SF3B1 facilitates HIF1-signaling and promotes malignancy in pancreatic cancer

Simmler, Patrik; Cortijo, Cédric; Koch, Lisa Maria; Galliker, Patricia; Angori, Silvia; Bolck, Hella Anna; Mueller, Christina; Vukolic, Ana; Mirtschink, Peter; Christinat, Yann; Davidson, Natalie R.; Lehmann, Kjong-Van; Pellegrini, Giovanni; Pauli, Chantal; Lenggenhager, Daniela; Guccini, Ilaria; Ringel, Till; Hirt, Christian; Marquart, Kim Fabiano; Schaefer, Moritz; Rätsch, Gunnar; Peter, Matthias; Moch, Holger; Stoffel, Markus; Schwank, Gerald

doi:10.1016/j.celrep.2022.111266

Cited by 9 publications

(3 citation statements)

References 43 publications

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“…Some of these share similar mechanisms aimed at inhibiting SF3B1 and, consequently, interfering with the RNU2 complex, destabilizing it and preventing the transition of the spliceosome complex. SF3B1 is known to physically interact with HIF1α and induce hypoxia, promoting PDAC malignancy [ 127 ]. The potential clinical utility of these SF3B1 targeting molecules and their derivates has been demonstrated in several studies.…”

Section: Splicing Modulation For Therapeutic Benefitmentioning

confidence: 99%

Splicing alterations in pancreatic ductal adenocarcinoma: a new molecular landscape with translational potential

Alors-Pérez,

Pedraza-Arevalo,

Blázquez-Encinas

et al. 2023

J Exp Clin Cancer Res

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Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers worldwide, mainly due to its late diagnosis and lack of effective therapies, translating into a low 5-year 12% survival rate, despite extensive clinical efforts to improve outcomes. International cooperative studies have provided informative multiomic landscapes of PDAC, but translation of these discoveries into clinical advances are lagging. Likewise, early diagnosis biomarkers and new therapeutic tools are sorely needed to tackle this cancer. The study of poorly explored molecular processes, such as splicing, can provide new tools in this regard. Alternative splicing of pre-RNA allows the generation of multiple RNA variants from a single gene and thereby contributes to fundamental biological processes by finely tuning gene expression. However, alterations in alternative splicing are linked to many diseases, and particularly to cancer, where it can contribute to tumor initiation, progression, metastasis and drug resistance. Splicing defects are increasingly being associated with PDAC, including both mutations or dysregulation of components of the splicing machinery and associated factors, and altered expression of specific relevant gene variants. Such disruptions can be a key element enhancing pancreatic tumor progression or metastasis, while they can also provide suitable tools to identify potential candidate biomarkers and discover new actionable targets. In this review, we aimed to summarize the current information about dysregulation of splicing-related elements and aberrant splicing isoforms in PDAC, and to describe their relationship with the development, progression and/or aggressiveness of this dismal cancer, as well as their potential as therapeutic tools and targets.

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Section: Splicing Modulation For Therapeutic Benefitmentioning

confidence: 99%

Splicing alterations in pancreatic ductal adenocarcinoma: a new molecular landscape with translational potential

Alors-Pérez,

Pedraza-Arevalo,

Blázquez-Encinas

et al. 2023

J Exp Clin Cancer Res

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“…To our knowledge, the transcriptome and alternative splicing landscape in single-cell resolution has not been studied in ccRCC despite the heterogeneity and complexity of its tumor microenvironment (Motzer et al 2022). However, various high-throughput studies point towards an important role of alternative splicing in ccRCC development and treatment response (Wang et al 2022; Simmler et al 2022; Zhang et al 2021a). For example, recent single-cell studies have suggested VCAM1-positive renal proximal tubule cells to be the likely origin of ccRCC (Zhang et al 2021b; Schreibing and Kramann 2022), which is consistent with the hypothesis that ccRCC is derived from the proximal tubules.…”

Section: Introductionmentioning

confidence: 99%

Heterogeneous and Novel Transcript Expression in Single Cells of Patient-Derived ccRCC Organoids

