CDK2 Inhibition Produces a Persistent Population of Polyploid Cancer Cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1242259 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32876370_1.fastq.gz | Fastqsanger.gz | |||
| SRR32876370_2.fastq.gz | Fastqsanger.gz | |||
| SRR32876371_1.fastq.gz | Fastqsanger.gz | |||
| SRR32876371_2.fastq.gz | Fastqsanger.gz | |||
| SRR32876372_1.fastq.gz | Fastqsanger.gz |
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Project description:Cyclin dependent kinase 2 (CDK2) regulate cell cycle and is an emerging target for cancer therapy. There are relatively small numbers of tumor models that exhibit strong dependence on CDK2 and undergo G1 cell cycle arrest following CDK2 inhibition. The expression of P16INK4A and cyclin E1 determines this sensitivity to CDK2 inhibition. The co-expression of these genes occurs in breast cancer patients highlighting their clinical significance as predictive biomarkers for CDK2-targeted therapies. In cancer models that are genetically independent of CDK2; pharmacological inhibitors suppress cell proliferation by inducing 4N cell cycle arrest and increasing the expressions of phospho-CDK1 (Y15) and cyclin B1. CRISPR screens identifiy CDK2 loss as a mediator of resistance to INX-315. Furthermore, CDK2 deletion reverses the G2/M block induced by CDK2 inhibitors and restores cell proliferation. Complementary drug screens define multiple means to cooperate with CDK2 inhibition beyond G1/S. These include the depletion of mitotic regulators as well as CDK4/6 inhibitors cooperate with CDK2 inhibition in multiple phases of the cell cycle. Overall, this study underscores two fundamentally distinct features of response to CDK2 inhibitors that are conditioned by tumor context and could serve as the basis for differential therapeutic strategies in a wide range of cancers.
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Project description:Cyclin dependent kinase 2 (CDK2) regulate cell cycle and is an emerging target for cancer therapy. There are relatively small numbers of tumor models that exhibit strong dependence on CDK2 and undergo G1 cell cycle arrest following CDK2 inhibition. The expression of P16INK4A and cyclin E1 determines this sensitivity to CDK2 inhibition. The co-expression of these genes occurs in breast cancer patients highlighting their clinical significance as predictive biomarkers for CDK2-targeted therapies. In cancer models that are genetically independent of CDK2; pharmacological inhibitors suppress cell proliferation by inducing 4N cell cycle arrest and increasing the expressions of phospho-CDK1 (Y15) and cyclin B1. CRISPR screens identifiy CDK2 loss as a mediator of resistance to INX-315. Furthermore, CDK2 deletion reverses the G2/M block induced by CDK2 inhibitors and restores cell proliferation. Complementary drug screens define multiple means to cooperate with CDK2 inhibition beyond G1/S. These include the depletion of mitotic regulators as well as CDK4/6 inhibitors cooperate with CDK2 inhibition in multiple phases of the cell cycle. Overall, this study underscores two fundamentally distinct features of response to CDK2 inhibitors that are conditioned by tumor context and could serve as the basis for differential therapeutic strategies in a wide range of cancers.
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Project description:Intrinsic immune checkpoints in microglia are vital for maintaining homeostatic immune response and preventing overactivation. Neuroinflammation, frequently driven by microglial overactivation, significantly influences a wide range of neurological disorders. While MEF2C has been associated with a syndromic form of autism spectrum disorder (ASD) and various other neurological disorders in humans, its specific role as an immune checkpoint remains poorly defined. By harnessing MEF2C-knockout (KO) induced microglia-like cells (iMGLs) through differentiation from human pluripotent stem cells (hPSCs), here we observed that these cells, following LPS stimulation, exhibited overactivation similar to patterns seen in various neurological disorders. High-throughput screening identified BMS265246, a CDK2 inhibitor, as effective in specifically suppressing the overactivated phenotypes of MEF2C-KO iMGLs, and in restoring inflammatory response closer to normal levels. Mechanistically, we uncovered that MEF2C regulates p21 transcription, a critical step in preventing CDK2 activation in microglia. Loss of MEF2C results in CDK2-induced RB phosphorylation and degradation, leading to enhanced NF-κB p65 subunit nuclear translocation and exacerbated inflammatory responses. Remarkably, BMS265246 treatment rectified microglial overactivation and ASD-like behaviors in both global and microglia-specific Mef2C heterozygous knockout mice. Overall, our findings elucidated a previously unknown immune checkpoint mechanism governed by MEF2C, and highlighted CDK2 as a potential key factor driving neuroinflammation through microglial overactivation. These insights positions CDK2 as a promising therapeutic target for treating various neurological diseases influenced by overactivated microglia.
