PAX8 orchestrates an angiogenic program through interaction with SOX17

Abstract

Worldwide, the number of new ovarian cancer cases approaches 300,000 with more than 180,000 deaths every year. The low survival-rate reflects the limitations of current therapies and highlights the importance of identifying new therapeutic targets. Despite significant recent efforts to identify novel vulnerabilities in ovarian cancer, none have led to effective durable therapies with improvement in overall survival. PAX8, a lineage-transcription factor, whose expression is a major molecular feature of ovarian carcinomas, represents a novel therapeutic target. Herein, we have identified SOX17 as a bona fide PAX8-interacting partner and elucidated the impact of this interaction on the development of ovarian cancer. Importantly, we found that PAX8 and SOX17 regulate tumor angiogenesis in vitro and in vivo. The role of PAX8 and SOX17 in the regulation of angiogenesis reveals a novel function for these factors in regulating the tumor microenvironment and highlight this pathway as a viable therapeutic target.

Single-cell transcriptomics identifies gene expression networks driving differentiation and tumorigenesis in the human fallopian tube

“…One of the greatest insights emerging from this work is the identification of transcription factors regulating the different stages of tubal epithelial cell differentiation. SOX17 was enriched in secretory cells; this factor had not been implicated in HGSC or fallopian biology until recently when this protein was described as a master transcription factor for HGSC and both a regulator of and binding partner for PAX8 (Chaves- Moreira et al, 2020;Reddy et al, 2019;Shi et al, 2019). NR2F2 and EGR1 regulons were enriched in early secretory and secretory 1 clusters.…”

A cellular and molecular portrait of endometriosis subtypes

“…Arguably the greatest insight into microenvironmental remodeling was revealed when we interrogated the transcriptional hallmarks of ARID1A mutant and wild-type endometrial-type epithelium. We observed dysregulated gene expression in endothelial associated with ARID1A-mutant epithelium, likely mediated by SOX17, a transcription factor which when expressed in Müllerian epithelium, induces a pro-angiogenic gene signature and altered secretion of angiogenesis-regulating proteins (Chaves-Moreira et al, 2020). Further investigations will be needed to functionally validate the impact of ARID1A and KRAS mutations on the behavior of endometriosis epithelial cells and altered interactions with microenvironmental populations, and to understand the specific context in which ARID1A mutations, in particular, result in endometriosis-associated ovarian cancer (Anglesio et al, 2015;Wiegand et al, 2010).…”

“…Additional targets included lysosome-associated protein transmembrane-4β (LAPTM4B; log2 FC= 0.51, P = 1.24x10 -44 ) and SRY-box 17 (SOX17; log2 FC= 0.50, adjusted P = 1.51x10 -33 , Figure 3L). We have recently identified SOX17 as a novel marker of secretory fallopian tube epithelia and high-grade serous ovarian cancer, where it positively regulates angiogenesis (Chaves-Moreira et al, 2020;Dinh et al, 2021;Reddy et al, 2019). SOX17 protein expression was validated in the same tissues using immunohistochemistry performed on 6 specimens with heterogenous ARID1A staining and 2 specimens with positive ARID1A staining.…”

Spatially resolved single-cell multiomics map of human trophoblast differentiation in early pregnancy

“…This is different from iEVT, where both TGFB1 and TGFBR1 are upregulated. Additional TFs involved in the hypoxic environment in tumours and vessel transformation are upregulated in eEVTs, including HMGA2 45 , PAX8 46 , PBX3 47 , PLAGL1 48 and MYCN. To summarise, our results point towards a key role for WNT inhibition, TGFβ and HIF1A activation in iEVT cell fate, while eEVT identity is marked by strong upregulation of NOTCH and HIF1A and strong downregulation of TGFβ signalling (Fig.…”

“…This is different from iEVT, where both TGFB1 and TGFBR1 are upregulated. Additional TFs involved in the hypoxic environment in tumours and vessel transformation are upregulated in eEVTs, including HMGA2 45 , PAX8 46 , PBX3 47 , PLAGL1 48 and MYCN .…”