SLFN11 is widely expressed in pediatric sarcoma and induces variable sensitization to 1 replicative stress caused by DNA damaging agents
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PROVIDER: PRJNA750705 | ENA |
REPOSITORIES: ENA
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Project description:Schlafen family member 11 (SLFN11) increases sensitivity to replicative stress and has been proposed as a biomarker to predict sensitivity to DNA damaging agents (DDA). However, the role of SLFN11 in pediatric cancer has not been well explored. In this study, we found that protein expression strongly correlated with response to the PARP inhibitor talazoparib and the topoisomerase I inhibitor irinotecan in sarcoma cell lines, with SLFN11 knockout resulting in significant loss of sensitivity in vitro and in vivo. However, in contrast to its activity in adult tumors, high SLFN11 expression did not correlate with favorable outcome in a retrospective study of children with sarcoma. Our work suggests that the potential of SLFN11 to act as a biomarker may be limited to certain tumor backgrounds or contexts, and that impaired apoptotic response may be one targetable mechanism of resistance to DDA-induced replicative stress
2022-04-08 | GSE181094 | GEO
Project description:Pediatric sarcomas represent a heterogeneous group of malignancies that exhibit variable response to DNA-damaging chemotherapy. Schlafen family member 11 protein (SLFN11) increases sensitivity to replicative stress and has been implicated as a potential biomarker to predict sensitivity to DNA-damaging agents (DDA). SLFN11 expression was quantified in 220 children with solid tumors using IHC. Sensitivity to the PARP inhibitor talazoparib (TAL) and the topoisomerase I inhibitor irinotecan (IRN) was assessed in sarcoma cell lines, including SLFN11 knock-out (KO) and overexpression models, and a patient-derived orthotopic xenograft model (PDOX). SLFN11 was expressed in 69% of pediatric sarcoma sampled, including 90% and 100% of Ewing sarcoma and desmoplastic small round-cell tumors, respectively, although the magnitude of expression varied widely. In sarcoma cell lines, protein expression strongly correlated with response to TAL and IRN, with SLFN11 KO resulting in significant loss of sensitivity in vitro and in vivo Surprisingly, retrospective analysis of children with sarcoma found no association between SLFN11 levels and favorable outcome. Subsequently, high SLFN11 expression was confirmed in a PDOX model derived from a patient with recurrent Ewing sarcoma who failed to respond to treatment with TAL + IRN. Selective inhibition of BCL-xL increased sensitivity to TAL + IRN in SLFN11-positive resistant tumor cells. Although SLFN11 appears to drive sensitivity to replicative stress in pediatric sarcomas, its potential to act as a biomarker may be limited to certain tumor backgrounds or contexts. Impaired apoptotic response may be one mechanism of resistance to DDA-induced replicative stress.
| S-EPMC8571037 | biostudies-literature
Project description:Large independent analyses on cancer cell lines followed by functional studies have identified Schlafen 11 (SLFN11), a putative helicase, as the strongest predictor of sensitivity to DNA-damaging agents (DDA), including platinum. However, its role as a prognostic biomarker is undefined, partially due to the lack of validated methods to score SLFN11 in human tissues. Here, we implemented a pipeline to quantify SLFN11 in human cancer samples. By analyzing a cohort of high-grade serous ovarian carcinoma (HGSOC) specimens prior platinum-based chemotherapy treatment, we show, for the first time, that SLFN11 density in both the neoplastic and microenvironmental components was independently associated with favorable outcome. We observed SLFN11 expression in both infiltrating innate and adaptive immune cells, and analyses in a second, independent, cohort revealed that SLFN11 is associated with immune activation in HGSOC. We found that platinum treatments activated immune-related pathways in ovarian cancer cells in a SLFN11-dependent manner, representative of tumor-immune transactivation. Moreover, SLFN11 expression was induced in activated, isolated, immune cell subpopulations, hinting that SLFN11 in the immune compartment may be an indicator of immune transactivation. In summary, we propose SLFN11 is a dual biomarker capturing simultaneously interconnected immunological and cancer-cell-intrinsic functional dispositions associated with sensitivity to DDA treatment.
2021-07-13 | GSE179896 | GEO
Project description:SLFN11 sensitizes cancer cells to a broad range of DNA-targeted therapies. Here we show that, in response to replication stress induced by camptothecin, SLFN11 tightly binds chromatin at stressed replication foci via RPA1 together with the replication helicase subunit MCM3. Unlike ATR, SLFN11 neither interferes with the loading of CDC45 and PCNA nor inhibits the initiation of DNA replication but selectively blocks fork progression while inducing chromatin opening across replication initiation sites. The ATPase domain of SLFN11 is required for chromatin opening, replication block and cell death but not for the tight binding of SLFN11 to chromatin. Replication stress by the CHK1 inhibitor Prexasertib also recruits SLFN11 to nascent replicating DNA together with CDC45 and PCNA. We conclude that SLFN11 is recruited to stressed replication forks carrying extended RPA filaments where it blocks replication by changing chromatin structure across replication sites.
2018-01-18 | GSE101516 | GEO
Project description:SLFN11 sensitizes cancer cells to a broad range of DNA-targeted therapies. Here we show that, in response to replication stress induced by camptothecin, SLFN11 tightly binds chromatin at stressed replication foci via RPA1 together with the replication helicase subunit MCM3. Unlike ATR, SLFN11 neither interferes with the loading of CDC45 and PCNA nor inhibits the initiation of DNA replication but selectively blocks fork progression while inducing chromatin opening across replication initiation sites. The ATPase domain of SLFN11 is required for chromatin opening, replication block and cell death but not for the tight binding of SLFN11 to chromatin. Replication stress by the CHK1 inhibitor Prexasertib also recruits SLFN11 to nascent replicating DNA together with CDC45 and PCNA. We conclude that SLFN11 is recruited to stressed replication forks carrying extended RPA filaments where it blocks replication by changing chromatin structure across replication sites.
