Hypoxia signaling in cancer development

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

My laboratory continues on the investigation focuses on the contribution of inherited and somatic variants in the development of cancer. These variants play critical roles in tumor formation and progression; however, the mechanisms appear to be different between them. Over the last few years, much of our research efforts have been dedicated to understanding somatic variants in tumorigenesis using various clinical opportunities, such as our discovery of Pacak-Zhuang syndrome (PZS), to guide mechanistic investigations. We have applied clinical, translational, and basic research approaches and have participated in several multidisciplinary efforts to gain insight into cancer genetics and cancer biology. The environment at Neuro-Oncology Branch (NOB) in the Center for Cancer Research (NCI intramural program) exposes the primary investigators to both the clinical and basic science settings, which provides critical guidance and direction to basic science questions. This allows my laboratory to not only maintain its main focus on hypoxia signaling in tumorigenesis and development of cancer therapeutics but also to take advantage of opportunities for new investigations when they arise from the clinic or the bench. My core focus is to investigate the pathophysiology of central nervous system (CNS) and other tumors by probing the cell of origin and underlying mechanisms and then to develop novel targeted cancer therapies. Hypoxia signaling is critical to normal tissue development and migration as well as to tumorigenesis, tumor progression, and metastasis. We previously investigated several neoplastic syndromes including von Hippel-Lindau (VHL) syndrome and elucidated the hypoxia mechanism underlying these vascular tumors. We have since identified another novel hypoxia-mediated syndrome, Pacak-Zhuang syndrome (PZS) including multiple paragangliomas, somatostatinoma, and polycythemia through collaboration with intramural and extramural clinicians and scientists. The gain-of-function pathogenic variant in EPAS1, encoding hypoxia-inducible factor 2 alpha (HIF-2 alpha), was found to be causative in this syndrome. We have subsequently generated a transgenic mouse model which recapitulates the findings in humans. Hypoxia signaling has been classically studied using the canonical pathway, first found in tumors associated with VHL, which shunts HIF1/2 alpha to proteasome degradation upon hydroxylation by prolyl hydroxylase (PHD). Most studies have focused on HIF-1 alpha signaling. However, work from our lab and others has indicated that HIF-2 alpha plays a particularly important role in the development of the tumors associated with hypoxia, which highlights the value of HIF-2 alpha as a therapeutic target. However, there remain many questions regarding both the fundamental hypoxia signaling pathway as well as the association of HIF-2 alpha with observed pathologies. During the past 4 years, we have continued to study hypoxia-mediated neoplastic syndromes to gain insight into hypoxia signaling and tumorigenesis/stem cell biology. Specifically, we have focused on the investigation of clinical and genetic manifestations of PZS in patients along with the transgenic mouse model developed in our lab. While the molecular pathogenesis of PZS, i.e., hypoxia signaling activation, is similar to many other tumor syndromes such as VHL, PZS is unique in that it is a somatic mosaicism. Our continuing investigation of PZS as a model of tumorigenesis has revealed critical fundamental mechanisms and furthered our understanding of the syndrome and hypoxia signaling mediated by HIF-2 alpha. We have found that the mosaic nature of the gain-of-function variant in PZS leads to a significantly different array of phenotypes than those found in germline inherited syndromes with classical loss of function of predisposition alleles. Therefore, PZS is not only a model to study hypoxia signaling, tumorigenesis, and stem cell biology, but it is also a model that provides insights into the somatic mechanisms of tumorigenesis influenced by early development in multiple organ systems and cell types. For example, while studying PZS, we discovered a unique epigenetic mechanism of early regulation of the HIF-2 alpha variant allele in the early embryo that explains the non-hereditary nature of the syndrome in the patients. In addition, our studies of PZS led us to discover the fundamental mechanism underlying sexual dimorphism not only present in this syndrome but also central to regulation of catecholamine production. Models like this are also valuable because we now know that other tumor syndromes, which we previously thought to be inherited through the germline, may instead have a sporadic or post-zygotic events. Indeed, we have discovered that HIF-2 alpha has a critical role in the development of congenital abnormalities throughout many organ systems such as the neural tube and cardiovascular system. We have now also identified that cardiovascular malformations and carotid body hyperplasia in patients are a result of early HIF-2 alpha somatic mosaicism impacting the development of organ systems. Appreciating this role of hypoxia signaling in this syndrome has wide-reaching implications for vasculogenesis in tumors, as well as the development of other system neoplasia and congenital anomalies, that we did not previously recognize. As such, my laboratory has expanded our investigations into other tumors of the nervous system that derive from neural progenitors and that are mechanistically linked to hypoxia signaling, including glioma, atypical teratoid/rhabdoid tumor (AT/RT), and clear cell meningioma (CCM). In fact, while studying the HIF-2 alpha -gain-of-function model, we made several critical observations that have broad impact in cancer biology.