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Single-cell RNA-seq profiling of ARID1A-loss-associated transcriptional heterogeneity and clonal diversification in pancreatic cancer cells

ABSTRACT: This Series contains additional single-cell RNA-seq datasets associated with a study of how loss of epigenetic regulators, particularly ARID1A, reshapes transcriptional heterogeneity in pancreatic ductal adenocarcinoma cells. The shPseuMO-Tag system couples genetic perturbation with clonal lineage tracing. The datasets include an initial epigenetic-modifier screen, an ARID1A knockdown time course, a large-scale pooled five-shRNA experiment, acute SMARCA4 degradation, independent experiments in multiple PDAC cell lines, and matched pre-injection and lung-colonization samples. In the independent multi-cell-line experiment, BxPC3, HPAC, SW1990, and SUIT-2 were profiled using independently derived clones, whereas HPAFII was analyzed as a pooled population because stable single-cell-derived HPAFII clones could not be established.

ORGANISM(S): Homo sapiens

PROVIDER: GSE348038 | GEO | 2026/09/22

REPOSITORIES: GEO

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Project description:Purpose: Chemotherapy is pivotal in the multimodal treatment of pancreatic cancer patients. In recent years, technical advances have developed experimental methods that unveiled a high degree of inter- and intratumoral heterogeneity in pancreatic cancer. We hypothesized that intratumoral heterogeneity (ITH) impacts response to gemcitabine treatment and demands specific targeting of resistant subclones. Experimental Design: We addressed the effect of ITH on response to gemcitabine treatment using single cell-derived cell lines (SCDCL) from the classical-like cell line BxPC3 and the basal-like cell line Panc-1 which were analyzed by mRNA-seq and mass spectrometry. Results: Individual SCDCLs of the parental tumor cell populations of BxPC3 and Panc-1 showed considerable heterogeneity in response to gemcitabine. Unsupervised principal component analysis (PCA) including the 1,000 most variably expressed genes showed a clustering of the SCDCLs according to their respective sensitivity to gemcitabine treatment for BxPC3, while this clustering was less clear for Panc-1. In BxPC3 SCDCLs, enriched signaling pathways EMT, TNF signaling via NfKB, and IL2STAT5 signaling correlated with more resistant behavior to gemcitabine. In Panc-1 SCDCLs MYC targets V1 and V2 as well as E2F targets were associated with stronger resistance to gemcitabine. Feature extraction of proteomes again identified less proteins whose expression was associated with the response of individual SCDCLs in Panc-1 compared to BxPC3. Based on molecular profiles, we could show that the gemcitabine-resistant SCDCLs of both BxPC3 and Panc-1 are more sensitive to the BET inhibitor JQ1 compared to the respective gemcitabine-sensitive SCDCLs. Conclusions: Our model system of SCDCLs identified gemcitabine-resistant subclones within a parental tumor population and provides evidence for the critical role of ITH for treatment response in pancreatic cancer. Through molecular profiling, we identified specific signaling pathways and protein signatures that might help to explain the differential response to treatment among clones. We exploited these molecular differences for an improved and more targeted therapy of resistant subclones of a heterogeneous tumor.

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Single-cell RNA-seq profiling of ARID1A-loss-associated transcriptional heterogeneity and clonal diversification in pancreatic cancer cells

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