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Hypoxic microenvironment induced spatial transcriptome changes in pancreatic cancer.

Huizhi Sun1,2, Danfang Zhang2, Chongbiao Huang1

  • 1Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.

Cancer Biology & Medicine
|June 4, 2021
PubMed
Summary

Hypoxia in pancreatic ductal adenocarcinoma (PDAC) alters spatial gene expression, reducing tumor cell subgroups. An invasive subgroup at the tumor front shows increased proliferation and suggests PI3K inhibitors as potential therapeutic targets.

Keywords:
Pancreatic cancerhypoxiaspatial transcriptomic

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Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Hypoxia is a critical hallmark of pancreatic ductal adenocarcinoma (PDAC), correlating with tumor progression and therapeutic resistance.
  • The spatial heterogeneity of hypoxia within PDAC and its impact on tumor biology remain incompletely understood.

Purpose of the Study:

  • To investigate the spatial transcriptomic landscape of pancreatic ductal adenocarcinoma under hypoxic conditions.
  • To identify hypoxia-induced spatial heterogeneity and potential therapeutic targets in PDAC.

Main Methods:

  • Utilized spatial transcriptomics (STs) to analyze gene expression in human PDAC xenografts in mice under hypoxic and normoxic conditions.
  • Clustered ST data based on differentially expressed genes to define spatial organization and molecular signatures.
  • Validated findings using The Cancer Genome Atlas and KM-plotter databases; identified therapeutic targets via CMAP analysis.

Main Results:

  • Spatial transcriptomics revealed a reduction from 9 to 7 tumor cell subgroups in hypoxic PDAC compared to controls.
  • Identified distinct positional characteristics and gene signatures for different subgroups, with subgroup 6 at the invasive front exhibiting enhanced proliferation and stress response under hypoxia.
  • Observed significant changes in hypoxia-related genes (LDHA, TPI1, ENO1); CMAP analysis identified ADZ-6482 (a PI3K inhibitor) as a potential therapeutic target for the invasive subgroup.

Conclusions:

  • This study provides the first spatial transcriptome analysis of hypoxia-induced changes in PDAC.
  • Identified specific tumor cell subgroups and their spatial distribution influenced by the hypoxic microenvironment.
  • Highlighted potential therapeutic strategies, including PI3K inhibition, for targeting invasive PDAC under hypoxic conditions.