Transcriptional Regulation of Heterogeneous Populations in Choroid Plexus Carcinoma
Abstract
The choroid plexus (CP) in each brain ventricle consists of a fibro-vascular core encapsulated by epithelium that differentiates from roof plate progenitors. Although neoplasms of the CP are rare, they mostly occur in childhood and comprise up to 20% of brain tumors in children under 1 year of age. CP papilloma is typically benign and can be resolved successfully through surgical resection, whereas malignant CP carcinoma (CPC) is poorly understood and highly lethal, with few treatment options. Even with treatments that include surgery, chemotherapy, and radiation, CPC usually responds poorly. CPC is prone to recurrence and metastasis, with only ~ 40% of children still alive 5 years after diagnosis. In addition, survivors often suffer from debilitating long-term treatment effects, including intellectual disability and increased cancer risk. Despite the dire consequence of CPC, knowledge of the molecular and cellular underpinnings of CPC is limited, severely hampering the development of therapies that can specifically suppress tumor growth without damaging the developing brain. Accurate experimental models for rare cancers such as CPC will help to gain knowledge of CPC pathogenesis and facilitate search for more effective and safer therapies. The Principal Investigator’s laboratory generated multiple mouse models of CP tumors driven by molecular defects commonly identified in human diseases. The proposed studies will utilize these animal models to address one Focus Area: the biology and etiology of CPC. The overarching theme of this application arises from the discovery that molecular mechanisms of CP differentiation are critically involved in CPC development. The proposed studies will not only illustrate the molecular details of the specification and differentiation of the CP, but significantly advance knowledge of CPC biology. Results from these studies will help to identify promising targets for innovative anti-tumor therapy and hopefully lead to successful clinical trials that will eventually improve outcome for patients with CPC. Sex-determining region Y-box 2 (SOX2) is a transcriptional regulator of stem cell pluripotency. In human cancers, dysregulated SOX2 is associated with poor survival. SOX2 promotes proliferation, survival, invasion/metastasis, cancer stemness, and drug resistance. Indeed, SOX2 is highly expressed in CP epithelial progenitors, CP tumors in humans and mice, while loss of Sox2 significantly decreases the growth of CP tumor in animal models. Human CP tumors also frequently display aberrant expression of critical transcriptional regulators of roof plate/CP differentiation, including LIM homeodomain transcription factors LMX1A, and orthodenticle homeobox 2 (OTX2). Accordingly, CP tumors in animal models exhibited dysregulation of these transcriptional programs. Therefore, Sox2, Lmx1a, and Otx2 may represent novel anti-cancer targets in CPC. In aim 1, we will determine the mechanisms of SOX2 and LMX1A functions and interactions in CP tumor. Gain- or loss-of-function studies will be conducted to examine the role of SOX2 in CP tumor cells. The effect of alterations in SOX2 expression on LMXA levels, and the role of LMX1A in SOX2 signaling will be evaluated. The global landscape of SOX2 and LMX1A binding at regulatory elements in CP tumors will be characterized. Integrated analysis will identify potential downstream targets of SOX2 and LMX1A and provide insights into regulatory mechanisms of SOX2 and LMX1A in tumor-initiating cells in CPC. The tumorigenic potential of Lmx1a<+>/Sox2<+> population will be investigated through gain- or loss-of-function genetic and transplantation studies. Sox2 will be inactivated in Lmx1a<+> progenitors in CPC, while Lmx1a<+>/Sox2<+> cells derived from CPC will be transplanted into recipients to define the cellular origin of CPC. In addition, oncogenic signals will be targeted to Lmx1a<+>/Sox2<+> progenitors in an inducible manner to drive CPC de
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310628
Entities
People
- Haotian Zhao
Organizations
- New York Institute of Technology
- United States Army