PPAR-delta acts as a metabolic master checkpoint for metastasis in pancreatic cancer

Parejo-Alonso, B.; Barneda, D.; Trabulo, S. M.; Courtois, S.; Compte-Sancerni, S.; Ruiz-Canas, L.; Zheng, Q.; Tang, J.; Chen, M.; Guo, Z.; Schmitz, U.; Irun, P.; Penin-Peyta, L.; Crusz, S. M.; Cano-Galiano, A.; Lopez-Escalona, S.; Jagust, P.; Espiau-Romera, P.; Yuneva, M.; Lin, M.-L.; Lanas, A.; Sainz, B.; Heeschen, C.; Sancho, P.

doi:10.1101/2021.11.15.468579

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bioRxiv · 10.1101/2021.11.15.468579

PPAR-delta acts as a metabolic master checkpoint for metastasis in pancreatic cancer

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Abstract

SO_SCPLOWUMMARYC_SCPLOWIn pancreatic cancer, emerging evidence suggests that PPAR-{delta} overexpression is associated with tumor progression and metastasis, but a mechanistic link is still missing. Here we now show that PPAR-{delta} acts as the integrating upstream regulator for the metabolic rewiring, which is preceding the subsequent initiation of an invasive/metastatic program. Specifically, paracrine and metabolic cues regularly found in the metastasis-promoting tumor stroma consistently enhance, via induction of PPAR-{delta} activity, the glycolytic capacity and reserve of pancreatic cancer cells, respectively, accompanied by decreased mitochondrial oxygen consumption. Consequently, genetic or pharmacological inhibition of PPAR-{delta} results in reduced invasiveness and metastasis. Mechanistically, PPAR-{delta} acts by shifting the MYC/PGC1A balance towards MYC, enhancing metabolic plasticity. Targeting MYC similarly prevents the metabolic switch and subsequent initiation of invasiveness. Therefore, our data demonstrate that PPAR-{delta} is a key initiator for the metabolic reprogramming in pancreatic cancer, thereby acting as a checkpoint for the phenotypic change towards invasiveness. These findings provide compelling evidence for a novel treatment strategy to combat pancreatic cancer progression.

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Parejo-Alonso, B., Barneda, D., Trabulo, S. M., Courtois, S., Compte-Sancerni, S., Ruiz-Canas, L., Zheng, Q., Tang, J., Chen, M., Guo, Z., Schmitz, U., Irun, P., Penin-Peyta, L., Crusz, S. M., Cano-Galiano, A., Lopez-Escalona, S., Jagust, P., Espiau-Romera, P., Yuneva, M., Lin, M.-L., Lanas, A., Sainz, B., Heeschen, C., Sancho, P.. 2021-11-16. PPAR-delta acts as a metabolic master checkpoint for metastasis in pancreatic cancer. https://doi.org/10.1101/2021.11.15.468579

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