Abstract 6782: Spatial transcriptomics of serous tubal intraepithelial carcinoma and its putative precursor lesions
Authors: Krishnan Rahul , Schweizer Lisa , Bilecz Agnes , Shimizu Aasa , Mendoza Rachelle , Yamada Diane , Lastra Ricardo , Mann Matthias , Lengyel Ernst 
Published: April 2023

Abstract
Background: Increasing evidence over the past two decades has implicated serous tubal intraepithelial carcinoma (STIC) of the fallopian tube (FT) epithelium as the putative precursor lesion for high-grade serous ovarian cancer (HGSC). Additional atypical lesions of the FT known as p53 signature lesions and serous tubal intraepithelial lesions (STIL) have been proposed as early precursors in the carcinogenic sequence based on morphology, histochemical and genetic studies. Little however is known about the molecular events that drive FT epithelial cells to transform into HGSC. Methods: To elucidate the molecular changes that underlie the progression from p53 signature to STIL to STIC, we performed spatial transcriptomics on formalin-fixed paraffin embedded (FFPE) tissue sections using the Nanostring GeoMx Whole Transcriptome Atlas panel (18,000 protein-encoding gene panel). Our study cohort consisted of 16 representative cases (3 p53 signature cases, 3 STIL cases, 3 STIC lesions, and 7 STIC cases with matched HGSC). Results: We characterized gene expression to a depth of over 9400 genes in these rare precursor cell populations. Our analysis demonstrated that by gene expression profiles, p53 signatures and STIL lesions bear close resemblance to normal FT secretory cells compared to FT ciliated cells or even STIC and invasive HGSC. We identify for the first time, several pathways altered in expression between normal fallopian tube epithelium and early p53 signature lesions including those related to signaling pathways (Trop-2), Wnt pathway (LGR5), identifying new pathways observed in the progression from normal FT cells to precursor intraepithelial lesion. Our data show that STIC lesions bear significant similarities to invasive HGSC by gene expression, especially compared to the earlier precursor lesions (p53 signature and STIL). We observed several alterations in cell-adhesion(EGR1) and signaling pathways, transcription factors (Trop-2) and metabolism that mark the transition from STIC to HGSC, representing possible mechanisms by which these intraepithelial lesions transform into disseminated invasive disease. Conclusion: Our data profile HGSC precursor lesions in high-depth with characterization of over 9400 genes providing new insight into the molecular alterations that characterize these intraepithelial lesions. Our future direction is to pair transcriptomics data with our established spatial proteomics platform (Deep Visual Proteomics) to measure matched spatial protein expression in our cohort.
Citation Format: Rahul Krishnan, Lisa Schweizer, Agnes Bilecz, Aasa Shimizu, Rachelle Mendoza, Diane Yamada, Ricardo Lastra, Matthias Mann, Ernst Lengyel. Spatial transcriptomics of serous tubal intraepithelial carcinoma and its putative precursor lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6782.