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Project description:Neuroinflammation driven by microglial overactivation is a significant contributor across a diverse range of neurological disorders. While MEF2C mutations have been associated with a syndromic form of autism spectrum disorder (ASD) and various other neurological disorders in humans, the role of MEF2C as a key immune checkpoint to restrain microglial overactivation remains elusive. In this study, we established MEF2C-knockout (KO) induced microglia-like cells (iMGLs) via differentiation of corresponding human pluripotent stem cells, and subsequently treated with LPS, as a disease model of overactivated microglia. Through high-throughput screening, we identified BMS265246, a CDK2 inhibitor, which effectively normalized overactivated phenotypes in LPS-stimulated MEF2C-KO iMGLs, nearing levels seen in WT counterparts. Mechanistically, absence of MEF2C instigated a sequential cascade encompassing p21 downregulation, CDK2 activation, RB phosphorylation and degradation, and NF-κB p65 subunit nuclear translocation, thereby intensifying inflammatory responses. Remarkably, BMS265246 treatment significantly rectified microglial overactivation and ASD behavioral defects in both global and microglia-specific Mef2C heterozygous mice. Overall, our findings elucidate a novel protective mechanism governed by MEF2C, and unveil CDK2 as a promising therapeutic target for treating various diseases influenced by overactivated microglia with aberrant MEF2C expression and/or CDK2 activation.
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Project description:Background: Advanced gastrointestinal stromal tumor (GIST) is characterized by genomic perturbations of key cell cycle regulators. Oncogenic activation of CDK4/6 results in RB1 inactivation and cell cycle progression. Given that single-agent CDK4/6 inhibitor therapy failed to show clinical activity in advanced GIST, we evaluated strategies for maximizing response to therapeutic CDK4/6 inhibition. Methods: Targeted next-generation sequencing and multiplexed protein imaging were used to detect cell cycle regulator aberrations in GIST clinical samples. The impact of inhibitors of CDK2, CDK4, and CDK2/4/6 was determined through cell proliferation and protein detection assays. CDK-inhibitor resistance mechanisms were characterized in GIST cell lines after long-term exposure. Results: We identify recurrent genomic aberrations in cell cycle regulators causing co-activation of the CDK2 and CDK4/6 pathways in clinical GIST samples. Therapeutic co-targeting of CDK2 and CDK4/6 is synergistic in GIST cell lines with intact RB1, through inhibition of RB1 hyperphosphorylation and cell proliferation. Moreover, RB1 inactivation and a novel oncogenic cyclin D1 resulting from an intragenic rearrangement (CCND1::chr11.g:70025223) are mechanisms of acquired CDK inhibitor resistance in GIST. Conclusions: These studies establish the biologic rationale for CDK2 and CDK4/6 co-inhibition as therapeutic strategy in patients with advanced GIST, including metastatic GIST progressing on tyrosine kinase inhibitors.
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Project description:Tetraploidization, or genome doubling, is a prominent event in tumorigenesis, primarily because cell division in polyploid cells is error-prone and produces aneuploid cells. This study investigates changes in gene expression evoked in acute and adapted tetraploid cells and their impact on cell-cycle progression. Acute polyploidy was generated by knockdown of essential regulator of cytokinesis Anillin, which resulted in cytokinesis failure and formation of binucleate cells, or by chemical inhibition of Aurora kinases, causing abnormal mitotic exit with formation of single cells with aberrant nuclear morphology. Transcriptome analysis of these acute tetraploid cells revealed common signatures of activation of the tumor-suppressor protein p53. Suppression of proliferation in these cells was dependent on p53 and its transcriptional target - Cdk inhibitor p21. Rare proliferating tetraploid cells can emerge from acute polyploid populations. Gene expression analysis of single-cell derived, adapted tetraploid clones showed upregulation of several p53 target genes and cyclin D2, the activator of Cdk4/6/2. Overexpression of cyclin D2 in diploid cells strongly potentiated the ability to proliferate with increased DNA content despite the presence of functional p53. These results point out that p53-mediated suppression of proliferation of polyploid cells can be averted by increased levels of oncogenes such as Cyclin D2, elucidating a possible route for tetraploidy-mediated genomic instability in carcinogenesis.
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2014-05-19 | E-GEOD-16480 | biostudies-arrayexpress
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