Refined molecular taxonomy and treatment remodeling of pancreatic cancer using single-cell resolution
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA834096 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19039304.fastq.gz | Fastqsanger.gz | |||
| SRR19039305.fastq.gz | Fastqsanger.gz | |||
| SRR19039306.fastq.gz | Fastqsanger.gz | |||
| SRR19039307.fastq.gz | Fastqsanger.gz | |||
| SRR19039308.fastq.gz | Fastqsanger.gz |
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and treatment-refractory cancer. Molecular stratification in pancreatic cancer remains rudimentary and does not yet inform clinical management or therapeutic development. Here we construct a high-resolution molecular landscape of the multicellular subtypes and spatial communities that compose PAC using single-nucleus RNA-seq and whole-transcriptome digital spatial profiling (SP) of 43 primary PDAC tumor specimens that either received neoadjuvant therapy or were treatment-naïve. We uncovered expression programs across malignant cells and fibroblasts, including a newly-identified neural-like progenitor malignant cell program that was enriched after chemotherapy and radiotherapy and associated with poor prognosis in independent cohorts. Integrating spatial and cellular profiles revealed three multicellular communities: classical, squamoid-basaloid, and treatment-enriched. Our refined molecular and cellular taxonomy can advance precision oncology in PAC through stratification in clinical trials and as roadmap for therapeutic targeting of specific cellular phenotypes and multicellular interactions.
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Project description:Taxonomy of fibroblasts and progenitors in the synovial joint at single-cell resolution
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Project description:Even though urothelial cancer (UC) is the fourth common tumor type among males, progress in treatment development has been deficient. Pathological assessment provides the urologists with only a broad classification, complicated by frequent disagreement among pathologist and the co-existence of different grading systems. Consequently, there is a great need for an objective, reproducible and biologically relevant classification system to make treatment more efficient. In the present investigation we present a molecular taxonomy for UC stratification based on integrated genomics. We used gene expression profiles from 308 UC to define seven molecular subtypes using step-by-step partitions and a bootstrap approach. Results were validated in three independent and publically available data sets. The subtypes differ significantly with respect to expression of cell cycle genes, of receptor tyrosine kinases particularity FGFR3, ERBB2 (HER2), and EGFR, of an FGFR3 associated gene expression signature, of cytokaratins, and of cell adhesion genes. The subtypes also differ significantly with respect to FGFR3, PIK3CA, and TP53 mutations. The expression of key proteins was validated by IHC on TMA. A further inspection indicated that the subtypes could be reduced to four major types of UC; Urobasal/D-driven, Genomically unstable/E-driven, Evolved urobasal, and Basal/SCC like, with characteristic and highly divergent molecular phenotypes. We show that the molecular subtypes cut across pathological classification and that tumors classified as one subtype maintain their characteristic molecular phenotype irrespective of pathological stage and grade. Available data from the Drugbank database and the Cochrane central registry of controlled trials indicate that susceptibility to specific drugs is more likely to be associated with the molecular stratification than with pathological classification. The presented molecular taxonomy stratifies UC into subtypes with distinct molecular phenotypes and biological properties. We anticipate that the molecular taxonomy will be a useful tool in future clinical investigations. Total RNA from fresh-frozen resection samples of 308 urothelial carcinomas was hybridized to the Illumina HumanHT-12 V3.0 expression beadchip arrays (Illumina Inc) at the SCIBLU Genomics Centre at Lund University Sweden (http://www.lth.se/sciblu). Supplementary files: GSE32894_non-normalized_308UCsamples.txt file = Raw intensity values for 308 UC (urothelial tumor) samples subjected only to background correction. GSE32894_reps_normals_preprocess*.txt files = Descriptive details and non-normalized data for technical replicates and normal samples that were used only in the preprocessing of the data. This dataset partly overlaps with Series GSE32549. Names of the overlapping sample names are the same, but the title of each sample is unique to the hybridization.
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Project description:Background and Aims: Acinar to ductal metaplasia (ADM) is crucial in the development of pancreatic ductal adenocarcinoma (PDAC). However, our understanding of the induction and resolution of ADM remains limited. We conducted comparative transcriptome analyses to identify conserved mechanisms of ADM in mouse and human. Methods: We identified Sox4 among the top upregulated genes. We validated the analysis by RNA in situ hybridization (ISH). We performed experiments in mice with acinar-specific deletion of Sox4 (Ptf1a: CreER; Rosa26-LSL-YFPLSL-YFP; Sox4fl/fl ) with and without an activating mutation in Kras (KrasLSL-G12D/+). Mice were given caerulein to induce pancreatitis. We performed phenotypic analysis by immunohistochemistry, tissue decellularization and single cell RNA sequencing. Results: We demonstrated that Sox4 is reactivated in ADM and PanINs. Contrary to findings in other tissues, Sox4 actually counteracts cellular dedifferentiation and helps maintain tissue homeostasis. Moreover, our investigations unveiled the indispensable role of Sox4 in the specification of mucin-producing cells and tuft-like cells from acinar cells. We identified Sox4-dependent non-cell-autonomous mechanisms regulating the stromal reaction during disease progression. Notably, Sox4-inferred targets are activated upon KRAS inactivation and tumor regression. Conclusions: Our results indicate that our transcriptome analysis can be used to investigate conserved mechanisms of tissue injury. We demonstrate that Sox4 acts as a switch to promote healing in pancreatic injury and cancer initiation and is activated upon Kras ablation and tumor regression in mice. By uncovering novel potential strategies to promote tissue homeostasis, our findings offer new avenues for preventing the development of PDAC.
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Project description:<p>Neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) has emerged to play parallel roles in both neurobiology and oncology. Apart from receptor-mediated signaling transduction pattern, serotonin can be covalently integrated into histone (the post-translational modification known as histone serotonylation) and serve as an epigenetic mark associated with permissive gene expression. However, how histone serotonylation influences tumorigenesis is yet to be understood. In this study, we observe the higher levels of histone serotonylation (H3K4me3Q5ser) and transglutaminases 2 (TGM2, the enzyme catalyzing serotonylation) in both pancreatic ductal adenocarcinoma (PDAC) tissues and cell lines in comparison with their normal counterparts, and inhibition of histone serotonylation suppresses PDAC development. Mechanistically, we demonstrate that TGM2-mediated histone serotonylation at promoter of the gene encoding stearoyl-CoA desaturase (SCD) up-regulates its expression and drives PDAC development by lipid metabolism remodeling. Collectively, this study reveals histone serotonylation as an important driver of PDAC tumorigenesis.Neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) has emerged to play parallel roles in both neurobiology and oncology. Apart from receptor-mediated signaling transduction pattern, serotonin can be covalently integrated into histone (the post-translational modification known as histone serotonylation) and serve as an epigenetic mark associated with permissive gene expression. However, how histone serotonylation influences tumorigenesis is yet to be understood. In this study, we observe the higher levels of histone serotonylation (H3K4me3Q5ser) and transglutaminases 2 (TGM2, the enzyme catalyzing serotonylation) in both pancreatic ductal adenocarcinoma (PDAC) tissues and cell lines in comparison with their normal counterparts, and inhibition of histone serotonylation suppresses PDAC development. Mechanistically, we demonstrate that TGM2-mediated histone serotonylation at promoter of the gene encoding stearoyl-CoA desaturase (SCD) up-regulates its expression and drives PDAC development by lipid metabolism remodeling. Collectively, this study reveals histone serotonylation as an important driver of PDAC tumorigenesis.</p>
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