Post-fast refeeding enhances intestinal stem cell-mediated regeneration and tumourigenesis through mTORC1-dependent polyamine synthesis

  • Res Sq. 2023 Jan 10:rs.3.rs-2320717. doi: 10.21203/rs.3.rs-2320717/v1.
Shinya Imada  1 ,  Heaji Shin  1 ,  Saleh Khawaled  1 ,  Sven W Meckelmann  2 ,  Charles A Whittaker  3 ,  Renan Oliveira Corrêa  1  4 ,  Dikshant Pradhan  3 ,  Gizem Calibasi-Kocal  1  5 ,  Luiza Martins Nascentes Melo  6 ,  Gabriele Allies  6 ,  Pia Wittenhofer  2 ,  Oliver J Schmitz  2 ,  Jatin Roper  7 ,  Marco Aurelio Ramirez Vinolo  4 ,  Chia-Wei Cheng  1  8 ,  Alpaslan Tasdogan  6 ,  Ömer H Yilmaz  9
Affiliations
  • 1. Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, MIT, Cambridge, MA 02139, USA.
  • 2. Applied Analytical Chemistry, University of Duisburg-Essen, 45141 Essen, Germany.
  • 3. Barbara K. Ostrom (1978) Bioinformatics and Computing Core Facility, Swanson Biotechnology Center, Koch Institute at the MIT, Cambridge, MA 02139, USA.
  • 4. Laboratory of Immunoinflammation, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, SP 13083-862, Brazil.
  • 5. Department of Translational Oncology, Institute of Oncology, Dokuz Eylul University, Izmir-Turkey, Turkey.
  • 6. Department of Dermatology, University Hospital Essen & German Cancer Consortium, Partner Site, Essen, 45147, Germany.
  • 7. Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, NC 27710, USA.
  • 8. Columbia Stem Cell Initiative, Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 9. Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, MIT, Cambridge, MA 02139, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
PMID: 36711807 DOI: 10.21203/rs.3.rs-2320717/v1
Abstract

For more than a century, fasting regimens have improved health, lifespan, and tissue regeneration in diverse organisms, including humans. However, how fasting and post-fast refeeding impact adult stem cells and tumour formation has yet to be explored in depth. Here, we demonstrate that post-fast refeeding increases intestinal stem cell (ISC) proliferation and tumour formation: Post-fast refeeding augments the regenerative capacity of Lgr5+ intestinal stem cells (ISCs), and loss of the tumour suppressor APC in ISCs under post-fast refeeding leads to a higher tumour incidence in the small intestine and colon than in the fasted or ad libitum (AL) fed states. This demonstrates that post-fast refeeding is a distinct state. Mechanistically, we discovered that robust induction of mTORC1 in post-fast-refed ISCs increases protein synthesis via polyamine metabolism to drive these changes, as inhibition of mTORC1, polyamine metabolite production, or protein synthesis abrogates the regenerative or tumourigenic effects of post-fast refeeding. Thus, fast-refeeding cycles must be carefully considered when planning diet-based strategies for regeneration without increasing Cancer risk, as post-fast refeeding leads to a burst not only in stem cell-driven regeneration but also in tumourigenicity.

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