Abstract 4395: Activation of TGFβ1 signaling pathway in ovarian cancer stem cells plays critical role in ovarian cancer tumorigenesis
Authors: Zhang Xiaoli , Shao Shuai , Li Lang , Wang Qi-En 
Published: September 2020

Ovarian cancer (OC) is the most lethal gynecological malignancy worldwide, primarily due to lack of a reliable early diagnostic method and high incidence of chemo-resistance induced tumor recurrence and relapse. Development of early screening and diagnosis biomarkers is the key for survival improvement of patients with OC. In this study, we applied a system biology approach to identify dysregulated genes and pathways during OC tumorigenesis, as well as to study the roles of OC stem cells (OCSCs) during this process.

In order to identify diagnostic/therapeutic biomarkers for OC, gene expression between OC patient malignant tumors and normal tissues were compared with datasets GSE4122 and GSE26712. 188 and 305 genes were found to be consistently downregulated and upregulated respectively (fold change ≥2, and FDR&lt;0.05) across the two datasets. Among the dysregulated genes, OCSC biomarkers CD24 and PROM1, and cancer cell stemness related genes such as SOX9, EPCAM, HMGA1, EZH2, BIRC5, and KRT7 were all significantly upregulated in OC. In contrast, many metabolism related genes were downregulated in OC, such as ABCA8, ACOX2, PFKP, ADH1B, and PKD2. Among the upregulated genes, over 30 genes were found to be significantly associated with tumor stemness scores (r&gt;0.40 and P&lt;.0001). The top associated genes such as CCNB2, NDC80, TTK, CDK1, NEK2, RAD54L, CDC20, KIF23, BIRC5, EZH2 (r&gt;0.40) were all previously reported to be associated with aggressive disease and poor diagnosis in different cancer types.

OCSCs were considerd to play critical roles in OC tumour initiation, dissemination, metastasis and recurrence. To elucidate the role of OCSCs during tumorigenesis, gene expression were compared between OCSCs and normal stem cells using dataset GSE90125. Interestingly, tumor microenvironment and EMT related genes such as IL33, WISP1, PRG2, FAP, ENPP2, and SBSN were found to be among the most upregulated genes in OCSCs, indicating important role of tumor microenvironment during the conversion of normal stem cells to tumor stem cells. Moreover, pathway analysis with the dysregulated genes showed that TGFβ1 signaling pathway was significantly activated in both OC tumors and OCSCs. Previous study showed that TGFβ1 signaling pathway promotes OC tumor growth by upregulating VCAN (upregulated in OC) in the tumor microenvironment. Therefore, we conclude that the modulation of tumor microenvironment through the activated TGFβ1 signaling pathway in OCSCs plays important roles during OC tumorigenesis and may be used as diagnostic and/or therapeutic targets for patients with OC.

Citation Format: Xiaoli Zhang, Shuai Shao, Lang Li, Qi-En Wang. Activation of TGFβ1 signaling pathway in ovarian cancer stem cells plays critical role in ovarian cancer tumorigenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4395.