Spatial transcriptomics reveals discrete tumour microenvironments and autocrine loops within ovarian cancer subclones

Elena Denisenko; Leanne de Kock; Adeline Tan; Aaron B Beasley; Maria Beilin; Matthew E Jones; Rui Hou; Dáithí Ó Muirí; Sanela Bilic; G Raj K A Mohan; Stuart Salfinger; Simon Fox; Khaing P W Hmon; Yen Yeow; Youngmi Kim; Rhea John; Tami S Gilderman; Emily Killingbeck; Elin S Gray; Paul A Cohen; Yu Yu; Alistair R R Forrest

doi:10.1038/s41467-024-47271-y

Spatial transcriptomics reveals discrete tumour microenvironments and autocrine loops within ovarian cancer subclones

Nat Commun. 2024 Apr 3;15(1):2860. doi: 10.1038/s41467-024-47271-y.

Authors

Elena Denisenko¹, Leanne de Kock^{2

3}, Adeline Tan⁴, Aaron B Beasley⁵, Maria Beilin⁶, Matthew E Jones², Rui Hou², Dáithí Ó Muirí², Sanela Bilic⁶, G Raj K A Mohan^{6

7}, Stuart Salfinger⁸, Simon Fox², Khaing P W Hmon², Yen Yeow², Youngmi Kim⁹, Rhea John⁹, Tami S Gilderman⁹, Emily Killingbeck⁹, Elin S Gray⁵, Paul A Cohen^{10

11}, Yu Yu^{12

13

14}, Alistair R R Forrest¹⁵

Affiliations

¹ Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, Perth, WA, 6009, Australia. [email protected].
² Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, Perth, WA, 6009, Australia.
³ Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
⁴ Anatomical Pathology Department, Clinipath, Sonic Healthcare, Perth, WA, 6017, Australia.
⁵ Centre for Precision Health, Edith Cowan University, Joondalup, WA, 6027, Australia.
⁶ Department of Gynaecological Oncology, Bendat Family Comprehensive Cancer Centre, St John of God Subiaco Hospital, 12 Salvado Rd, Subiaco, WA, 6008, Australia.
⁷ School of Medicine, University of Notre Dame, Fremantle, WA, 6160, Australia.
⁸ Western Australian Gynae and Surgery, Perth, WA, Australia.
⁹ NanoString Technologies, Seattle, WA, USA.
¹⁰ Division of Obstetrics and Gynaecology, Medical School, University of Western Australia, 35 Stirling Highway, Crawley, WA, 6009, Australia. [email protected].
¹¹ Institute for Health Research, The University of Notre Dame Australia, 32 Mouat Street Fremantle, Fremantle, WA, 6160, Australia. [email protected].
¹² Division of Obstetrics and Gynaecology, Medical School, University of Western Australia, 35 Stirling Highway, Crawley, WA, 6009, Australia. [email protected].
¹³ Curtin Medical School, Curtin University, 410 Koorliny Way, Bentley, WA, 6102, Australia. [email protected].
¹⁴ Curtin Health Innovation Research Institute, Curtin University B305, Bentley, WA, 6102, Australia. [email protected].
¹⁵ Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, Perth, WA, 6009, Australia. [email protected].

Abstract

High-grade serous ovarian carcinoma (HGSOC) is genetically unstable and characterised by the presence of subclones with distinct genotypes. Intratumoural heterogeneity is linked to recurrence, chemotherapy resistance, and poor prognosis. Here, we use spatial transcriptomics to identify HGSOC subclones and study their association with infiltrating cell populations. Visium spatial transcriptomics reveals multiple tumour subclones with different copy number alterations present within individual tumour sections. These subclones differentially express various ligands and receptors and are predicted to differentially associate with different stromal and immune cell populations. In one sample, CosMx single molecule imaging reveals subclones differentially associating with immune cell populations, fibroblasts, and endothelial cells. Cell-to-cell communication analysis identifies subclone-specific signalling to stromal and immune cells and multiple subclone-specific autocrine loops. Our study highlights the high degree of subclonal heterogeneity in HGSOC and suggests that subclone-specific ligand and receptor expression patterns likely modulate how HGSOC cells interact with their local microenvironment.

MeSH terms

DNA Copy Number Variations
Endothelial Cells / metabolism
Female
Gene Expression Profiling
Humans
Ovarian Neoplasms* / pathology
Tumor Microenvironment* / genetics

Grants and funding

GNT1154524/Department of Health | National Health and Medical Research Council (NHMRC)