Single-cell RNA-sequencing reveals an intratumor heterogeneity in pancreatic adenocarcinoma [ATAC-seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE191203 | GEO | 2023/04/19
REPOSITORIES: GEO
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Project description:We examined the intratumor heterogeneity in S2-VP10 xenograft by single-cell RNA-sequencing. We found a hierarchical tumor progression originating from ROR1high cells with a partial EMT gene signature. We also found that ROR1high cells have the strong capacity as tumor-initiating cells to support tumorigenecity, chemoresistance, and metastasis. CUT&RUN and ATAC-sequencing revealed that ROR1 gene expression is regulated through YAP-BRD4 axis. Together, these data uncover a role for ROR1high cells in tumor progression, suggesting that ablating ROR1high tumor-initiating cells may be the alternative therapeutic strategy in pancreatic adenocarcinoma.
2023-04-19 | GSE191202 | GEO
Project description:We examined the intratumor heterogeneity in S2-VP10 xenograft by single-cell RNA-sequencing. We found a hierarchical tumor progression originating from ROR1high cells with a partial EMT gene signature. We also found that ROR1high cells have the strong capacity as tumor-initiating cells to support tumorigenecity, chemoresistance, and metastasis. CUT&RUN and ATAC-sequencing revealed that ROR1 gene expression is regulated through YAP-BRD4 axis. Together, these data uncover a role for ROR1high cells in tumor progression, suggesting that ablating ROR1high tumor-initiating cells may be the alternative therapeutic strategy in pancreatic adenocarcinoma.
2023-04-19 | GSE191198 | GEO
Project description:We examined the intratumor heterogeneity in S2-VP10 xenograft by single-cell RNA-sequencing. We found a hierarchical tumor progression originating from ROR1high cells with a partial EMT gene signature. We also found that ROR1high cells have the strong capacity as tumor-initiating cells to support tumorigenecity, chemoresistance, and metastasis. CUT&RUN and ATAC-sequencing revealed that ROR1 gene expression is regulated through YAP-BRD4 axis. Together, these data uncover a role for ROR1high cells in tumor progression, suggesting that ablating ROR1high tumor-initiating cells may be the alternative therapeutic strategy in pancreatic adenocarcinoma.
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Project description:Intratumor heterogeneity is a major obstacle to effective cancer treatment. Current methods to study intratumor heterogeneity using single-cell RNA sequencing (scRNAseq) lack information on the spatial organization of cells. While state-of-the art spatial transcriptomics methods capture the spatial distribution, they either lack single cell resolution or have relatively low transcript counts. Here, we introduce spatially annotated single cell sequencing, based on the previously developed functional single cell sequencing (FUNseq) technique, to spatially profile tumor cells with deep scRNA-seq and single cell resolution. Using our approach, we profiled cells located at different distances from the center of a 2D epithelial cell mass. By profiling the cell patch in concentric bands of varying width, we showed that cells at the outermost edge of the patch responded strongest to their local microenvironment, behaved most invasively, and activated the process of epithelial-to-mesenchymal transition (EMT) to migrate to lowconfluence areas. We inferred cell-cell communication networks and demonstrated that cells in the outermost ~10 cell wide band, which we termed the invasive edge, induced similar phenotypic plasticity in neighboring regions. Applying FUNseq to spatially annotate and profile tumor cells enables deep characterization of tumor subpopulations, thereby unraveling the mechanistic basis for intratumor heterogeneity.
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Project description:We previously reported that ROR1 is a crucial downstream gene for the TTF-1/NKX2-1 lineage-survival oncogene in lung adenocarcinoma, while others have found altered expression of ROR1 in multiple cancer types. Accumulated evidence therefore indicates ROR1 as an attractive molecular target, though it has yet to be determined whether targeting Ror1 can inhibit tumor development and growth in vivo. To this end, genetically engineered mice carrying homozygously floxed Ror1 alleles and an SP-C promoter-driven human mutant EGFR transgene were generated. Ror1 ablation resulted in marked retardation of tumor development and progression in association with reduced malignant characteristics and significantly better survival. Interestingly, gene set enrichment analysis identified a hypoxia-induced gene set (HALLMARK_HYPOXIA) as most significantly downregulated by Ror1 ablation in vivo, which led to findings showing that ROR1 knockdown diminished HIF-1α expression under normoxia and clearly hampered HIF-1α induction in response to hypoxia in human lung adenocarcinoma cell lines. The present results directly demonstrate the importance of Ror1 for in vivo development and progression of lung adenocarcinoma, and also identify Ror1 as a novel regulator of Hif-1α. Thus, a future study aimed at the development of a novel therapeutic targeting ROR1 for treatment of solid tumors such as seen in lung cancer, which are frequently accompanied with a hypoxic tumor microenvironment, is warranted.
