biostudies-literatureDelanne-Cumenal MCanadian Government | Canadian Institutes of Health Research (CIHR)e2500632122https://www.ebi.ac.uk/biostudies/studies/S-EPMC12184428biostudies-literatureUnknown122(24)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 significantlProceedings of the National Academy of Sciences of the United States of AmericaNeuronal ALKAL2 and its ALK receptor contribute to the development of colitis-associated colorectal cancer.PMC12184428388441Hirota SDelanne-Cumenal MDefaye MAltier CDelanne-Cumenal AAlhassoun MSvendsen KAbdullah NSMager LAhmed MHo VSchlessinger JfalseNeuronal ALKAL2 and its ALK receptor contribute to the development of colitis-associated colorectal cancer.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 significantl2025-01-01T00:00:00Z2025 Jun2026-06-07T04:55:43.845Z2026-06-07T03:07:01.711ZS-EPMC121844284049318310.1073/pnas.2500632122