Organoid-based single cell sequencing revealed the lineage evolution during docetaxel treatment in gastric cancer

Dejun Yang1, Xin Zhang2, Zunqi Hu1

  • 1Department of Gastrointestinal Surgery, Second Affiliated Hospital (Changzheng Hospital) of Naval Medical University, Huangpu District, No. 415 Fengyang Road, Shanghai, 200003, China.

Cancer Letters
|March 21, 2025
PubMed

Insights

This study identified key genes (FOS, IFI27, PTTG1IP) driving docetaxel resistance in gastric cancer. Targeting these genes can restore drug sensitivity and improve treatment outcomes for patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Docetaxel resistance is a significant obstacle in gastric cancer treatment.
  • Understanding the cellular and molecular mechanisms of resistance is crucial for developing effective therapies.

Purpose of the Study:

  • To investigate the cellular and molecular alterations associated with docetaxel resistance in gastric cancer.
  • To identify key genes involved in docetaxel resistance.
  • To evaluate the therapeutic potential of targeting these resistance-related genes.

Main Methods:

  • Establishment of docetaxel-sensitive and -resistant gastric cancer organoids.
  • Single-cell RNA sequencing to analyze cellular and molecular changes.
  • Pseudo-time trajectory analysis to understand cell differentiation.
  • Gene knockdown experiments in cell lines and organoids.
  • In vivo studies to assess tumor growth.

Main Results:

  • Resistant gastric cancer organoids showed increased secretory, immune-chemotactic, and transitional cell populations.
  • Upregulation of FOS, IFI27, and PTTG1IP was observed in resistant organoids and patient samples.
  • Resistant cells were found at terminal differentiation stages.
  • Knockdown of FOS, IFI27, and PTTG1IP restored docetaxel sensitivity by modulating ROS, autophagy, and apoptosis.
  • In vivo silencing of these genes reduced tumor growth under docetaxel treatment.

Conclusions:

  • FOS, IFI27, and PTTG1IP are key drivers of docetaxel resistance in gastric cancer.
  • Targeting FOS, IFI27, and PTTG1IP presents a promising strategy to overcome docetaxel resistance.
  • This approach could lead to improved treatment outcomes for gastric cancer patients.