Abstract B036: Spatial transcriptomics reveals stepwise biomolecular changes in ovarian cancer tumor microenvironments
Authors: Shimizu Aasa , Krishnan Rahul , Schweizer Lisa , Kelliher Lucy , Lengyel Ernst 
Published: March 2024

Background: Recent pathological and genetic evidence suggests that high-grade serous ovarian cancer (HGSC) presents a stepwise developmental process. Serous tubal intraepithelial carcinoma (STIC) of the fallopian tube epithelium may be a precursor lesion to HGSC. In addition, p53 signature and serous tubal intraepithelial lesions (STIL) are recognized as the earliest precursors lesions. However, the molecular mechanism by which a precursor's lesion evolves into an invasive tumor is not fully understood. Moreover, even though the tumor microenvironment is clearly an important aspect of the tumor organ, the role of the fallopian tube stroma in the early transformation of HGSC is unclear. Methods: Spatial transcriptomics analysis of formalin-fixed paraffin-embedded tissue sections by Nanostring GeoMx Whole Transcriptome Atlas (including more than 18,000 protein-encoding genes) was performed to determine the molecular changes that contribute to the progression from a normal fallopian tube to a p53 signature, STIL, STIC to HGSC in both the epithelium and stroma compartment. The transcriptomics analysis was conducted on 290 specific lesions from 16 representative cases (3 p53 signature cases, 3 STIL cases, 3 STIC lesions, and 7 STIC lesions with matched HGSC). Result In these rare precursor cell populations, we characterized gene expression over 9700 genes. Based on the gene expression profiles, p53 signature and STIL lesions are very similar to FT secretory cells as compared to FT ciliated cells. Additionally, STIC epithelial lesions and HGSC epithelial lesions share many gene alterations. Meanwhile, in the stroma, gene expression dramatically changed during the STIC-HGSC transition. Specific new genetic alterations in epithelium and stroma were found that might contribute to tumor progression. In the stroma compartment, Biglycan and SPARC, known to be involved in cancer-associated fibroblast organization and extracellular structure remodeling, were upregulated from normal fallopian tube, to STIC and HGSC. Interestingly, epithelial lesions also showed upregulation of these genes. Our results suggest co-evolution of epithelial and stroma cell in the process of carcinogenesis towards HGSC. Conclusion: A comprehensive analysis of over 9700 genes in HGSC precursor lesions provides new insights into the earliest molecular alterations that occur in intraepithelial lesions and the evolving tumor microenvironment. We are currently integrating spatial transcriptomics and proteomics to match transcript and protein expression. Results: are currently validated in fallopian tube-derived organoids.

Citation Format: Aasa Shimizu, Rahul Krishnan, Lisa Schweizer, Lucy Kelliher, Ernst Lengyel. Spatial transcriptomics reveals stepwise biomolecular changes in ovarian cancer tumor microenvironments [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B036.