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Publications

Journal Article Ppublish

PubMed: 40493183 DOI: 10.1073/pnas.2500632122

Neuronal ALKAL2 and its ALK receptor contribute to the development of colitis-associated colorectal cancer.

Proc Natl Acad Sci U S A 122(24):e2500632122

Authors: Mélissa Delanne-Cuménal, Manon Defaye, Améline Delanne-Cuménal, Mansoor Ahmed, Valerie Ho, Nasser S Abdullah, Mohamad Alhassoun, Kristofer Svendsen, Lukas Mager, Joseph Schlessinger, Simon Hirota, Christophe Altier

Affiliations

  • Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N4N1, Canada. Department of Physiology and Pharmacology, Inflammation Research Network-Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N4N1, Canada. Department of Physiology and Pharmacology, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N4N1, Canada. Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N4N1, Canada.
  • Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N4N1, Canada.
  • Department of Physiology and Pharmacology, Inflammation Research Network-Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N4N1, Canada.
  • Department of Physiology and Pharmacology, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N4N1, Canada.
  • Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N4N1, Canada.
  • Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N4N1, Canada. Department of Physiology and Pharmacology, Inflammation Research Network-Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N4N1, Canada. Department of Physiology and Pharmacology, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N4N1, Canada. Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB T2N4N1, Canada.
  • Department of Pharmacology, Yale University School of Medicine, New Haven, CT 0620.
  • Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N4N1, Canada. Department of Physiology and Pharmacology, Inflammation Research Network-Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N4N1, Canada. Department of Physiology and Pharmacology, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N4N1, Canada.
  • Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N4N1, Canada. Institute of Internal Medizine I, University Hospital Tübingen, Tübingen 72076, Germany.
  • Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB T2N4N1, Canada.

Abstract

Tumor-infiltrating nerves play a critical role in cancer progression and treatment resistance. Our recent work identified ALKAL2, a ligand for the Anaplastic Lymphoma Kinase (ALK) receptor, as a key mediator of inflammatory pain, with its expression significantly elevated in TRPV1+ sensory neurons during inflammation. Here, we explored the regulation of neuronal ALKAL2 in a colitis-associated colorectal cancer (CAC) model. We found that neuronal ALKAL2 is upregulated at early stages of CAC, which in turn activates ALK signaling in the colonic mucosa. Notably, treating mouse colonic organoids with exogenous ALKAL2 triggered ALK activation. In vivo, mice treated with the ALK inhibitor lorlatinib at the onset of colitis exhibited a remarkable 90% reduction in tumor burden without significantly affecting overall inflammation. Moreover, activating TRPV1+ neurons using DREADD technology exacerbated tumor growth, whereas silencing these neurons significantly reduced it. These findings reveal that TRPV1+ nociceptors drive CAC progression via the ALKAL2/ALK pathway.

MeSH

Colitis, Neurons, Neoplasms, Colitis-Associated Neoplasms, Signal Transduction, Colorectal Neoplasms