pancreata of nude mice and collected tumors after 4 weeks.

RESULTS:

We identified terpenoid backbone biosynthesis genes as essential for PDAC tumor development. Specifically, we identified the non-sterol isoprenoid product of the mevalonate pathway, geranylgeranyl diphosphate (GGPP), as an essential lipid for tumor growth. Mechanistically, we observed that restricting mevalonate pathway activity using statins and SREBP inhibitors synergistically induced apoptosis and caused disruptions in small G protein prenylation that have pleiotropic effects on cellular signaling pathways. Finally, we demonstrated that geranylgeranyl diphosphate synthase 1 (GGPS1) knockdown significantly reduces tumor burden in an orthotopic xenograft mouse model.

CONCLUSIONS:

These findings indicate that PDAC tumors selectively require GGPP over other lipids such as cholesterol and fatty acids and that this is a targetable vulnerability of pancreatic cancer cells.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Fosfatos de Poliisoprenilo / Proliferación Celular / Ratones Desnudos Límite: Animals / Humans Idioma: En Revista: Mol Metab Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Fosfatos de Poliisoprenilo / Proliferación Celular / Ratones Desnudos Límite: Animals / Humans Idioma: En Revista: Mol Metab Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania