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.
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.