2018-01-18 | GSE101512 | GEO
Project description:SLFN11 sensitizes cancer cells to a broad range of DNA-targeted therapies. Here we show that, in response to replication stress induced by camptothecin, SLFN11 tightly binds chromatin at stressed replication foci via RPA1 together with the replication helicase subunit MCM3. Unlike ATR, SLFN11 neither interferes with the loading of CDC45 and PCNA nor inhibits the initiation of DNA replication but selectively blocks fork progression while inducing chromatin opening across replication initiation sites. The ATPase domain of SLFN11 is required for chromatin opening, replication block and cell death but not for the tight binding of SLFN11 to chromatin. Replication stress by the CHK1 inhibitor Prexasertib also recruits SLFN11 to nascent replicating DNA together with CDC45 and PCNA. We conclude that SLFN11 is recruited to stressed replication forks carrying extended RPA filaments where it blocks replication by changing chromatin structure across replication sites.
2018-01-18 | GSE101515 | GEO
Project description:Impairment of ribosome biogenesis (RiBi) is triggered by the inhibition of rRNA synthesis and processing and leads to various biological effects. We discovered that Schlafen 11 (SLFN11)-dependent sensitization to replication stress produced by chemotherapeutic drugs induces RiBi impairment. Mechanistically, SLFN11 alters the chromatin structure of rDNA in response to replication stress, sequestering RNA polymerase I on chromatin while inhibiting rRNA synthesis and nucleolar R-loop formation. SLFN11-induced RiBi impairment inhibits translation overall, depleting extremely short-lived proteins, particularly MCL1, an ubiquitous anti-apoptotic protein. Consequently, SLFN11 activates apoptosis in an MCL1-dependent but TP53-independent manner. Comparable effects were observed with RNA polymerase I inhibitors and other RiBi inhibitory conditions regardless of SLFN11. These findings were validated across 34 diverse human cancer cell lines. Thus, we demonstrate that RiBi impairment is a robust inactivator of MCL1 and an activator of apoptosis and identify an additional mechanism by which SLFN11 sensitizes cancer cells to chemotherapeutic agents.
2025-05-22 | PXD052471 | JPOST Repository
Project description:Schlafen 11 (SLFN11) has recently arisen as a novel cellular restriction factor against replication stress. Here we show that SLFN11 increases chromatin accessibility genome-wide, dominantly at promoters in response to replication stress induced by the CHK1 inhibitor prexasertib and the topoisomerase I inhibitor, camptothecin. Concomitantly SLFN11 selectively activates cellular stress response pathways by inducing the transcription of the Immediate Early Genes (IEGs) including JUN, FOS, EGR1, NFKB2 and ATF3. Both chromatin opening and IEG activation require the putative helicase activity of SLFN11 whereas extrinsic IEG activation by serum induction is SLFN11-independent. SLFN11-dependent IEG activation is also observed across 55 non-isogenic NCI-60 cell lines by comparing transcriptome data before and after camptothecin treatment. We conclude that SLFN11 acts as a global regulator of chromatin structure and an intrinsic IEG activator with the potential to engage the native immune activation in response to replicative stress.
2020-01-17 | GSE140175 | GEO
Project description:Schlafen 11 (SLFN11) has recently arisen as a novel cellular restriction factor against replication stress. Here we show that SLFN11 increases chromatin accessibility genome-wide, dominantly at promoters in response to replication stress induced by the CHK1 inhibitor prexasertib and the topoisomerase I inhibitor, camptothecin. Concomitantly SLFN11 selectively activates cellular stress response pathways by inducing the transcription of the Immediate Early Genes (IEGs) including JUN, FOS, EGR1, NFKB2 and ATF3. Both chromatin opening and IEG activation require the putative helicase activity of SLFN11 whereas extrinsic IEG activation by serum induction is SLFN11-independent. SLFN11-dependent IEG activation is also observed across 55 non-isogenic NCI-60 cell lines by comparing transcriptome data before and after camptothecin treatment. We conclude that SLFN11 acts as a global regulator of chromatin structure and an intrinsic IEG activator with the potential to engage the native immune activation in response to replicative stress.
2020-01-17 | GSE140936 | GEO
Project description:Schlafen 11 (SLFN11) has recently arisen as a novel cellular restriction factor against replication stress. Here we show that SLFN11 increases chromatin accessibility genome-wide, dominantly at promoters in response to replication stress induced by the CHK1 inhibitor prexasertib and the topoisomerase I inhibitor, camptothecin. Concomitantly SLFN11 selectively activates cellular stress response pathways by inducing the transcription of the Immediate Early Genes (IEGs) including JUN, FOS, EGR1, NFKB2 and ATF3. Both chromatin opening and IEG activation require the putative helicase activity of SLFN11 whereas extrinsic IEG activation by serum induction is SLFN11-independent. SLFN11-dependent IEG activation is also observed across 55 non-isogenic NCI-60 cell lines by comparing transcriptome data before and after camptothecin treatment. We conclude that SLFN11 acts as a global regulator of chromatin structure and an intrinsic IEG activator with the potential to engage the native immune activation in response to replicative stress.
2020-01-17 | GSE140935 | GEO