Kawakubo, K. | Search bioRxiv

bioRxiv2026

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

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.

cancer biology↗

bioRxiv2023

RNA G-quadruplexes forming scaffolds for alpha-synuclein aggregation lead to progressive neurodegeneration

Synucleinopathies, including Parkinsons disease, dementia with Lewy bodies, and multiple system atrophy, are triggered by the aggregation of -synuclein, leading to progressive neurodegeneration1,2,3,4,5,6,7,8. However, the intracellular mechanism of -synuclein aggregation remains unclear. Here we show that assembly of RNA G-quadruplexes forming scaffolds for -synuclein aggregation, contributing to neurodegeneration. Purified -synuclein binds RNA G-quadruplexes directly through the N-terminus. RNA G-quadruplex itself undergoes phase separation and assembly by Ca2+, accelerating the sol-gel phase transition of -synuclein. In -synuclein preformed fibrils-treated neurons, RNA G-quadruplexes assembly composed of synaptic mRNAs co-aggregates with -synuclein upon Ca2+ excess influx into cytoplasm, eliciting synaptic dysfunction. Forced assembly of RNA G-quadruplexes using an optogenetic approach evokes -synuclein aggregation, neuronal dysfunction and neurodegeneration. Administration of 5-aminolevulinic acid, a prodrug of protoporphyrin IX that prevents phase separation of RNA G-quadruplexes9, attenuating -synuclein aggregation, neurodegeneration, and progressive motor deficits in -synuclein preformed fibrils-injected synucleinopathy mice. Together, assembly of RNA G-quadruplexes due to dysregulation of intracellular Ca2+ homeostasis accelerates -synuclein phase transition and aggregation may contribute to pathogenesis of synucleinopathies.

molecular biology↗