Stem cell self-renewal programs in rhabdomyosarcoma

横纹肌肉瘤的干细胞自我更新计划

基本信息

批准号：
10321242
负责人：
David Michael Langenau
金额：
$ 37.77万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-10 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10321242
关键词：
Adult Affect Animals Biological Markers Cancer Model Cell Count Cell division Cell physiology Cells Chemosensitization Child Clinical Data Diagnosis Disease Drug Targeting Embryonal Rhabdomyosarcoma Goals Grant Growth Human Image Impairment In Vitro Label Malignant Neoplasms Modeling Molecular Monomeric GTP-Binding Proteins Mus Muscle Neoplasm Metastasis Operative Surgical Procedures Outcome Pathway interactions Patients Pharmaceutical Preparations Process RHOA gene Refractory Relapse Research Resolution Rhabdomyosarcoma Role Signal Pathway Signal Transduction Survival Rate Testing Therapeutic Time Transgenic Organisms Tumor Expansion Tumor Markers United States Unresectable Validation WNT Signaling Pathway Work Xenograft procedure Zebrafish base cell growth cell type chemotherapy experimental study gain of function high risk human model in vivo innovation insight irradiation loss of function malignant muscle neoplasm neoplastic cell new therapeutic target novel novel strategies novel therapeutics patient derived xenograft model planar cell polarity pre-clinical preclinical efficacy programs self-renewal stem cell division stem cell self renewal targeted treatment translational impact treatment strategy tumor tumor growth

项目摘要

PROJECT SUMMARY Rhabdomyosarcoma (RMS) is a devastating malignancy of muscle that is diagnosed in hundreds of children and adults annually in the USA. Survival rates are less than 30% in patients with unresectable, metastatic, or relapsed RMS, with continued tumor growth being maintained by a small number of self-renewing, tumor- propagating cells (TPCs). Yet, to date, targeted approaches to kill TPCs or to differentiate them into non- proliferative, differentiated RMS cell types have not been developed. The long-term goal of our work is to uncover therapeutically relevant pathways that drive RMS growth through their regulatory effects on TPCs. The overall objective of this application is to determine the extent to which non-canonical Wnt/Planar Cell Polarity (Wnt/PCP) signaling regulates TPC self-renewal and can be targeted to inhibit RMS growth. Our central hypothesis is that Van Gogh-like 2 (Vangl2), a core regulator of the Wnt/PCP signaling pathway, modulates self-renewal and growth of RMS TPCs. We also hypothesize that Vangl2 expression is confined to TPCs and can be used to isolate and characterize these cells. Our preliminary data indicate that Vangl2 and Wnt/PCP signaling regulate TPC self-renewal in both zebrafish and human RMS. VANGL2 inactivation leads to reduced TPC number, decreased tumor cell growth, and elevated differentiation in human RMS cells both in vitro and in vivo using mouse xenografts. Fluorescent transgenic zebrafish models of embryonal RMS also showed that Vangl2 expression enriches for self-renewing TPCs, providing novel approaches to dynamically visualize these cells in live animals and to quantify effects of altering Wnt/PCP signaling on self-renewal. The rationale for our work is that VANGL2 is active in a vast majority of human RMS and is required for continued tumor growth and self-renewal, suggesting that therapeutic strategies based on VANGL2 inhibition would benefit a large fraction of high-risk patients. Aim 1 will assess the role for Wnt/PCP signaling in RMS growth and self-renewal in a fluorescent-transgenic zebrafish model and patient-derived xenografts, testing our hypothesis that Vangl2 and the Wnt/PCP pathway regulate self-renewal and expansion of TPCs in RMS. Aim 2 will characterize Vangl2 as a marker of TPCs in both zebrafish and human RMS, providing unprecedented access to dynamically visualize roles for the Wnt/PCP pathway in regulating self-renewal and cell fate choices following cell division. Aim 3 will elucidate the effector pathways downstream of VANGL2 and Wnt/PCP signaling, testing our working hypothesis that VANGL2 drives self-renewal through the activation of RHOA small GTPase signaling. Our work will uncover the molecular pathways by which VANGL2 and the Wnt/PCP pathway drive human RMS growth and self-renewal. Such insights will provide new biomarkers for assessing drug effects on TPCs and will likely identify novel drug targets beyond VANGL2 for the treatment of RMS. Our work is predicted to have a large positive translational impact, advancing our understanding of processes that control self-renewal in cancer and providing pre-clinical efficacy of targeting VANGL2 to suppress growth of patient derived xenografts.

