SFPQ Depletion Is Synthetically Lethal with BRAFV600E in Colorectal Cancer Cells

Klotz-Noack, Kathleen; Klinger, Bertram; Rivera, Maria; Bublitz, Natalie; Uhlitz, Florian; Riemer, Pamela; Lüthen, Mareen; Sell, Thomas; Kasack, Katharina; Gastl, Bastian; Ispasanie, Sylvia; Simon, Tincy; Janssen, Nicole; Schwab, Matthias; Zuber, Johannes; Horst, David; Blüthgen, Nils; Schäfer, Reinhold; Morkel, Markus; Sers, Christine

doi:10.1016/j.celrep.2020.108184

Cited by 26 publications

(34 citation statements)

References 92 publications

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“…Our study also identified further cancer traits in CRC cell clusters with relevance to therapy. For instance, TC1 cells were defined by high levels of replication stress, which can be functionally associated with high MAPK activity (Sheu et al , 2012; Klotz-Noack et al , 2020). Tumors with high TC1 cell content were strongly positive for PARP, an important therapeutic target (Sun et al , 2020).…”

Section: Discussionmentioning

confidence: 99%

Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

Uhlitz

Bischoff

Peidli³

et al. 2020

Preprint

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In colorectal cancer, oncogenic mutations transform a hierarchically organized and homeostatic epithelium into invasive cancer tissue. To define differences in cellular composition between the normal colon and colorectal cancer, and to map potential cellular interactions between tumor cells and their microenvironment, we profiled transcriptomes of >50,000 single cells from tumors and matched normal tissues of eight colorectal cancer patients. We find that tumor formation is accompanied by changes in epithelial, immune and stromal cell compartments in all patients. In the epithelium, we identify a continuum of five tumor-specific stem cell and progenitor-like populations, and persistent multilineage differentiation. We find multiple stromal and immune cell types to be consistently expanded in tumor compared to the normal colon, including cancer-associated fibroblasts, pericytes, monocytes, macrophages and a subset of T cells. We identify epithelial tumor cells and cancer-associated fibroblasts as relevant for assigning colorectal cancer consensus molecular subtypes. Our survey of growth factors in the tumor microenvironment identifies cell types responsible for increased paracrine EGFR, MET and TGF-β signaling in tumor tissue compared to the normal colon.We show that matched colorectal cancer organoids retain cell type heterogeneity, allowing to define a distinct differentiation trajectory encompassing stem and progenitor-like tumor cells. In summary, our single-cell analyses provide insights into cell types and signals shaping colorectal cancer cell plasticity.

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Section: Discussionmentioning

confidence: 99%

Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

Uhlitz

Bischoff

Peidli³

et al. 2020

Preprint

Self Cite

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“…It is a multifunctional RBP and regulates a wide range of cellular processes, including pre-mRNA splicing, transcription, nuclear RNA retention, paraspeckle formation, RNA transport, DNA repair, translation, apoptosis, and response to viral infection 17 – 23 . Though the functional impact of SFPQ has been shown in various diseases such as neurological 24 – 26 , immune-metabolic 27 , genetic 28 , and cancer 29 , 30 , there is no prior report of changes in the SFPQ expression level in CF diseased state. Here, we find reduced levels of nuclear-localized SFPQ protein in F508del-CFTR CF lung epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…It binds to both DNA and RNA and is implicated in the regulation of gene expression pathways, including alternative splicing, transcription, nuclear RNA retention, paraspeckle formation, RNA transport, DNA repair, translation, apoptosis, and response to viral infection 17 – 23 . The involvement of SFPQ has been demonstrated in several diseases such as neurological 24 – 26 , immune-metabolic 27 , genetic 28 , and cancer 29 , 30 . However, whether SFPQ has any role in the regulation of CF lung disease is completely unknown.…”

Section: Introductionmentioning

confidence: 99%

SFPQ rescues F508del-CFTR expression and function in cystic fibrosis bronchial epithelial cells

Kumar

Soni

Sen

et al. 2021

Sci Rep

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Cystic fibrosis (CF) occurs as a result of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which lead to misfolding, trafficking defects, and impaired function of the CFTR protein. Splicing factor proline/glutamine-rich (SFPQ) is a multifunctional nuclear RNA-binding protein (RBP) implicated in the regulation of gene expression pathways and intracellular trafficking. Here, we investigated the role of SFPQ in the regulation of the expression and function of F508del-CFTR in CF lung epithelial cells. We find that the expression of SFPQ is reduced in F508del-CFTR CF epithelial cells compared to WT-CFTR control cells. Interestingly, the overexpression of SFPQ in CF cells increases the expression as well as rescues the function of F508del-CFTR. Further, comprehensive transcriptome analyses indicate that SFPQ plays a key role in activating the mutant F508del-CFTR by modulating several cellular signaling pathways. This is the first report on the role of SFPQ in the regulation of expression and function of F508del-CFTR in CF lung disease. Our findings provide new insights into SFPQ-mediated molecular mechanisms and point to possible novel epigenetic therapeutic targets for CF and related pulmonary diseases.

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“…It is a multifunctional RBP and regulates a wide range of cellular processes, including pre-mRNA splicing, transcription, nuclear RNA retention, paraspeckle formation, RNA transport, DNA repair, translation, apoptosis, and response to viral infection [17][18][19][20][21][22][23] . Though the functional impact of SFPQ has been shown in various diseases such as neurological [24][25][26] , immune-metabolic 27 , genetic 28 , and cancer 29,30 , there is no prior report of changes in the SFPQ expression level in CF diseased state. Here, we find reduced levels of nuclearlocalized SFPQ protein in F508del-CFTR CF lung epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

SFPQ Rescues F508del-CFTR Expression and Function in Cystic Fibrosis Bronchial Epithelial Cells

Kumar

Soni

Sen

et al. 2021

Preprint

View full text Add to dashboard Cite

Cystic Fibrosis (CF) occurs as a result of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which lead to misfolding, trafficking defects, and impaired function of the CFTR protein. Splicing factor proline/glutamine-rich (SFPQ) is a multifunctional nuclear RNA-binding protein (RBP) implicated in the regulation of gene expression pathways and intracellular trafficking. Here, we investigated the role of SFPQ in the regulation of the expression and function of F508del-CFTR in CF lung epithelial cells. We find that the expression of SFPQ is reduced in F508del-CFTR CF epithelial cells compared to WT-CFTR control cells. Interestingly, the overexpression of SFPQ in CF cells increases the expression as well as rescues the function of F508del-CFTR. Further, comprehensive transcriptome analyses indicate that SFPQ plays a key role in activating the mutant F508del-CFTR by modulating several cellular signaling pathways. This is the first report on the role of SFPQ in the regulation of expression and function of F508del-CFTR in CF lung disease. Our findings provide new insights into SFPQ-mediated molecular mechanisms and point to possible novel epigenetic therapeutic targets for CF and related pulmonary diseases.

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SFPQ Depletion Is Synthetically Lethal with BRAFV600E in Colorectal Cancer Cells

Cited by 26 publications

References 92 publications

Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

SFPQ rescues F508del-CFTR expression and function in cystic fibrosis bronchial epithelial cells

SFPQ Rescues F508del-CFTR Expression and Function in Cystic Fibrosis Bronchial Epithelial Cells

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