2. Academic Validation
  3. Integrative single-cell RNA-seq and spatial transcriptomics analyses reveal diverse apoptosis-related gene expression profiles in EGFR-mutated lung cancer

Integrative single-cell RNA-seq and spatial transcriptomics analyses reveal diverse apoptosis-related gene expression profiles in EGFR-mutated lung cancer

  • Cell Death Dis. 2024 Aug 9;15(8):580. doi: 10.1038/s41419-024-06940-y.
Motohiro Izumi # 1,  Masanori Fujii # 1,  Ikei S Kobayashi 1,  Vivian Ho 1,  Yukie Kashima 2,  Hibiki Udagawa 2 3,  Daniel B Costa 1,  Susumu S Kobayashi 4 5 6
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
  • 2 Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, 277-8577, Japan.
  • 3 Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, 277-8577, Japan.
  • 4 Department of Medicine, Division of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. skobbidmc@gmail.com.
  • 5 Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, 277-8577, Japan. skobbidmc@gmail.com.
  • 6 Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, 113-8431, Japan. skobbidmc@gmail.com.
  • # Contributed equally.
PMID: 39122703 DOI: 10.1038/s41419-024-06940-y
Abstract

In EGFR-mutated lung Cancer, the duration of response to tyrosine kinase inhibitors (TKIs) is limited by the development of acquired drug resistance. Despite the crucial role played by apoptosis-related genes in tumor cell survival, how their expression changes as resistance to EGFR-TKIs emerges remains unclear. Here, we conduct a comprehensive analysis of apoptosis-related genes, including Bcl-2 and IAP family members, using single-cell RNA sequence (scRNA-seq) and spatial transcriptomics (ST). scRNA-seq of EGFR-mutated lung Cancer cell lines captures changes in apoptosis-related gene expression following EGFR-TKI treatment, most notably BCL2L1 upregulation. scRNA-seq of EGFR-mutated lung Cancer patient samples also reveals high BCL2L1 expression, specifically in tumor cells, while MCL1 expression is lower in tumors compared to non-tumor cells. ST analysis of specimens from transgenic mice with EGFR-driven lung Cancer indicates spatial heterogeneity of tumors and corroborates scRNA-seq findings. Genetic ablation and pharmacological inhibition of BCL2L1/Bcl-xL overcome or delay EGFR-TKI resistance. Overall, our findings indicate that BCL2L1/Bcl-xL expression is important for tumor cell survival as EGFR-TKI resistance emerges.

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