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Project description:Emerging biomarkers based on medical images and molecular characterization of tumor biopsies open up for combining the two disciplines and exploiting their synergy in treatment planning. We compared pretreatment classification of cervical cancer patients by two previously validated imaging- and gene-based hypoxia biomarkers, evaluated the influence of intratumor heterogeneity, and investigated the benefit of combining them in prediction of treatment failure. The imaging-based biomarker was hypoxic fraction, determined from diagnostic dynamic contrast enhanced (DCE)-MR images. The gene-based biomarker was a hypoxia gene expression signature determined from tumor biopsies. Paired data were available for 118 patients. Intratumor heterogeneity was assessed by variance analysis of MR images and multiple biopsies from the same tumor. The two biomarkers were combined using a dimension-reduction procedure. The biomarkers classified 75% of the tumors with the same hypoxia status. Both intratumor heterogeneity and distribution pattern of hypoxia from imaging were unrelated to inconsistent classification by the two biomarkers, and the hypoxia status of the slice covering the biopsy region was representative of the whole tumor. Hypoxia by genes was independent on tumor cell fraction and showed minor heterogeneity across multiple biopsies in 9 tumors. This suggested that the two biomarkers could contain complementary biological information. Combination of the biomarkers into a composite score led to improved prediction of treatment failure (HR:7.3) compared to imaging (HR:3.8) and genes (HR:3.0) and prognostic impact in multivariate analysis with clinical variables. In conclusion, combining imaging- and gene-based biomarkers enables more precise and informative assessment of hypoxia-related treatment resistance in cervical cancer, independent of intratumor heterogeneity.
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Project description:Esophageal squamous cell carcinoma (ESCC) is among the most common malignancies, but little is known about the spatial intratumor heterogeneity (ITH) and the temporal clonal evolutionary processes in this cancer. Interestingly, the epigenetic profiling also showed strong evidence of spatial ITH, and the phyloepigenetic trees were extremely similar with the phylogenetic ones, indicating the interplay and co-dependency of genetic and epigenetic alterations in ESCC. We found that several genes were both mutated and hypermethylated at their promoters, such as ASXL1 and EPHA7. Our integrated investigations of the spatial ITH and the temporal clonal evolution might provide insights into developing biomarkers for early diagnosis of ESCC, as well as personalized therapeutic targets for treating this malignancy. DNA methylation profiles of 12 tumor regions and 2 matched normal esophageal epithelial tissues from three M-WES-examined ESCC cases (ESCC01, ESCC03 and ESCC05) were performed using Illumina Infinium HumanMethylation450K platform (Illumina, San Diego, CA) at the Epigenome Center of University of Southern California.
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Project description:To examine the functional consequences of intratumor heterogeneity, subclonal populations (SCPs) were derived from the MDA-MB-468 triple-negative breast cancer cell line. Characterization of these SCPs revealed considerable variation in SCP tumor forming capacity with SCP #32 (SCP32) having an exceptional high tumor forming capacity. To investigate the proteomic differences between tumors of SCP32 and other SCPs, in TMT1, isobaric tandem mass tag (TMT) labeling combined with LC-MS/MS (TMT-MS) was performed on tumors of SCP03, SCP29 and SCP32 (n = 3 each) collected at 2 months post transplantation. In TMT2, isobaric tandem mass tag (TMT) labeling combined with LC-MS/MS (TMT-MS) was performed on tumors of the parental MDA-MB-468 cell line (n = 2), and both barcoded and non-barcoded versions SCP29 and SCP32 (two each) collected at 2 months post transplantation.
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