Abstract 2434: Regulation of initiation and establishment of ovarian cancer metastasis by metastasis initiating cells
Authors: Wang Ji , Dasari Subramanyam , Zhang Chi , Mitra Anirban Kumar 
Published: April 2023

Ovarian cancer (OC) is the deadliest gynecologic malignancy with a dismal prognosis worldwide. A key reason for this is that most patients already have extensive metastasis at the time of diagnosis. Therefore, it is metastatic disease that is being treated in the clinic. However, metastasis remains one of the least understood aspects of cancer biology and a better understanding of the mechanisms involved will be helpful in devising more effective therapies. Transcoelomic metastasis is prevalent in ovarian cancer, which involves exfoliation of cancer cells in the primary tumor, floatation and spreading in the peritoneal fluid, followed by attachment, and colonization of the peritoneal organs. The most common site being the omentum. Recent research has indicated that a small percentage of OC cells, called metastasis-initiating cells (MICs) are able to survive at the metastatic site and establish metastases. However, the characteristics of MICs, their productive interactions with the metastatic microenvironment, and how they colonize metastatic sites, remain poorly understood. We attempted to address this issue with a focus on high grade serous OC (HGSOC), the most prevalent and lethal subtype of OC. We used HGSOC cells isolated from patient ascites and seeded them on an organotypic 3D culture model of the surface layers of the omentum to mimic early stage of metastatic colonization. The same cells were injected intraperitoneally in NSG mice to generate patient derived xenografts, representing advanced metastasis. Single cell transcriptomics was performed in both these models to identify the heterogeneity of the patient derived OC cells and the changes in their subpopulation profiles during early and advanced metastasis. Inference of activity scores of gene sets (AUCell), analysis of regulons (SCENIC) and identification of markers (Seurat and CytoTRACE) of the single-cell transcriptomic data helped characterize the MICs. We identified one distinctive population of OC cells with MIC-like phenotype. Utilizing trajectory analysis (Monocle3) we have determined the potentially targetable differentiation trajectories between the MICs and other cancer cells populating the established metastases. Intra-tumoral interactions were also investigated using CellCall to identify targetable ligand-receptor pairs. Elimination of MICs, interference of intra-tumoral communications inducing stemness of MICs, or interruption of their differentiation trajectory paths that help establish the metastases, may be a novel therapeutic opportunity leading to improved outcomes for the OC patients who are diagnosed with metastasis.

Citation Format: Ji Wang, Subramanyam Dasari, Chi Zhang, Anirban Kumar Mitra. Regulation of initiation and establishment of ovarian cancer metastasis by metastasis initiating cells [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 2434.