TY - JOUR
T1 - Splicing modulation as novel therapeutic strategy against diffuse malignant peritoneal mesothelioma
AU - Sciarrillo, Rocco
AU - Wojtuszkiewicz, Anna
AU - El Hassouni, Btissame
AU - Funel, Niccola
AU - Gandellini, Paolo
AU - Lagerweij, Tonny
AU - Buonamici, Silvia
AU - Blijlevens, Maxime
AU - Zeeuw van der Laan, Eveline A
AU - Zaffaroni, Nadia
AU - Deraco, Marcello
AU - Kusamura, Shigeki
AU - Würdinger, Tom
AU - Peters, Godefridus J
AU - Molthoff, Carla F M
AU - Jansen, Gerrit
AU - Kaspers, Gertjan J L
AU - Cloos, Jacqueline
AU - Giovannetti, Elisa
PY - 2019/1
Y1 - 2019/1
N2 - INTRODUCTION: Therapeutic options for diffuse malignant peritoneal mesothelioma (DMPM) are limited to surgery and locoregional chemotherapy. Despite improvements in survival rates, patients eventually succumb to disease progression. We investigated splicing deregulation both as molecular prognostic factor and potential novel target in DMPM, while we tested modulators of SF3b complex for antitumor activity.METHODS: Tissue-microarrays of 64 DMPM specimens were subjected to immunohistochemical assessment of SF3B1 expression and correlation to clinical outcome. Two primary cell cultures were used for gene expression profiling and in vitro screening of SF3b modulators. Drug-induced splicing alterations affecting downstream cellular pathways were detected through RNA sequencing. Ultimately, we established bioluminescent orthotopic mouse models to test the efficacy of splicing modulation in vivo.RESULTS: Spliceosomal genes are differentially upregulated in DMPM cells compared to normal tissues and high expression of SF3B1 correlated with poor clinical outcome in univariate and multivariate analysis. SF3b modulators (Pladienolide-B, E7107, Meayamycin-B) showed potent cytotoxic activity in vitro with IC50 values in the low nanomolar range. Differential splicing analysis of Pladienolide-B-treated cells revealed abundant alterations of transcripts involved in cell cycle, apoptosis and other oncogenic pathways. This was validated by RT-PCR and functional assays. E7107 demonstrated remarkable in vivo antitumor efficacy, with significant improvement of survival rates compared to vehicle-treated controls.CONCLUSIONS: SF3B1 emerged as a novel potential prognostic factor in DMPM. Splicing modulators markedly impair cancer cell viability, resulting also in potent antitumor activity in vivo. Our data designate splicing as a promising therapeutic target in DMPM.
AB - INTRODUCTION: Therapeutic options for diffuse malignant peritoneal mesothelioma (DMPM) are limited to surgery and locoregional chemotherapy. Despite improvements in survival rates, patients eventually succumb to disease progression. We investigated splicing deregulation both as molecular prognostic factor and potential novel target in DMPM, while we tested modulators of SF3b complex for antitumor activity.METHODS: Tissue-microarrays of 64 DMPM specimens were subjected to immunohistochemical assessment of SF3B1 expression and correlation to clinical outcome. Two primary cell cultures were used for gene expression profiling and in vitro screening of SF3b modulators. Drug-induced splicing alterations affecting downstream cellular pathways were detected through RNA sequencing. Ultimately, we established bioluminescent orthotopic mouse models to test the efficacy of splicing modulation in vivo.RESULTS: Spliceosomal genes are differentially upregulated in DMPM cells compared to normal tissues and high expression of SF3B1 correlated with poor clinical outcome in univariate and multivariate analysis. SF3b modulators (Pladienolide-B, E7107, Meayamycin-B) showed potent cytotoxic activity in vitro with IC50 values in the low nanomolar range. Differential splicing analysis of Pladienolide-B-treated cells revealed abundant alterations of transcripts involved in cell cycle, apoptosis and other oncogenic pathways. This was validated by RT-PCR and functional assays. E7107 demonstrated remarkable in vivo antitumor efficacy, with significant improvement of survival rates compared to vehicle-treated controls.CONCLUSIONS: SF3B1 emerged as a novel potential prognostic factor in DMPM. Splicing modulators markedly impair cancer cell viability, resulting also in potent antitumor activity in vivo. Our data designate splicing as a promising therapeutic target in DMPM.
KW - Mesothelioma
KW - RNA-sequencing
KW - SF3b modulation
KW - Splicing
KW - Therapy
UR - http://www.scopus.com/inward/record.url?scp=85058706274&partnerID=8YFLogxK
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85058706274&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30581150
U2 - https://doi.org/10.1016/j.ebiom.2018.12.025
DO - https://doi.org/10.1016/j.ebiom.2018.12.025
M3 - Article
C2 - 30581150
SN - 2352-3964
VL - 39
SP - 215
EP - 225
JO - eBioMedicine
JF - eBioMedicine
ER -