HuPSA and MoPSA Atlases Reveal Novel Cell Populations and Lineage Plasticity in Prostate Cancer at Single-Cell Level
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1031681 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26501562_1.fastq.gz | Fastqsanger.gz | |||
| SRR26501562_2.fastq.gz | Fastqsanger.gz | |||
| SRR26501563_1.fastq.gz | Fastqsanger.gz | |||
| SRR26501563_2.fastq.gz | Fastqsanger.gz | |||
| SRR26501564_1.fastq.gz | Fastqsanger.gz |
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Project description:Androgen deprivation therapy has improved patient survival. Nevertheless, treatment resistance inevitably emerges due to the complex interplay of tumor heterogeneity and lineage plasticity. We integrated scRNAseq data from multiple studies, comprising both publicly available cohorts and data generated by our research team, and established the HuPSA (Human Prostate Single cell Atlas) and MoPSA (Mouse Prostate Single cell Atlas) datasets. Through unsupervised clustering and manual annotation, we found that both atlases consisted of previously known cell clusters including prostate adenocarcinoma (AdPCa), neuroendocrine prostate cancer (NEPCa), stromal, and immune cell populations. Our analysis also unearthed the less described populations including MMP7+ prostate club cells and two novel lineage plastic cancerous populations, namely Progenitor-like and KRT7. Immunohistochemical staining analysis confirmed the presence of these populations in both human and mouse PCa tissues, reinforcing their significance in PCa pathobiology. Furthermore, employing HuPSA based deconvolution, we scrutinized 877 high-quality human PCa bulk RNAseq samples and reclassified them into different molecular subtypes, including the newly discovered KRT7 and Progenitor-like categories. Moreover, employing supervised dimensional reduction and label transferring techniques, we projected the scRNAseq data derived from C4-2B xenograft tumors onto HuPSA. Our analysis effectively identified the diverse subpopulations within the tumor, including C4-2B derived AdPCa and NEPCa cells as well as the murine cells in the tumor microenvironment. We launched the “PCaAtlas” app (https://pcatools.shinyapps.io/ProAtlas_dev/) for users to visualize genes expression in re-classified human prostatic tissue samples. In conclusion, our study has successfully integrated multiple scRNAseq datasets and made these data easily accessible to researchers. Our results elucidate a roadmap of PCa progression, showcasing the development of heterogeneous populations and the involvement of lineage plasticity. This understanding holds promise for guiding the development of precision medicine in PCa field. Additionally, the HuPSA and MoPSA provide invaluable blueprints for analyzing and interpreting user-generated PCa single-cell RNAseq data.
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Thus, the senescent immune system specifically employs ATLOs to control dichotomic atherosclerosis T cell immune responses. We assembled transcriptome maps of wt and apoe-/- aortae and aorta-draining RLNs and identified ATLOs as major sites of atherosclerosis-specific T cell responses during aging: Transcriptome atlases of wt and apoe-/- abdominal aortae and associated draining RLNs were constructed from laser capture microdissection (LCM)-based whole genome mRNA expression microarrays yielding 6 maps: wt adventitia (tissue-1); wt RLN (tissue-2); apoe-/- ATLOs (tissue-3); apoe-/- RLN (tissue-4); apoe-/- adventitia without adjacent plaques (tissue-5), and plaques (tissue-6). 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In addition, they demonstrate that T cell responses in the diseased aorta are highly territorialized. Finally, these data show that the immune responses carried out in ATLOs differ significantly from those carried out in plaques. We next identified three major clusters within the transcriptome atlases through ANOVA analyses and application of strict filters: An adventitia cluster, a plaque/ATLO cluster, and a LN/plaque cluster. The total number of differentially expressed genes in each cluster were examined for GO terms immune response, inflammatory response, T cell activation, positive regulation of T cell response, and T cell proliferation. 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Finally, the lymph node cluster revealed that though the majority of immune response regulating genes resides in both wt and apoe-/- RLNs (with little differences between them) ATLOs express a selected set of immune response regulating genes at a higher level when compared to LNs. In addition, the inflammatory component of ATLOs when compared to LNs is documented by the finding that many more genes regulating inflammation reside in ATLOs even when compared to those of plaques. Key words: T cell response in atherosclerosis; Laser capture microdissection; transcriptome atlas of atherosclerosis. Citations: Gräbner R. et al. Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice. J Exp Med 2009 Jan 16;206(1):233-48. PMID: 19139167; Moos M. et al. The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2005 Nov;25(11):2386-91. Epub 2005 Sep 22. PMID: 16179593; Beer M. et al. Laser-capture microdissection of hyperlipidemic/ApoE-/- mouse aorta atherosclerosis. Methods Mol Biol. 2011;755:417-28. PMID: 21761324; Weih F. et al. Control of Dichotomic Innate and Adaptive Immune Responses by Artery Tertiary Lymphoid Organs in Atherosclerosis. Front Physiol. 2012;3:226. Epub 2012 Jul 6. PMID: 22783198. Wild-type and apoE-deficient mice on the C57BL/6J genetic background were maintained on a standard mouse chow. Total aortae were removed at the age of 6 (n=3), 32 (n=3), or 78 (n=3) w and microarrays were prepared from total RNA extracts or extracts of atherosclerotic lesions and adventitiae obtained by the use of a laser dissection microscope. In addition, aorta associated LNs or distant LNs were prepared from both mouse genotypes.
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