Scholarlink

<p>Pancreatic ductal adenocarcinoma (PDAC) is a high-mortality cancer characterized by its aggressive, treatment-resistant phenotype and a complex tumour microenvironment (TME) featuring significant hypoxia. Bulk transcriptomic analysis has identified the “classical” and “basal-like” transcriptional subtypes which have prognostic value; however, it is not well-established how microenvironmental heterogeneity contributes to these transcriptional signatures. Here, we exploited the TRACER platform to perform single cell transcriptome analysis of organoids at specific spatial locations to explore the effect of gen and other cell-generated microenvironmental gradients on organoid heterogeneity. We found that the microenvironmental gradients present in TRACER significantly impact the distribution of organoid transcriptional phenotypes and the enrichment of gene sets linked to cancer progression and treatment resistance. More significantly, we found that microenvironmental gradients, predominantly oxygen, drive changes in the expression of classical and basal-like transcriptional subtype gene signatures. This work suggests that hypoxia contributes to determining transcriptional subtypes in PDAC tumour cells independent of additional cells in the TME and broadly highlights the importance of considering microenvironmental gradients such as oxygen in organoid-based studies.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Analysis of an engineered organoid model of pancreatic cancer identifies hypoxia as a contributing factor in determining transcriptional subtypes

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月2日

查看全文
  • Natalie Landon-Brace,
  • Simon Latour,
  • Brendan T. Innes,
  • Michelle Nurse,
  • Jose L. Cadavid,
  • Ileana L. Co,
  • Cassidy M. Tan,
  • Ferris Nowlan,
  • Sibyl Drissler,
  • Faiyaz Notta,
  • Hartland Warren Jackson,
  • Gary D. Bader,
  • Alison P. McGuigan

摘要

Pancreatic ductal adenocarcinoma (PDAC) is a high-mortality cancer characterized by its aggressive, treatment-resistant phenotype and a complex tumour microenvironment (TME) featuring significant hypoxia. Bulk transcriptomic analysis has identified the “classical” and “basal-like” transcriptional subtypes which have prognostic value; however, it is not well-established how microenvironmental heterogeneity contributes to these transcriptional signatures. Here, we exploited the TRACER platform to perform single cell transcriptome analysis of organoids at specific spatial locations to explore the effect of gen and other cell-generated microenvironmental gradients on organoid heterogeneity. We found that the microenvironmental gradients present in TRACER significantly impact the distribution of organoid transcriptional phenotypes and the enrichment of gene sets linked to cancer progression and treatment resistance. More significantly, we found that microenvironmental gradients, predominantly oxygen, drive changes in the expression of classical and basal-like transcriptional subtype gene signatures. This work suggests that hypoxia contributes to determining transcriptional subtypes in PDAC tumour cells independent of additional cells in the TME and broadly highlights the importance of considering microenvironmental gradients such as oxygen in organoid-based studies.