Sex of central neurons controls intestinal niche signalling to drive sex differences in stem cell activity and cancer susceptibility
Abstract
Sex differences in cancers arising in non-reproductive organs are widespread. While sex hormones and the intrinsic sexual identity of cancer cells are well-established contributors, it is unknown whether other mechanisms are involved. Here, we reveal an unexpected source of sex-biased cancer vulnerability in a Drosophila model of tumorigenesis. By combining genetically induced tumours with tissue- and cell type-specific sex reversals, we show that sex differences in oncogenesis can arise independently of both gonadal hormone signalling and the sexual identity of tumour cells themselves. Unexpectedly, we find that a sexually dimorphic neuronal circuit, classically associated with mating behaviour, is both necessary and sufficient to drive sex-biased intestinal tumorigenesis. The sex of these gut-innervating neurons controls tumour growth by stimulating local production of an insulin-like growth factor in the visceral muscles, a key component of the intestinal stem cell niche. Our findings reveal a previously unrecognised class of tumour-promoting input: the sex of central neurons can reprogram peripheral tumour-supportive environments. Under physiological conditions, this brain–gut pathway also modulates stem cell activity and organ size in a sex-specific manner to promote reproduction. Our work opens a new line of inquiry into how neuronal sex, particularly within the brain–gut axis, shapes physiology and disease, a field still predominantly studied in a male-only context.
Related
- PZLS-1/PDZRN controls muscle polarity downstream of Wnt-Ror-Dvl signalling in C. elegans muscles
- Cyclic di-AMP signalling affects cell division and penicillin susceptibility in Streptococcus pneumoniae.
- NKCC1 coordinates SPAK–PP1 signalling to regulate KCC2 membrane stability and seizure susceptibility
- Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress
- Intestinal lipid metabolism controls molecular and behavioral immunity through NHR-68 and gut–brain signaling in Caenorhabditis elegans
BibTeX
@article{clot2026central,
title = {{Sex of central neurons controls intestinal niche signalling to drive sex differences in stem cell activity and cancer susceptibility}},
author = {Charlène Clot and Rénald Delanoue and Laura Helena Lavocat and Sélia Namouchi and Chloé Hérault and Bruno Hudry},
journal = {Nature Communications},
year = {2026},
month = aug,
doi = {10.1038/s41467-026-76998-z},
url = {https://hal.science/hal-05836846v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Sex of central neurons controls intestinal niche signalling to drive sex differences in stem cell activity and cancer susceptibility
AU - Charlène Clot
AU - Rénald Delanoue
AU - Laura Helena Lavocat
AU - Sélia Namouchi
AU - Chloé Hérault
AU - Bruno Hudry
PY - 2026
DA - 2026/08/22
JO - Nature Communications
DO - 10.1038/s41467-026-76998-z
UR - https://hal.science/hal-05836846v1
AB - Sex differences in cancers arising in non-reproductive organs are widespread. While sex hormones and the intrinsic sexual identity of cancer cells are well-established contributors, it is unknown whether other mechanisms are involved. Here, we reveal an unexpected source of sex-biased cancer vulnerability in a Drosophila model of tumorigenesis. By combining genetically induced tumours with tissue- and cell type-specific sex reversals, we show that sex differences in oncogenesis can arise independently of both gonadal hormone signalling and the sexual identity of tumour cells themselves. Unexpectedly, we find that a sexually dimorphic neuronal circuit, classically associated with mating behaviour, is both necessary and sufficient to drive sex-biased intestinal tumorigenesis. The sex of these gut-innervating neurons controls tumour growth by stimulating local production of an insulin-like growth factor in the visceral muscles, a key component of the intestinal stem cell niche. Our findings reveal a previously unrecognised class of tumour-promoting input: the sex of central neurons can reprogram peripheral tumour-supportive environments. Under physiological conditions, this brain–gut pathway also modulates stem cell activity and organ size in a sex-specific manner to promote reproduction. Our work opens a new line of inquiry into how neuronal sex, particularly within the brain–gut axis, shapes physiology and disease, a field still predominantly studied in a male-only context.
SN - 2041-1723
SN - 2041-1723
ER -