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Reversal of lineage plasticity in RB1/TP53-deleted prostate cancer through FGFR and Janus kinase inhibition

ABSTRACT: Reversal of lineage plasticity in RB1/TP53-deleted prostate cancer through FGFR and Janus kinase inhibition

PROVIDER: PRJNA778250 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16821448_1.fastq.gz	Fastqsanger.gz
	SRR16821448_2.fastq.gz	Fastqsanger.gz
	SRR16821449_1.fastq.gz	Fastqsanger.gz
	SRR16821449_2.fastq.gz	Fastqsanger.gz
	SRR16821450_1.fastq.gz	Fastqsanger.gz

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Reversal of lineage plasticity in RB1/TP53-deleted prostate cancer through FGFR and Janus kinase inhibition

Project description:The inherent plasticity of tumor cells provides a mechanism of resistance to many molecularly targeted therapies, exemplified by adeno-to-neuroendocrine lineage transitions seen in prostate and lung cancer. Here we investigate the root cause of this lineage plasticity in a primary murine prostate organoid model that mirrors the lineage transition seen in patients. These cells lose luminal identity within weeks following deletion of Trp53 and Rb1, ultimately acquiring an Ar-negative, Syp+ phenotype after orthotopic in vivo transplantation. Single-cell transcriptomic analysis revealed progressive mixing of luminal-basal lineage features after tumor suppressor gene deletion, accompanied by activation of Jak/Stat and Fgfr pathway signaling and interferon-a and -g gene expression programs prior to any morphologic changes. Genetic or pharmacologic inhibition of Jak1/2 in combination with FGFR blockade restored luminal differentiation and sensitivity to antiandrogen therapy in models with residual AR expression. Collectively, we show lineage plasticity initiates quickly as a largely cell-autonomous process and, through newly developed computational approaches, identify a pharmacological strategy that restores lineage identity using clinical grade inhibitors.

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Combined TP53 and RB1 Loss Promotes Prostate Cancer Resistance to a Broad Spectrum of Cancer Therapeutics and Confers Vulnerability to Replication Stress

Project description:Prostate cancers (PC) with loss of the potent tumor suppressors TP53 and RB1 exhibit poor outcomes that include resistance to androgen receptor (AR) pathway antagonists. TP53 and RB1 also influence cell plasticity and are frequently lost in PCs with neuroendocrine (NE) differentiation. Therapeutic strategies that address these aggressive variant PCs are urgently needed. Using deep genomic profiling of 410 metastatic biopsies, we determined the relationships between combined TP53 and RB1 loss and PC phenotypes. Notably, 40% of TP53/RB1 deficient tumors were classified as AR-active adenocarcinomas indicating that NE differentiation is not an obligate consequence of TP53/RB1 inactivation. A gene expression signature reflecting TP53/RB1 loss was associated with diminished responses to AR antagonists and reduced survival. These tumors exhibit high proliferation rates and evidence of elevated DNA repair processes. While tumor cells lacking TP53/RB1 were highly resistant to all single agent therapeutics, the combination of pharmacological PARP and ATR inhibition produced significant responses, reflecting a clinically-exploitable vulnerability resulting from replication stress.

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Project description:MicroRNAs (miRNAs) are important regulators of gene expression. Their levels are precisely controlled through modulating the activity of the microprocesser complex (MC). Here we report that JANUS, a homology of the conserved U2 snRNP assembly factor in yeast and human, is required for miRNA accumulation. JANUS associates with MC components Dicer-like 1 and SERRATE (SE) and directly binds the stem-loop of pri-miRNAs. In a hypomorphic janus mutant, the activity of DCL1, the numbers of MC, and the interaction of primary miRNA transcript (pri-miRNAs) with MC are reduced. These data suggest that JANUS promotes the assembly and activity of MC through its interaction with MC and/or pri-miRNAs. In addition, JANUS modulates the transcription of some pri-miRNAs as it binds the promoter of pri-miRNAs and promotes Pol II occupancy of at their promoters. Moreover, global splicing defects are detected in janus. Taken together, our study reveals a novel role of a conserved splicing factor in miRNA biogenesis.

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Project description:Safe and efficient antibacterial materials are urgently needed to combat drug-resistant bacteria and biofilm-associated infections. The rational design of nanoparticles for flexible elimination of biofilms by alternative strategies remains challenging. Herein, we propose the fabrication of Janus-structured nanoparticles targeting extracellular polymeric substance to achieve dispersion or near-infrared (NIR) light-activated photothermal elimination of drug-resistant biofilms, respectively. Asymmetrical Janus-structured dextran-bismuth selenide (Dex-BSe) nanoparticles are fabricated by a facile strategy to exploit synergistic effects of both components. The biocompatible dextran domain with the maximum exposure endows the Janus nanoparticles with biofilm penetration, targeting, and dispersion functions. Interestingly, Janus Dex-BSe nanoparticles realize enhanced dispersal of biofilms over time compared with dextran nanoparticles while the underlying molecular mechanisms are further revealed by RNA-sequencing transcriptomics analysis. Alternatively, taking advantage of the preferential accumulation of nanoparticles at infection sites, the self-propelled active motion induced by the unique Janus structure enhances the photothermal killing effect under NIR light irradiation, thereby eradicating the biofilm. Given these favorable features, the antibiofilm activity of Janus Dex-BSe against methicillin-resistant Staphylococcus aureus (MRSA) was first validated in vitro. More importantly, the flexible application of Janus Dex-BSe nanoparticles for biofilm removal or NIR-triggered eradication in vivo was demonstrated by MRSA-infected mouse excisional wound model and abscess model, respectively. The currently developed Janus nanoplatform holds great promise for the efficient elimination of drug-resistant biofilms in diverse antibacterial scenarios.

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