Abstract 218P
Background
The recent phenotype plasticity model proposes that cancer stem cells (CSCs) constitute a dynamic subpopulation of cancer cells, capable of reversible transition from non-CSC states. Prior studies lacked a nuanced examination of gene expression patterns in this continuum, and the spatial structure of CSCs remained unclear.
Methods
Addressing these limitations, we conducted a comprehensive study that integrated single-cell data (92,820 cells from 40 samples) and spatial data (34,661 spots from 14 samples) to establish a CSC signature and unveil its spatial structure.
Results
A CSC signature comprising 127 genes was developed using Weighted Gene Co-expression Network Analysis (WGCNA). Notably, DSG2 within the CSC signature correlated with chemotherapy resistance in the ORIENT-3 clinical trial. Furthermore, DSG2 emerged as a serum marker for predicting the response to EGFR-TKI-targeted therapy, based on serum proteomics data from 186 patients in the BPI-7711 clinical trial. Spatial analysis revealed the presence of DSG2+ CSCs at the tumor boundary, co-located with POSTN+ myofibroblasts (myCAF), validated by multiplex immunofluorescence. POSTN+ myCAFs expressed metalloproteinases (MMP9 and MMP12) associated with epithelial-mesenchymal transition, constructing an invasive front supporting DSG2+ CSC maintenance. Both DSG2+ CSCs and POSTN+ myCAF were correlated with unfavorable immunotherapy responses in ORIENT-3 clinical trial. Within the co-location area, the MDK signaling pathway exhibited the highest activity in cell-cell communication, identifying MDK-NCL as the main ligand-receptor pair.
Conclusions
This study successfully constructed a CSC signature and demonstrated the co-location of DSG2+ CSCs and POSTN+ myCAF at the tumor boundary, contributing to immunotherapy resistance.
Clinical trial identification
ORIENT-3 phase III trial (NCT03150875); BPI-7711 phase I (NCT03386955) and phase IIa (NCT03812809).
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.