项目概要横纹肌肉瘤 (RMS) 是一种毁灭性的肌肉恶性肿瘤，数百名儿童被诊断出患有这种疾病和成人每年在美国。无法切除、转移或患有癌症的患者的生存率低于 30% 复发的 RMS，肿瘤持续生长是由少数自我更新的肿瘤细胞维持的增殖细胞（TPC）。然而，迄今为止，还没有针对性的方法来杀死 TPC 或将其区分为非 TPC。尚未开发出增殖、分化的 RMS 细胞类型。我们工作的长期目标是揭示通过对 TPC 的调节作用推动 RMS 生长的治疗相关途径。这此应用程序的总体目标是确定非规范 Wnt/平面细胞极性的程度 (Wnt/PCP) 信号传导调节 TPC 自我更新，并可靶向抑制 RMS 生长。我们的中央假设 Van Gogh-like 2 (Vangl2) 是 Wnt/PCP 信号通路的核心调节因子，可调节 RMS TPC 的自我更新和生长。我们还假设 Vangl2 表达仅限于 TPC 可用于分离和表征这些细胞。我们的初步数据表明 Vangl2 和 Wnt/PCP 信号传导调节斑马鱼和人类 RMS 中 TPC 的自我更新。 VANGL2失活导致减少 TPC 数量、肿瘤细胞生长减少以及人 RMS 细胞在体外和体内的分化增加体内使用小鼠异种移植物。胚胎 RMS 荧光转基因斑马鱼模型还表明 Vangl2 表达丰富了自我更新的 TPC，提供了动态可视化这些 TPC 的新方法活体动物细胞并量化改变 Wnt/PCP 信号传导对自我更新的影响。我们的理由研究表明，VANGL2 在绝大多数人类 RMS 中都很活跃，并且是肿瘤持续生长所必需的自我更新，表明基于 VANGL2 抑制的治疗策略将在很大程度上受益的高危患者。目标 1 将评估 Wnt/PCP 信号在 RMS 生长和自我更新中的作用荧光转基因斑马鱼模型和患者来源的异种移植物，检验了我们的假设，即 Vangl2 和 Wnt/PCP 通路调节 RMS 中 TPC 的自我更新和扩展。目标 2 将 Vangl2 描述为斑马鱼和人类 RMS 中 TPC 的标记，提供前所未有的动态可视化途径 Wnt/PCP 通路在细胞分裂后调节自我更新和细胞命运选择中的作用。目标 3 将阐明 VANGL2 和 Wnt/PCP 信号传导下游的效应器通路，测试我们的工作假设 VANGL2 通过激活 RHOA 小 GTP 酶信号来驱动自我更新。我们的工作将揭示 VANGL2 和 Wnt/PCP 途径驱动人类 RMS 生长的分子途径和自我更新。这些见解将为评估药物对 TPC 的影响提供新的生物标志物，并且可能会确定 VANGL2 以外的治疗 RMS 的新药物靶点。我们的工作预计会有很大积极的转化影响，增进我们对控制癌症自我更新过程的理解提供靶向 VANGL2 抑制患者来源异种移植物生长的临床前功效。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Single-cell imaging of human cancer xenografts using adult immunodeficient zebrafish.

DOI：
10.1038/s41596-020-0372-y
发表时间：
2020-09
期刊：
Nature protocols
影响因子：
14.8
作者：
Yan C;Do D;Yang Q;Brunson DC;Rawls JF;Langenau DM
通讯作者：
Langenau DM

Insights into pediatric rhabdomyosarcoma research: Challenges and goals

DOI：
10.1002/pbc.27869
发表时间：
2019-10-01
期刊：
PEDIATRIC BLOOD & CANCER
影响因子：
3.2
作者：
Yohe, Marielle E.;Heske, Christine M.;Langenau, David M.
通讯作者：
Langenau, David M.

Single-cell imaging of T cell immunotherapy responses in vivo.

DOI：
10.1084/jem.20210314
发表时间：
2021-10-04
期刊：
The Journal of experimental medicine
影响因子：
0
作者：
Yan C;Yang Q;Zhang S;Millar DG;Alpert EJ;Do D;Veloso A;Brunson DC;Drapkin BJ;Stanzione M;Scarfò I;Moore JC;Iyer S;Qin Q;Wei Y;McCarthy KM;Rawls JF;Dyson NJ;Cobbold M;Maus MV;Langenau DM
通讯作者：
Langenau DM

Single-cell analysis and functional characterization uncover the stem cell hierarchies and developmental origins of rhabdomyosarcoma.

DOI：
10.1038/s43018-022-00414-w
发表时间：
2022-08
期刊：
NATURE CANCER
影响因子：
22.7
作者：
Wei, Yun;Qin, Qian;Yan, Chuan;Hayes, Madeline N.;Garcia, Sara P.;Xi, Haibin;Do, Daniel;Jin, Alexander H.;Eng, Tiffany C.;McCarthy, Karin M.;Adhikari, Abhinav;Onozato, Maristela L.;Spentzos, Dimitrios;Neilsen, Gunnlaugur P.;Iafrate, A. John;Wexler, Leonard H.;Pyle, April D.;Suva, Mario L.;Dela Cruz, Filemon;Pinello, Luca;Langenau, David M.
通讯作者：
Langenau, David M.