MET functions in tumour progression and therapy resistance are repressed by intronic polyadenylation

Boldina, G.; Vallejos, M.; Allard, D.; Cadix, M.; Labbe, C.; Vacher, S.; Hemmingsson, O.; Gestraud, P.; Teissandier, A.; Martineau, S.; Auboeuf, D.; Andre, F.; Kamal, M.; Servant, N.; Bieche, I.; Dutertre, M.; Robert, C.; Vagner, S.

doi:10.1101/2023.08.09.552237

bioRxiv · 10.1101/2023.08.09.552237

MET functions in tumour progression and therapy resistance are repressed by intronic polyadenylation

Boldina, G.·Vallejos, M.·Allard, D.·Cadix, M.·Labbe, C.·Vacher, S.·Hemmingsson, O.·Gestraud, P.·Teissandier, A.·Martineau, S.·Auboeuf, D.·Andre, F.·Kamal, M.·Servant, N.·Bieche, I.·Dutertre, M.·Robert, C.·Vagner, S.

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Abstract

Intronic polyadenylation (IPA) leads to the production of transcript isoforms with alternative last exons in thousands of mammalian genes. Widespread regulation of IPA isoforms was observed during oncogenic transformation and in tumours versus healthy tissues, and several IPA isoforms were involved in oncogenesis. However, little is known about the potential involvement of IPA in tumour progression, such as cancer cell invasiveness and metastasis, and in resistance to anticancer therapies. Here, we show that an IPA isoform of MET (short MET) whose production is inhibited by U1 snRNP (U1), an essential ribonucleoprotein complex that recognizes the 5 exon-intron junction of pre-mRNA, is associated with better prognosis in breast cancer. Induction of the short MET isoform, using a steric-blocking antisense oligonucleotide targeting the U1 binding site in the vicinity of the short MET alternative polyadenylation site, antagonizes cell invasiveness. U1 blockade with an antisense oligonucleotide targeting the U1 snRNA also decreases breast cancer cell invasiveness, in both human and mouse cancer cell models, and this effect involves IPA induction in MET and several genes belonging to the RAS/RAF/MAPK signalling pathway. Finally, short MET relieves melanoma cell resistance to MAPK cascade-targeted therapy in vitro and in vivo. IPA isoform levels of MET and a few other genes (mTOR, EGFR and CTNNA1) help predict such resistance in patients. Altogether, our findings provide evidence for a role of IPA in both cancer cell invasiveness and resistance to therapy. This suggests that IPA isoforms can be exploited as biomarkers and therapeutic targets to combat tumour progression.

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Boldina, G., Vallejos, M., Allard, D., Cadix, M., Labbe, C., Vacher, S., Hemmingsson, O., Gestraud, P., Teissandier, A., Martineau, S., Auboeuf, D., Andre, F., Kamal, M., Servant, N., Bieche, I., Dutertre, M., Robert, C., Vagner, S.. 2023-08-09. MET functions in tumour progression and therapy resistance are repressed by intronic polyadenylation. https://doi.org/10.1101/2023.08.09.552237

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