Secreted Wnt Inhibitors in the Biology of Osteosarcoma

描述（由申请人提供）：申请人：黄博士，候选人，目前是在加州大学欧文分校终身助理教授。从他的传记中可以看出，这位候选人表现出对学术医学事业的坚定承诺。为此，他想继续他的研究培训在一个指导的环境，成为一个独立的研究者在肌肉骨骼肿瘤的目标。 工作环境：该候选人由几位国内和国际公认的人类癌症Wnt信号传导和骨肉瘤遗传学专家共同指导。加州大学欧文分校是一个大学环境，具有培养年轻临床科学家职业发展的传统。 研究：骨肉瘤（OS）仍然是一种儿科骨癌，由于转移率高，死亡率高。虽然Wnt信号在几种人类恶性肿瘤中被激活，但其在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抑制剂调节OS中的以下促侵袭途径：（1）转录阻遏物Slug和Twist，（2）MMP-2和9，以及（3）肝细胞生长因子受体Met。通过显性负性受体或分泌的抑制剂Dkk-3阻断受体介导的Wnt信号传导显著降低OS细胞的侵袭潜力和运动性。这些发现引导我们提出以下具体目标：1）检测分泌型Wnt抑制剂是否通过抑制E-钙粘蛋白转录抑制因子来降低OS细胞的侵袭能力：2）验证分泌型Wnt抑制剂通过抑制MMP-2和MMP-9或通过调节Met依赖性活性来降低OS细胞侵袭能力的假设; 3）确定Wnt抑制剂的过表达是否会在尾静脉注射裸鼠模型中减少体内肺转移。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空白。从这项调查中吸取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者进行未来研究的基础。

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.