L-pentahomoserine correlates with therapy outcome in esophageal cancer and promotes metabolic adaptations that support cell survival under nutrient-deprived conditions

Kelly, M. E.; Huerta-Uribe, A.; Cerna, M.; Hughes, K. B.; Ahmed, H.; Fernandes, M. F.; Rattigan, K. M.; Deshmukh, R.; Moura, D. S.; Arya, S.; May, S.; Müller, M.; Drake, T. M.; Georgakopoulou, A.; Bird, T. G.; Hisbergues, M.; Piessen, G.; Stewart, A. J.; Watson, A. J. B.; Sumpton, D.; Villar, V. H.; FREGAT Working Group,

doi:10.64898/2026.01.15.699640

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bioRxiv · 10.64898/2026.01.15.699640

L-pentahomoserine correlates with therapy outcome in esophageal cancer and promotes metabolic adaptations that support cell survival under nutrient-deprived conditions

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Abstract

Esophageal adenocarcinoma (EAC) is the sixth-leading cause of cancer-related death. Although pyrimidine analogue-based neoadjuvant and adjuvant therapies are widely used, patient responses remain variable. Emerging evidence indicates that bacteria-derived metabolites influence tumor biology and therapy outcomes. To identify non-canonical plasma metabolites linked to cancer biology, we performed correlation analyses between untargeted metabolomics profiles and overall survival. This approach revealed a bacterial metabolite called L-pentahomoserine, or L-2-amino-5-hydroxypentanoic acid (L-2A5HPA), to be positively associated with overall survival. Notably, L-2A5HPA promoted cell survival under nutrient limitation by redirecting glucose metabolism towards aspartate and pyrimidine biosynthesis. In vitro, L-2A5HPA uptake varied among cell lines and was controlled by stereospecific transporters. Furthermore, metabolic profiling in mouse models of liver cancer showed different levels of L-2A5HPA and a strong correlation with pyrimidine intermediates, dihydroorotate and orotate. The link between L-2A5HPA, pyrimidine nucleotide metabolism, and cell survival provides mechanistic insight into its association with patient outcome. Our findings position L-2A5HPA as a metabolite with potential to become a prognostic biomarker for EAC and underscores its role in metabolic adaptation under nutrient-deprived conditions.

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Kelly, M. E., Huerta-Uribe, A., Cerna, M., Hughes, K. B., Ahmed, H., Fernandes, M. F., Rattigan, K. M., Deshmukh, R., Moura, D. S., Arya, S., May, S., Müller, M., Drake, T. M., Georgakopoulou, A., Bird, T. G., Hisbergues, M., Piessen, G., Stewart, A. J., Watson, A. J. B., Sumpton, D., Villar, V. H., FREGAT Working Group,. 2026-01-15. L-pentahomoserine correlates with therapy outcome in esophageal cancer and promotes metabolic adaptations that support cell survival under nutrient-deprived conditions. https://doi.org/10.64898/2026.01.15.699640

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