Co-targeting an AMPK--MAPK axis reprograms CAFs and suppresses PDAC

Yamamura, R.; Satoh, Y.; Fukuda, J.; Kimura, T.; Otsuka, T.; Sekiya, S.; Hirata, T.; Hata, S.; Sato, R.; Kamijo, C.; Moriguchi, T.; Kosuge, S.; Kato, T.; Urano, Y.; Hatanaka, K. C.; Tyakht, A. V.; Harada, K.; Kawamoto, Y.; Kawakubo, K.; Kuwatani, M.; Takeuchi, S.; Wada, M.; Asano, T.; Nakamura, T.; Jin, S.; Mitsuhashi, T.; Sueishi, F.; Yamagata, K.; Masamune, A.; Oshima, M.; Abe, T.; Shinohara, N.; Matsuno, Y.; Hatanaka, Y.; Tanaka, S.; Shimono, Y.; Matoba, K.; Ley, R. E.; Sakamoto, N.; Hirano, S.; Soga, T.; Fukuda, S.; Enomoto, A.; Sonoshita, M.

doi:10.64898/2026.03.16.711738

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bioRxiv · 10.64898/2026.03.16.711738

Co-targeting an AMPK--MAPK axis reprograms CAFs and suppresses PDAC

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a fatal cancer characterized by limited therapeutic options and a highly treatment-resistant tumor microenvironment. Beyond tumor-intrinsic genetic alterations, growing evidence indicates that host-microbiome interactions influence cancer progression through microbial metabolites. However, how microbiome-derived metabolites influence oncogenic signaling in PDAC remains unclear. Here, integrated profiling revealed a consistent reduction of the microbial metabolite acetic acid in fecal samples from treatment-naive patients with PDAC and in a genetically defined Drosophila model recapitulating key PDAC driver alterations. Acetic acid activates AMP-activated protein kinase, and pharmacological activation of this pathway together with inhibition of mitogen-activated protein kinase signaling suppressed tumor growth in fly and mouse models. Combined pathway targeting restored AMPK activity and suppressed cancer-associated fibroblast activation. These findings identify a microbiome-associated metabolic vulnerability in PDAC and suggest that coordinated targeting of metabolic and oncogenic signaling may restrain tumor progression and improve therapeutic strategies.

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Yamamura, R., Satoh, Y., Fukuda, J., Kimura, T., Otsuka, T., Sekiya, S., Hirata, T., Hata, S., Sato, R., Kamijo, C., Moriguchi, T., Kosuge, S., Kato, T., Urano, Y., Hatanaka, K. C., Tyakht, A. V., Harada, K., Kawamoto, Y., Kawakubo, K., Kuwatani, M., Takeuchi, S., Wada, M., Asano, T., Nakamura, T., Jin, S., Mitsuhashi, T., Sueishi, F., Yamagata, K., Masamune, A., Oshima, M., Abe, T., Shinohara, N., Matsuno, Y., Hatanaka, Y., Tanaka, S., Shimono, Y., Matoba, K., Ley, R. E., Sakamoto, N., Hirano, S., Soga, T., Fukuda, S., Enomoto, A., Sonoshita, M.. 2026-03-18. Co-targeting an AMPK--MAPK axis reprograms CAFs and suppresses PDAC. https://doi.org/10.64898/2026.03.16.711738

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