Therapy-induced secretion of spliceosomal components mediates pro-survival crosstalk between ovarian cancer cells. / Shender, Victoria O; Anufrieva, Ksenia S; Shnaider, Polina V et al.
In: Nature Communications, Vol. 15, No. 1, 5237, 19.06.2024.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Therapy-induced secretion of spliceosomal components mediates pro-survival crosstalk between ovarian cancer cells
AU - Shender, Victoria O
AU - Anufrieva, Ksenia S
AU - Shnaider, Polina V
AU - Arapidi, Georgij P
AU - Pavlyukov, Marat S
AU - Ivanova, Olga M
AU - Malyants, Irina K
AU - Stepanov, Grigory A
AU - Zhuravlev, Evgenii
AU - Ziganshin, Rustam H
AU - Butenko, Ivan O
AU - Bukato, Olga N
AU - Klimina, Ksenia M
AU - Veselovsky, Vladimir A
AU - Grigorieva, Tatiana V
AU - Malanin, Sergey Y
AU - Aleshikova, Olga I
AU - Slonov, Andrey V
AU - Babaeva, Nataliya A
AU - Ashrafyan, Lev A
AU - Khomyakova, Elena
AU - Evtushenko, Evgeniy G
AU - Lukina, Maria M
AU - Wang, Zixiang
AU - Silantiev, Artemiy S
AU - Nushtaeva, Anna A
AU - Kharlampieva, Daria D
AU - Lazarev, Vassili N
AU - Lashkin, Arseniy I
AU - Arzumanyan, Lorine K
AU - Petrushanko, Irina Yu
AU - Makarov, Alexander A
AU - Lebedeva, Olga S
AU - Bogomazova, Alexandra N
AU - Lagarkova, Maria A
AU - Govorun, Vadim M
N1 - This work was supported by grant 075-15-2019-1669 from the Ministry of Science and Higher Education of the Russian Federation (V.O.S., P.V.S., G.P.A., O.M.I., M.A.L., V.N.L., K.S.A., K.M.K. for RNAseq analyses); by the Russian Science Foundation project nos. 22-15-00462 (V.O.S., G.P.A, P.V.S., M.M.L., O.M.I. for proteomic analysis and experiments with cell cultures), 22-14-00234 (M.S.P. for splicing analysis), and 22-75-10153 (G.A.S. for RNA synthesis); by the State funding project 12403120004-7 (G.P.A. for bioinformatics analysis). We thank Dr. Roman Trikin, Dr. Eugen N. Imyanitov, and Dr. Sergey V. Razin for the critical reading and editing of the manuscript. © 2024. The Author(s).
PY - 2024/6/19
Y1 - 2024/6/19
N2 - Ovarian cancer often develops resistance to conventional therapies, hampering their effectiveness. Here, using ex vivo paired ovarian cancer ascites obtained before and after chemotherapy and in vitro therapy-induced secretomes, we show that molecules secreted by ovarian cancer cells upon therapy promote cisplatin resistance and enhance DNA damage repair in recipient cancer cells. Even a short-term incubation of chemonaive ovarian cancer cells with therapy-induced secretomes induces changes resembling those that are observed in chemoresistant patient-derived tumor cells after long-term therapy. Using integrative omics techniques, we find that both ex vivo and in vitro therapy-induced secretomes are enriched with spliceosomal components, which relocalize from the nucleus to the cytoplasm and subsequently into the extracellular vesicles upon treatment. We demonstrate that these molecules substantially contribute to the phenotypic effects of therapy-induced secretomes. Thus, SNU13 and SYNCRIP spliceosomal proteins promote therapy resistance, while the exogenous U12 and U6atac snRNAs stimulate tumor growth. These findings demonstrate the significance of spliceosomal network perturbation during therapy and further highlight that extracellular signaling might be a key factor contributing to the emergence of ovarian cancer therapy resistance.
AB - Ovarian cancer often develops resistance to conventional therapies, hampering their effectiveness. Here, using ex vivo paired ovarian cancer ascites obtained before and after chemotherapy and in vitro therapy-induced secretomes, we show that molecules secreted by ovarian cancer cells upon therapy promote cisplatin resistance and enhance DNA damage repair in recipient cancer cells. Even a short-term incubation of chemonaive ovarian cancer cells with therapy-induced secretomes induces changes resembling those that are observed in chemoresistant patient-derived tumor cells after long-term therapy. Using integrative omics techniques, we find that both ex vivo and in vitro therapy-induced secretomes are enriched with spliceosomal components, which relocalize from the nucleus to the cytoplasm and subsequently into the extracellular vesicles upon treatment. We demonstrate that these molecules substantially contribute to the phenotypic effects of therapy-induced secretomes. Thus, SNU13 and SYNCRIP spliceosomal proteins promote therapy resistance, while the exogenous U12 and U6atac snRNAs stimulate tumor growth. These findings demonstrate the significance of spliceosomal network perturbation during therapy and further highlight that extracellular signaling might be a key factor contributing to the emergence of ovarian cancer therapy resistance.
KW - Female
KW - Humans
KW - Ovarian Neoplasms/metabolism
KW - Spliceosomes/metabolism
KW - Cisplatin/pharmacology
KW - Cell Line, Tumor
KW - Drug Resistance, Neoplasm
KW - Animals
KW - Mice
KW - Extracellular Vesicles/metabolism
KW - Cell Survival/drug effects
KW - Antineoplastic Agents/pharmacology
KW - RNA, Small Nuclear/metabolism
KW - DNA Repair
UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85196403437&origin=inward&txGid=2bc097ef43481f75f7742f38473daa05
U2 - 10.1038/s41467-024-49512-6
DO - 10.1038/s41467-024-49512-6
M3 - Article
C2 - 38898005
VL - 15
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 5237
ER -
ID: 60381874