CDK12 tumor suppressor function and therapeutic targeting in newly developed mouse models of serous ovarian cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1196980 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31686461_1.fastq.gz | Fastqsanger.gz | |||
| SRR31686461_2.fastq.gz | Fastqsanger.gz | |||
| SRR31686462_1.fastq.gz | Fastqsanger.gz | |||
| SRR31686462_2.fastq.gz | Fastqsanger.gz | |||
| SRR31686463_1.fastq.gz | Fastqsanger.gz |
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Project description:Adenocarcinoma of the ovary is the fifth leading cause of cancer death among American women. Most mortality results from high-grade serous ovarian carcinoma (HGS-OvCa)—a disease type resistant to conventional chemotherapy, and therein requiring urgent preclinical modeling for pharmaceutical testing. We generated a novel serous ovarian carcinoma model by employing Ovgp1-driven Cre recombinase to catalyze CRISPR-Cas9-medicated ablation of the Trp53, Rb1 and Nf1 tumor suppressor genes in the mouse ovary (m-sgPRN mice). The gene encoding cyclin dependent kinase 12 (CDK12) is among the most frequently inactivated in HGS-OvCa. Its loss corresponds with increased mortality, DNA damage (including tandem duplications) and tumor immunogenicity. Co-ablation of Cdk12 in the m-sgPRN model (m-sgPRN; Cdk12KO mice) accelerated tumor progression leading to bona fide HGS-OvCa, and early mortality. In a conventional (Cre-lox-medicated) Trp53/ Nf1/ Rb1 triple knockout model, Cdk12 ablation (PRN; Cdk12KO mice) effected immune infiltration characterized by CD3, CD8, CD4, and Granzyme B positivity like that seen in clinical HGS-OvCa. We observed recapitulation of this immunogenic phenotype—with corresponding sensitivity to immune checkpoint blockade—in a novel syngeneic allograft model derived from these animals. To screen for synthetic lethal interactions with Cdk12 loss, we conducted a CRISPR-Cas9 screen in PRN; Cdk12KO cell lines. The gene encoding CDK12 paralog CDK13 emerged as the most depleted, suggesting CDK13 could be targeted to promote paralog-induced synthetic lethality as previously demonstrated in CDK12-mutant prostate cancer. Indeed, m-sgPRN; Cdk12KO and PRN; Cdk12KO -derived cell lines exhibited enhanced sensitivity to the CDK13/12 degrader YJ1206. Our work defines CDK13-targeting as a novel treatment modality for CDK12-inactive HGS-OvCa while establishing biological resources for the in vivo modeling of this disease.
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Project description:We describe the epigenetic profiling of the H3K9me2 and HP1a in Drosophila third instar larvae before and after CDK12 depletion by RNA interference (RNAi). Here we show that CDK12 regulates heterochromatin dynamics in Drosophila chromosomes. Depletion of CDK12 induces the increased HP1a and H3K9me2 binding profile on the coding region of euchromatic genes, with the X chromosome being the most affected. These results are consistent with the polytene chromosome immunostaining pattern of HP1a and H3K9me2 after CDK12 knockdown in our initial cytological observations, which show that CDK12 depletion induce heterochromatin spreading on euchromatic arms, especially on the X chromosome. This study describes a novel role of the CDK12 complex in controlling the epigenetic transition between euchromatin and heterochromatin. Examination of the genome-wide H3K9me2 and HP1a binding profile in wildtype larvae (WT) and CDK12-depleted larvae (CDK12-KD). Examination of the genome-wide CDK12 binding profile in wildtype larvae (WT). Twelve independent immunoprecipitations were conducted for each antibody. Two biological replicates were performed.
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Project description:Cyclin-dependent kinase 12 (CDK12) phosphorylates the carboxyl-terminal domain (CTD) of RNA polymerase II (pol II) but its roles in transcription beyond the expression of DNA damage response genes remain unclear. Here, we have used TT-seq and mNET-seq to monitor the direct effects of rapid CDK12 inhibition on transcription activity and CTD phosphorylation in human cells. CDK12 inhibition causes a genome-wide defect in transcription elongation and a global reduction of CTD Ser2 and Ser5 phosphorylation. The elongation defect is explained by the loss of the elongation factors LEO1 and CDC73, part of PAF1 complex, and SPT6 from the newly-elongating pol II. Our results indicate that CDK12 is a general activator of pol II transcription elongation and indicate that it targets both Ser2 and Ser5 residues of the pol II CTD.
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Project description:Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype of metastatic castration resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 loss per se is sufficient to drive prostate cancer development—either alone, or in the context of other genetic alterations—and whether CDK12-mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation is sufficient to induce preneoplastic lesions in the mouse prostate. Allograft-based CRISPR screening demonstrated that Cdk12 loss is positively associated with p53 inactivation, but negatively associated with Pten inactivation—similar to what is seen in human mCRPC. Consistent with this, ablation of Cdk12 in prostate organoids with concurrent p53 loss promotes their proliferation and ability to form tumors in mice, while Cdk12 knockout in the Pten-null prostate cancer mouse model abrogates tumor growth. Bigenic CDK12 and p53 loss allografts represent a new syngeneic model for the study of prostate cancer. Cdk12-null organoids (either with or without p53 co-ablation) and patient-derived xenografts from tumors with CDK12 inactivation are highly sensitive to inhibition or degradation of its paralog kinase, CDK13. Together, these data identify CDK12 as a bona fide tumor suppressor gene with impact on tumor progression and paralog-based synthetic lethality is a promising strategy for treating CDK12 mutant mCRPC.
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Project description:Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype of metastatic castration resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 loss per se is sufficient to drive prostate cancer development—either alone, or in the context of other genetic alterations—and whether CDK12-mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation is sufficient to induce preneoplastic lesions in the mouse prostate. Allograft-based CRISPR screening demonstrated that Cdk12 loss is positively associated with p53 inactivation, but negatively associated with Pten inactivation—similar to what is seen in human mCRPC. Consistent with this, ablation of Cdk12 in prostate organoids with concurrent p53 loss promotes their proliferation and ability to form tumors in mice, while Cdk12 knockout in the Pten-null prostate cancer mouse model abrogates tumor growth. Bigenic CDK12 and p53 loss allografts represent a new syngeneic model for the study of prostate cancer. Cdk12-null organoids (either with or without p53 co-ablation) and patient-derived xenografts from tumors with CDK12 inactivation are highly sensitive to inhibition or degradation of its paralog kinase, CDK13. Together, these data identify CDK12 as a bona fide tumor suppressor gene with impact on tumor progression and paralog-based synthetic lethality is a promising strategy for treating CDK12 mutant mCRPC.
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