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Endosomal trafficking bypassed by RAB5B-CD109 interplay promotes axonogenesis in KRAS-mutant pancreatic cancer

ABSTRACT: Perineural invasion (PNI) represents a unique biological feature causing the poor prognosis of pancreatic ductal adenocarcinoma (PDAC), especially with KRAS mutation. Extracellular vesicle (EVs)-packaged circRNAs function as essential mediator for tumor microenviroment communication to trigger PDAC cells invading into the surrounding regions and lead to distant metastasis. However, the regulatory mechanism of exosomal circRNA in PNI of KRAS-mutated PDAC has not been elucidated. Herein, we identified an KRASG12D-mutation responsive exosomal circRNA-circPNIT, which was positively correlated with PNI of PDAC. Functionally, KRASG12D PDAC-derived EV-packaged circPNIT promotes axonogenesis and PNI both in vitro and in vivo. Mechanistically, circPNIT-mediated Rab5B-CD109 interplay bypassed traditional endosomal trafficking to anchor Rab5B in the lipid rafts of multivescular body and fostered the secretion of circPNIT as a cargo of CD109+EVs. Subsequently, CD109+EVs achieved the targeted delivery of circPNIT to neurons by recognizing their surface receptor TRPV1 and facilitated DSCAML1 transcription-induced axonogenesis, which in turn enhanced the PNI by activating GFRα1/RET pathway. Importantly, we established an engineered si-cirPNIT-loaded CD109+EVs to dramatically inhibit PNI of PDAC in a KRASG12D/+ Trp53R172H/+ Pdx-1-Cre mice model. Collectively, Our findings highlight the mechanism underlying EV-packaed circRNA mediating PNI of KRAS mutated-PDAC dependent of a Rab5B endosomal bypass, supporting circPINT as an effective target for the treatment of neuro-metastatic PDAC

ORGANISM(S): Mus musculus

PROVIDER: GSE251916 | GEO | 2024/12/27

REPOSITORIES: GEO

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Project description:The maintenance of advanced malignancies relies on continued activity of driver oncogenes, although their rate-limiting role is highly context-dependent with respect to tumor types and associated genetic alterations. Oncogenic Kras mutation is the signature event in human pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible KrasG12D-driven p53 mutant PDAC mouse model establishes that advanced PDAC remains strictly dependent on continued KrasG12D expression and that KrasG12D serves a vital role in the control of tumor metabolism, through stimulation of glucose uptake and channeling of glucose intermediates through the hexosamine biosynthesis pathway (HBP) and the pentose phosphate pathway (PPP). Notably, these studies reveal that oncogenic Kras regulates ribose biogenesis. Unlike canonical models of PPP-mediated ribose biogenesis, we demonstrate that oncogenic Kras drives intermediates from enhanced glycolytic flux into the non-oxidative arm of the PPP, thereby decoupling ribose biogenesis from NADPNADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in Kras-driven PDAC. Primary pancreatic tumor lines were established from p48Cre tetO_LKrasG12D ROSA_rtTAL+ p53L+ mice. Five independent tumor lines (iKras1-5) were used for pancreatic injection into nude mice to generate orthotopic tumors. The mice were kept on doxycycline for 2 weeks until obvious tumor formation. Half of the animals were pulled off doxycycline for 24 hours. Tumors with over 75% cellularity were collected for total RNA prepartion. For in vitro expression profiles, the same five tumor lines were cultured in the presence or absence of doxycycline for 24 hours and total cellular RNA was prepared. For control samples, two independent tumor lines from LSL-KrasG12D p53L+ tumors were cultured in the presence or absence of doxycycline for 24 hours and total cellular RNA was prepared.

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Endosomal trafficking bypassed by RAB5B-CD109 interplay promotes axonogenesis in KRAS-mutant pancreatic cancer

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