Karakulak,

Zajac,

Bolck

et al. 2024

Preprint

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Splicing is often dysregulated in cancer, leading to alterations in the expression of canonical and alternative splice isoforms. This complex phenomenon can be revealed by an in-depth understanding of cellular heterogeneity at the single-cell level. Recent advances in single-cell long-read sequencing technologies enable comprehensive transcriptome sequencing at the single-cell level. In this study, we have generated single-cell long-read sequencing of Patient-Derived Organoid (PDO) cells of clear-cell Renal Cell Carcinoma (ccRCC), an aggressive and lethal form of cancer that arises in kidney tubules. We have used the Multiplexed Arrays Sequencing (MAS-ISO-Seq) protocol of PacBio to sequence full-length transcripts exceptionally deep across 2,599 single cells to obtain the most comprehensive view of the alternative landscape of ccRCC to date. On average, we uncovered 303,547 transcripts across PDOs, of which 40.5% were previously uncharacterized. In contrast to known transcripts, many of these novel isoforms appear to exhibit cell-specific expression. Nonetheless, 37.5% of these novel transcripts, expressed in more than three cells, were predicted to possess a complete protein-coding open reading frame. This finding suggests a biological role for these transcripts within kidney cells. Moreover, an analysis of the most dominant transcript switching revealed that many switching events were cell and sample-specific, underscoring the heterogeneity of alternative splicing events in ccRCC. Interestingly, one of the ccRCC organoids seemed to have a VHL-negative phenotype despite a VHL P25L mutation, underscoring the benign nature of the mutation. Overall, our research elucidates the intricate transcriptomic architecture of ccRCC, potentially exposing the mechanisms underlying its aggressive phenotype and resistance to conventional cancer therapies.

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“…SF3B1 mutations cause aberrant splicing and activation of inflammatory immune signaling in myelodysplastic syndromes [10][11][12]. SF3B1 promotes malignancy in pancreatic cancer, endometrial cancer, and glioblastoma [13][14][15]. Pladienolide B is an SF3B1 inhibitor widely used in cancer research.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of SF3B1 improves the immune microenvironment through pyroptosis and synergizes with αPDL1 in ovarian cancer

Wang,

Liu,

Xiao

et al. 2023

Cell Death Dis

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Ovarian cancer is resistant to immune checkpoint blockade (ICB) treatment. Combination of targeted therapy and immunotherapy is a promising strategy for ovarian cancer treatment benefit from an improved immune microenvironment. In this study, Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) cohorts were used to screen prognosis and cytotoxic lymphocyte infiltration-associated genes in upregulated genes of ovarian cancer, tissue microarrays were built for further verification. In vitro experiments and mouse (C57/BL6) ovarian tumor (ID8) models were built to evaluate the synergistic effect of the combination of SF3B1 inhibitor and PD-L1 antibody in the treatment of ovarian cancer. The results show that SF3B1 is shown to be overexpressed and related to low cytotoxic immune cell infiltration in ovarian cancer. Inhibition of SF3B1 induces pyroptosis in ovarian cancer cells and releases mitochondrial DNA (mtDNA), which is englobed by macrophages and subsequently activates them (polarization to M1). Moreover, pladienolide B increases cytotoxic immune cell infiltration in the ID8 mouse model as a SF3B1 inhibitor and increases the expression of PD-L1 which can enhance the antitumor effect of αPDL1 in ovarian cancer. The data suggests that inhibition of SF3B1 improves the immune microenvironment of ovarian cancer and synergizes ICB immunotherapy, which provides preclinical evidence for the combination of SF3B1 inhibitor and ICB to ovarian cancer treatment.

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SF3B1 facilitates HIF1-signaling and promotes malignancy in pancreatic cancer

Cited by 9 publications

References 43 publications

Splicing alterations in pancreatic ductal adenocarcinoma: a new molecular landscape with translational potential

Splicing alterations in pancreatic ductal adenocarcinoma: a new molecular landscape with translational potential

Heterogeneous and Novel Transcript Expression in Single Cells of Patient-Derived ccRCC Organoids

Inhibition of SF3B1 improves the immune microenvironment through pyroptosis and synergizes with αPDL1 in ovarian cancer

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