Stem cell self-renewal programs in rhabdomyosarcoma
Stem cell self-renewal programs in rhabdomyosarcoma
批准号:
10321242
负责人:
David Michael Langenau
金额:
$37.77万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-01-10 至 2022-12-31
关键词:
AdultAffectAnimalsBiological MarkersCancer ModelCell CountCell divisionCell physiologyCellsChemosensitizationChildClinicalDataDiagnosisDiseaseDrug TargetingEmbryonal RhabdomyosarcomaGoalsGrantGrowthHumanImageImpairmentIn VitroLabelMalignant NeoplasmsModelingMolecularMonomeric GTP-Binding ProteinsMusMuscleNeoplasm MetastasisOperative Surgical ProceduresOutcomePathway interactionsPatientsPharmaceutical PreparationsProcessRHOA geneRefractoryRelapseResearchResolutionRhabdomyosarcomaRoleSignal PathwaySignal TransductionSurvival RateTestingTherapeuticTimeTransgenic OrganismsTumor ExpansionTumor MarkersUnited StatesUnresectableValidationWNT Signaling PathwayWorkXenograft procedureZebrafishbasecell growthcell typechemotherapyexperimental studygain of functionhigh riskhuman modelin vivoinnovationinsightirradiationloss of functionmalignant muscle neoplasmneoplastic cellnew therapeutic targetnovelnovel strategiesnovel therapeuticspatient derived xenograft modelplanar cell polaritypre-clinicalpreclinical efficacyprogramsself-renewalstem cell divisionstem cell self renewaltargeted treatmenttranslational impacttreatment strategytumortumor growth
中文摘要
项目总结
英文摘要
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.
期刊论文(6)
专著(0)
科研奖励(0)
会议论文
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
DOI:
10.1084/jem.20210314
发表时间:
2021-10-04
期刊:
The Journal of experimental medicine
影响因子:
--
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
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.
Oncogenic Drivers of Rhabdomyosarcoma Cell State, Cancer Stem Cells and Metastasis
-
批准号:10658091
-
项目类别:
-
资助金额:$59.87万
-
财政年份:2023
-
负责人:David Michael Langenau
-
依托单位:
Mechanisms of aggressive Rhabdomyosarcoma.
-
批准号:10560866
-
项目类别:
-
资助金额:$54.0万
-
财政年份:2023
-
负责人:David Michael Langenau
-
依托单位:
Developing preclinical xenograft models in zebrafish.
-
批准号:10334672
-
项目类别:
-
资助金额:$79.46万
-
财政年份:2022
-
负责人:David Michael Langenau
-
依托单位:
Developing preclinical xenograft models in zebrafish.
-
批准号:10578692
-
项目类别:
-
资助金额:$79.46万
-
财政年份:2022
-
负责人:David Michael Langenau
-
依托单位:
New models and therapeutic approaches in alveolar rhabdomyosarcoma
-
批准号:9899960
-
项目类别:
-
资助金额:$38.54万
-
财政年份:2018
-
负责人:David Michael Langenau
-
依托单位:
New models and therapeutic approaches in alveolar rhabdomyosarcoma
-
批准号:10375518
-
项目类别:
-
资助金额:$37.77万
-
财政年份:2018
-
负责人:David Michael Langenau
-
依托单位:
Oncogenic pathways and therapeutic targets in T cell acute lymphoblastic leukemia
-
批准号:10225314
-
项目类别:
-
资助金额:$39.12万
-
财政年份:2017
-
负责人:David Michael Langenau
-
依托单位:
Oncogenic pathways and therapeutic targets in T cell acute lymphoblastic leukemia
-
批准号:9383339
-
项目类别:
-
资助金额:$39.12万
-
财政年份:2017
-
负责人:David Michael Langenau
-
依托单位:
Oncogenic pathways and therapeutic targets in T cell acute lymphoblastic leukemia
-
批准号:9751256
-
项目类别:
-
资助金额:$37.94万
-
财政年份:2017
-
负责人:David Michael Langenau
-
依托单位:
Immune Compromised Zebrafish for Cell Transplantation
-
批准号:10454455
-
项目类别:
-
资助金额:$17.12万
-
财政年份:2013
-
负责人:David Michael Langenau
-
依托单位:
Immune Compromises Zebrafish for Cell Transplantation
-
批准号:8711587
-
项目类别:
-
资助金额:$58.11万
-
财政年份:2013
-
负责人:David Michael Langenau
-
依托单位:
Immune Compromises Zebrafish for Cell Transplantation
-
批准号:8550879
-
项目类别:
-
资助金额:$63.2万
-
财政年份:2013
-
负责人:David Michael Langenau
-
依托单位:
Immune Compromises Zebrafish for Cell Transplantation
-
批准号:8914144
-
项目类别:
-
资助金额:$24.25万
-
财政年份:2013
-
负责人:David Michael Langenau
-
依托单位:
Immune Compromised Zebrafish for Cell Transplantation
-
批准号:10199089
-
项目类别:
-
资助金额:$59.87万
-
财政年份:2013
-
负责人:David Michael Langenau
-
依托单位:
Genetics of Rhabdomyosarcoma
-
批准号:8618780
-
项目类别:
-
资助金额:$34.7万
-
财政年份:2011
-
负责人:David Michael Langenau
-
依托单位:
Chemical Inhibitors of Rhabdomyosarcoma Self-Renawal
-
批准号:8029019
-
项目类别:
-
资助金额:$22.43万
-
财政年份:2011
-
负责人:David Michael Langenau
-
依托单位:
Genetics of Rhabdomyosarcoma
-
批准号:8022532
-
项目类别:
-
资助金额:$35.77万
-
财政年份:2011
-
负责人:David Michael Langenau
-
依托单位:
Genetics of Rhabdomyosarcoma
-
批准号:8816045
-
项目类别:
-
资助金额:$35.77万
-
财政年份:2011
-
负责人:David Michael Langenau
-
依托单位:
Chemical Inhibitors of Rhabdomyosarcoma Self-Renawal
-
批准号:8208105
-
项目类别:
-
资助金额:$19.25万
-
财政年份:2011
-
负责人:David Michael Langenau
-
依托单位:
Genetics of Rhabdomyosarcoma
-
批准号:8230502
-
项目类别:
-
资助金额:$35.77万
-
财政年份:2011
-
负责人:David Michael Langenau
-
依托单位:
海外基金