Abstract Figure
Graphical abstract
Key points
pancreatic tumour cell lines and cells from patient biopsies form tunnelling nanotubes in 2D culture
formation of tunnelling nanotubes is promoted by gemcitabine
polyadenylated mRNAs, ribosomal components and assembled ribosomes are present in tunnelling nanotubes
ribosomes and their components are transferred via nanotubes to acceptor cells
silencing of ribosomal proteins S6 and L24 reduces the number of assembled ribosomes
global protein synthesis and number of ribosomes in pancreatic cancer cells with silenced ribosomal proteins increases when co-cultured with translationally unimpaired cells
Background
Pancreatic ductal adenocarcinoma (PDAC) is considered as one of the deadliest types of cancer. Tunnelling nanotubes (TNTs) are thin, membranous, intercellular communication structures observed in normal and cancer cells, where they mediate the exchange of intracellular material and promote cell fitness, cancer spread and treatment resistance.
Results
PDAC cells increase the formation of TNTs upon exposure to gemcitabine. In the PANC-1 cell line and in tumour explants from patients, we observe polyadenylated mRNA, 5.8S rRNA, ribosomal proteins and assembled 80S ribosomes within the TNTs. Using HaloTag-labelled small ribosomal subunit component RPS9 we demonstrate the transport of ribosomes via TNTs into acceptor cells. Downregulation of ribosomal proteins S6 and L24 decreases the number of assembled ribosomes and the global protein translation in PDAC cells, while a co-culture with translationally unimpaired cells partially restores protein synthesis in cells with impaired protein translation.
Conclusions
PDAC cells can exchange components of the protein translation machinery and mRNA. The intercellular transfer of these components causes a partial restoration of protein translation in cells with impaired protein synthesis, which may contribute to the resilience of pancreatic cancer cells, highlighting the potential of targeting TNT dynamics as a therapeutic approach for PDAC.