Secreted Wnt Inhibitors in the Biology of Osteosarcoma

申请人：黄博士，候选人，目前是加州大学欧文分校的终身教职助理教授。从他的传记中可以明显看出，这位候选人表现出了对学术医学事业的坚定承诺。为此，他希望在有指导的环境中继续他的研究培训，目标是成为肌肉骨骼肿瘤学的独立研究员。 环境：候选人由几位国内和国际公认的人类癌症Wnt信号和骨肉瘤遗传学方面的专家共同指导。加州大学欧文分校是一个大学环境，有着培养年轻临床科学家职业发展的传统。 研究：骨肉瘤(OS)仍然是一种儿童骨癌，由于高转移率而具有相当高的死亡率。虽然Wnt信号在几种人类恶性肿瘤中被激活，但它在OS进展的病理生物学中的作用在很大程度上是未知的。我们的初步工作表明，分泌的Wnt抑制物在OS中调节以下亲侵袭途径：(1)转录抑制物Slug和Twist，(2)MMP-2和9，以及(3)肝细胞生长因子受体Met。用显性负性受体或分泌抑制物DKK-3阻断受体介导的Wnt信号，可显著降低OS细胞的侵袭能力和运动能力。这些发现导致我们提出了以下具体目标：1)检测分泌型Wnt抑制剂是否可以通过抑制E-钙粘素转录抑制物来降低OS细胞的侵袭能力；2)检验分泌型Wnt抑制剂通过抑制Met-2和9或通过调节Met依赖的活性来降低OS侵袭性的假设；3)在尾静脉注射裸鼠模型中确定过表达Wnt抑制剂是否会减少体内肺转移。这些研究将弥补我们对分泌型Wnt抑制剂在OS生物学中的作用的认识上的差距。从这项调查中学到的经验教训可能适用于更广泛的人类肉瘤，并作为申请人作为肌肉骨骼肿瘤学独立研究员未来研究的基础。

DESCRIPTION (provided by applicant): Applicant: Dr. Hoang, the candidate, is currently a tenure-track Assistant Professor at the University of California, Irvine. As evident from his biography, the candidate has demonstrated a steadfast commitment to a career in academic medicine. To this end, he would like to continue his research training in a mentored environment with the goal of becoming an independent investigator in musculoskeletal oncology. Environment: The candidate is jointly mentored by several nationally and internationally recognized experts in Wnt signaling in human cancer and the genetics of osteosarcoma. The University of California, Irvine is a collegial environment with a tradition of nurturing career development of young clinician scientists. Research: Osteosarcoma (OS) remains a pediatric bone cancer with substantial mortality due to a high metastatic rate. Although Wnt signaling is activated in several human malignancies, its role in the pathobiology of OS progression is largely unknown. Our preliminary work suggested that secreted Wnt inhibitors modulate the following pro-invasive pathways in OS: (1) Transcriptional repressors Slug and Twist, (2) MMP-2 and 9, and (3) the hepatocyte growth factor receptor Met. Blocking receptor-mediated Wnt signaling by a dominant negative receptor or by the secreted inhibitor Dkk-3 dramatically decreases the invasive potential and motility of OS cells. These findings lead us to propose the following specific aims: 1) To examine whether secreted Wnt inhibitors can decrease invasive capacity of OS cells by suppressing E-cadherin transcriptional repressors; 2) To test the hypothesis that secreted Wnt inhibitors decrease OS invasiveness by suppressing MMP-2 and 9 or by regulating Met-dependent activity; 3) To determine whether overexpression of Wnt inhibitors will reduce lung metastasis in vivo in a tail-vein injection nude mouse model. These studies will bridge a gap in our knowledge on the role of secreted Wnt inhibitors in the biology of OS. Lessons learned from this investigation may be applicable to a wider range of human sarcomas and serves as a basis for future studies by the applicant as an independent investigator in musculoskeletal oncology.