Exploring drug resistance via intercellular crosstalk using spatial transcriptomics in high-grade serous ovarian...

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Poly(ADP-ribose) polymerase inhibitors (PARPis) have improved outcomes for high-grade serous ovarian carcinoma (HGSOC) patients.
• However, not all patients respond to PARPi therapy, necessitating research into resistance mechanisms.
• Spatial transcriptomics offers a novel approach to dissect the tumor microenvironment's role in treatment response.

Purpose of the Study:

• To investigate the molecular mechanisms underlying PARPi resistance in HGSOC using spatial transcriptomics.
• To identify specific signaling pathways and molecular markers associated with PARPi resistance and patient survival.

Main Methods:

• Analysis of eight HGSOC tumor samples using Visium spatial transcriptomics.
• Integrated and spatially resolved transcriptomic analyses to identify key signaling pathways.
• Deconvolution of bulk RNA-sequencing data using single-cell RNA-sequencing data to correlate receptor expression with overall survival (OS).

Main Results:

• Both integrated and spatial analyses identified midkine (MDK) signaling as a key factor in PARPi resistance.
• Specific receptors enhancing MDK signaling in cancer cells were identified.
• High expression of SDC4 in cancer cells was significantly associated with poor OS in HGSOC patients.

Conclusions:

• Midkine (MDK) signaling plays a crucial role in mediating resistance to PARPi in high-grade serous ovarian carcinoma (HGSOC).
• SDC4 expression in cancer cells is a potential prognostic biomarker for poor overall survival in HGSOC patients treated with PARPi.