2. Academic Validation
  3. Intestinal Apc-inactivation induces HSP25 dependency

Intestinal Apc-inactivation induces HSP25 dependency

  • EMBO Mol Med. 2022 Nov 2;e16194. doi: 10.15252/emmm.202216194.
Sanne M van Neerven # 1 2 3 4,  Wouter L Smit # 3 5,  Milou S van Driel 1 2 3 4,  Vaishali Kakkar 1 2 3 4,  Nina E de Groot 1 2 3 4,  Lisanne E Nijman 1 2 3 4,  Clara C Elbers 1 2 3 4,  Nicolas Léveillé 1 2 3 4,  Jarom Heijmans # 3 5 6,  Louis Vermeulen # 1 2 3 4
Affiliations

Affiliations

  • 1 Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.
  • 2 Cancer Center Amsterdam, Amsterdam, The Netherlands.
  • 3 Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
  • 4 Oncode Institute, Amsterdam, The Netherlands.
  • 5 Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.
  • 6 Department of Internal Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.
  • # Contributed equally.
PMID: 36321561 DOI: 10.15252/emmm.202216194
Abstract

The majority of colorectal cancers (CRCs) present with early mutations in tumor suppressor gene APC. APC mutations result in oncogenic activation of the Wnt pathway, which is associated with hyperproliferation, cytoskeletal remodeling, and a global increase in mRNA translation. To compensate for the increased biosynthetic demand, Cancer cells critically depend on protein chaperones to maintain proteostasis, although their function in CRC remains largely unexplored. In order to investigate the role of molecular chaperones in driving CRC initiation, we captured the transcriptomic profiles of murine wild type and Apc-mutant organoids during active transformation. We discovered a strong transcriptional upregulation of Hspb1, which encodes small heat shock protein 25 (HSP25). We reveal an indispensable role for HSP25 in facilitating Apc-driven transformation, using both in vitro Organoid cultures and mouse models, and demonstrate that chemical inhibition of HSP25 using brivudine reduces the development of premalignant adenomas. These findings uncover a hitherto unknown vulnerability in intestinal transformation that could be exploited for the development of chemopreventive strategies in high-risk individuals.

Keywords

Apc mutations; Wnt signaling; colorectal cancer; heat shock proteins; intestinal stem cells.

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