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

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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.