PASCAL · Pax8 as a marker of Ovarian cancer Originating in the Fallopian tube
FP7 — People (Marie Curie Actions)
- Duration
- 2014-12-01 → 2018-11-30
- EU contribution
- €100,000
- Participants
- 1
- Scheme
- MC-CIG
Lines connect the coordinator with its partners.
Results in brief
Periodic Report Summary 2 - PASCAL (Pax8 as a marker of Ovarian cancer Originating in the Fallopian tube)
Ovarian cancer is the deadliest gynecological malignancy in the western world. In recent years we and others have established that a large proportion of high grade serous carcinomas (HGSC), the most common subtype of ovarian cancer, arises in the fallopian tube. This understanding has highlighted the role of the fallopian tube lineage marker, the transcription factor PAX8. PAX8 is expressed in the fallopian tube secretory epithelial cell (FTSEC), the proposed cell-of-origin of HGSC, and, as we have shown, in nearly 100% of HGSC. We have shown that PAX8 is essential for HGSC and knockdown of PAX8 leads to cancer cell death (apoptosis). We have shown that the essential role of PAX8 in HGSC is mediated by activating two proteins, both playing a role that is opposite to their normal role. One such protein activated by PAX8 is p53, which normally acts as a tumor suppressor gene, but in 65% of HGSC it plays an opposite growth promoting role. The other protein activated by PAX8 (and by p53) is p21, which normally leads to growth arrest of cells, and we have shown that in many HGSC cases it plays an opposite growth promoting role. This growth promoting role is mediated by mis-localization of p21, which is normally localized in the cell nucleus, but in HGSC is often localized in the cytoplasm of cells. This work was published in the journal Oncogene in 2018. The work described in this proposal is the corner stone of the work done in the Perets lab in the last four years. Since the acceptance of this grant our lab has grown significantly. We now have 4 graduate students, two undergraduate students, a post-doctoral fellow, a technician and a research associate overseeing the research in the lab. The findings supported by this grant lay the foundation for the many other sources of funding we received since. Many of the results derived from this grant would be the foundation of the research papers published by our lab in the coming years, and I expect them to have a significant impact on our understanding of ovarian cancer biology, as a cornerstone to drive new and specific ovarian cancer therapies.
Data: CORDIS, © European Union
Project objective
Epithelial ovarian cancer is a disease with grim prognosis and high-grade serous carcinoma (HGSC) is its most common subtype. Recent literature suggests that HGSC arises in the fallopian tube (FT) epithelium, rather then in the ovary, and metastasizes to the ovary early on in the process of transformation. This hypothesis is based, among other findings, on common morphologic and immunophenotypic traits between HGSC and the fallopian tube secretory epithelial cell (FTSEC). One of the shared markers between HGSC and FTSEC is the transcription factor PAX8. PAX8 is known to play a critical role in FT organogenesis and as we have shown it is highly conserved in HGSC. I propose to study the role of PAX8 in FTSEC and in HGSC, thereby establishing its role as an essential lineage marker.In Aim 1 I will investigate whether PAX8 is a critical factor in cells of the FTSEC lineage. For this purpose we will use PAX8 knock down in HGSC cell lines and immortalized FTSEC lines to reveal PAX8’s activity in benign and malignant cells. As part of this aim (Aim 1b) we will test whether BCL2 is a target gene of PAX8 and a direct mediator of PAX8’s anti apoptotic role in FTSEC and HGSC. I will then use expression profiling to suggest and validate additional mediators of PAX8’s activity, thereby defining additional serous determinants.In Aim 2 I will reveal the genomic binding locations of PAX8 in benign, non-invasive and invasive carcinomas. Towards this aim we will use our unique genetically engineered mouse model of HGSC arising from the FTSEC. We will study PAX8 as a model to ask whether a transcription factor lineage marker, which is conserved throughout transformation, preserves its DNA binding profile, its target genes and its transcriptional regulatory network.Taken together, the results generated in this study will allow better understanding of the role of PAX8 in FT transformation, and will clarify the role of a transcription factor lineage marker during transformation.""
Original text from CORDIS.
Participants
- THE HEALTH CORPORATION - RAMBAM · HaifaCoordinatorIsrael
Links
Data: CORDIS, © European Union