Ribosome transfer via tunnelling nanotubes rescues protein synthesis in pancreatic cancer cells

Abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/597772v3_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@1f66716org.highwire.dtl.DTLVardef@1ea14eeorg.highwire.dtl.DTLVardef@1044da2org.highwire.dtl.DTLVardef@184d8a3_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG Key pointsO_LIpancreatic tumour cell lines and cells from patient biopsies form tunnelling nanotubes in 2D culture C_LIO_LIformation of tunnelling nanotubes is promoted by gemcitabine C_LIO_LIpolyadenylated mRNAs, ribosomal components and assembled ribosomes are present in tunnelling nanotubes C_LIO_LIribosomes and their components are transferred via nanotubes to acceptor cells C_LIO_LIsilencing of ribosomal proteins S6 and L24 reduces the number of assembled ribosomes C_LIO_LIglobal protein synthesis and number of ribosomes in pancreatic cancer cells with silenced ribosomal proteins increases when co-cultured with translationally unimpaired cells C_LI BackgroundPancreatic 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. ResultsPDAC 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. ConclusionsPDAC 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.