title: SPDEF is a mediator of tumorigenicity in SSEA1- tumor-initiating cells in high grade serous ovarian cancer
creator: Zickgraf, Franziska Maria
subject: ddc-500
subject: 500 Natural sciences and mathematics
description: High Grade Serous Ovarian Adenocarcinoma (HGSOC) is a highly aggressive disease with poor prognosis and the leading cause of gynecological tumor-related deaths. The poor prognosis is related to the fact that already during early stages tumor cells start to spread into the peritoneum. This metastatic spread and the colonization of organs located within the  peritoneum are the biggest problems with regard to therapy of HGSOC. Tumors often consist of a functionally heterogeneous population of cancer cells with distinct features. Subsets of tumor cell populations are able to promote tumor progression, metastatic spread and  colonization, as well as outgrowth of tumor cells at distant organs. Therefore, the identification and targeting of so-called tumor-initiating cells is crucial. Knowledge about the intrinsic features of tumor-initiating cells and targeting them may ultimately lead to tumor  regression and improved patient survival. However, no conclusive evidence about markers for a tumor-initiating population has been provided so far and even less is understood regarding the molecular mechanisms driving tumor-initiating cancer cell populations in HGSOC.    My work shows that Stage Specific Embryonic Antigen 1 negative (SSEA1-) cells are enriched for tumor-initiating abilities in human HGSOC. Furthermore, SSEA1- cells can give  rise to both SSEA1- and SSEA1+ cells whereas SSEA1+ cells only give rise to SSEA1+ cells demonstrating a hierarchical organization with SSEA1- cells being on top. Gene expression  profiling demonstrated an enrichment of the transcription factor SAM-pointed ETS domaincontaining factor (SPDEF) in SSEA1- cells. Lentiviral knockdown of SPDEF impaired in vivo  tumor growth and in vitro colony formation, whereas overexpression of SPDEF resulted in increased colony formation in vitro and tumor formation in vivo. Strikingly, also SSEA1+ cells acquired the capacity to initiate tumors in vivo and form colonies in vitro after SPDEF  expression was re-introduced. I also show, that SPDEF negatively regulates the expression of the transcription factor Forkhead box protein A2 (FOXA2). FOXA2 overexpression resulted in decreased tumor-promoting capacity in an in vivo tumor formation assay.  Based on these results, I propose that the transcriptional programs modulated by SPDEF, as well as those genes changed due to suppressed FOXA2 target gene transcription, lead to  increased survival, clonogenicity and stemness of SSEA1- SPDEFhigh FOXA2low cells and may therefore promote ovarian cancer tumor initiation and metastatic spread.    In summary, the data I generated indicate that SSEA1- cells represent a cellular subpopulation with increased tumor-initiating ability in HGSOC. These cells express higher levels of SPDEF, which exerts its tumorigenic potential by suppressing FOXA2 expression.  Developing SPDEF inhibitors might be promising to target the SSEA1- tumor-initiating population and might ultimately lead to tumor regression and improved patient survival.
date: 2021
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/25543/1/2018_FRANZISKA_M_ZICKGRAF_Dissertation.pdf
identifier: DOI:10.11588/heidok.00025543
identifier: urn:nbn:de:bsz:16-heidok-255430
identifier:   Zickgraf, Franziska Maria  (2021) SPDEF is a mediator of tumorigenicity in SSEA1- tumor-initiating cells in high grade serous ovarian cancer.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/25543/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng