GEO series

Single-cell transcriptome analysis reveals subtype-specific clonal evolution and microenvironmental changes in liver metastasis of pancreatic adenocarcinoma and their clinical implications

GSE263733 Homo sapiens Expression profiling by high throughput sequencing 218 samples Submitted 2024/04/25 Platform GPL20795

Summary

Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes. However, the precise characterization of diverse cell populations and their crosstalk associated with PDAC progression and metastasis is still challenging. We performed single-cell RNA sequencing (scRNA-seq) of treatment-naive primary PDAC samples with and without paired liver metastasis samples to understand the interplay between ITH and TME in the PDAC evolution and its clinical associations. scRNA-seq analysis revealed that even a small proportion (~30%) of basal-like malignant ductal cells could lead to poor chemotherapy response and patient survival and that epithelial-mesenchymal transition programs were largely subtype-specific. The clonal homogeneity significantly increased with more prevalent and pronounced copy number gains of oncogenes, such as KRAS and ETV1, and losses of tumor suppressor genes, such as SMAD2 and MAP2K4, along PDAC progression and metastasis. Moreover, diverse immune cell populations, including naive SELLhi regulatory T cells (Tregs) and activated TIGIThi Tregs, contributed to shaping immunosuppressive TMEs of PDAC through cellular interactions with malignant ductal cells in PDAC evolution. Importantly, the proportion of basal-like ductal cells negatively correlated with that of immunoreactive cell populations, such as cytotoxic T cells, but positively correlated with that of immunosuppressive cell populations, such as Tregs. We uncover that the proportion of basal-like subtype is a determinant for chemotherapy response and patient outcome, and that PDAC clonally evolves with subtype-specific dosage changes of cancer-associated genes by forming immunosuppressive microenvironments in its progression and metastasis.

Published in

Park JK, Jeong HO, Kim H et al. · Molecular cancer 2024 · PMID 38702773 · doi:10.1186/s12943-024-02003-0

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Direct links to NCBI, no account and no request form: the whole study as GSE263733_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 218 samples. Raw sequencing reads are also available from ENA.

Whole study · RAW.tar ↓ Series matrix ↓ All supplementary files ↗ Raw reads on ENA ↗

Also filed as BioProject PRJNA948891 and SRA study SRP429394. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 38702773) ↗

Study design

8 conditions, mostly with about 8 replicates each

adult pancreas; PB2032-PAAD-T_S1_L ×8 adult pancreas; PB2032-PAAD-T_S2_L ×8 adult pancreas; PB2032-PAAD-T_S3_L ×8 adult pancreas; PB2032-PAAD-T_S4_L ×8 adult pancreas; PB2032-PAAD-T2_S17_L ×2 adult pancreas; PB2032-PAAD-T2_S18_L ×2 adult pancreas; PB2032-PAAD-T2_S19_L ×2 adult pancreas; PB2032-PAAD-T2_S20_L ×2

Supports a between-group comparison across 40 samples.

8 replicated groups read from the first 40 of 218 sample titles; they account for 40 of them. Check it against the sample list below before relying on it.

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