Mechanisms and Therapeutic Targets of SCC Metastasis
SCC转移的机制和治疗靶点
基本信息
- 批准号:10731726
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-10-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAffectBiological ModelsBlood VesselsCause of DeathCell LineCell LineageCellsCessation of lifeClinicCoculture TechniquesDataDisseminated Malignant NeoplasmDistant MetastasisDyesExclusionExposure toExtracellular MatrixExtracellular Matrix ProteinsFibroblastsFrequenciesFutureGene ExpressionGeneticGenetically Engineered MouseHead and neck structureHematopoieticHumanImageImmunocompetentIn VitroInvadedKRASG12DKeratinLinkLungMalignant Epithelial CellMalignant NeoplasmsMetastatic Neoplasm to Lymph NodesMetastatic Neoplasm to the LungMetastatic Squamous Cell CarcinomaModelingMolecularMonitorMusMutationMyeloid CellsNeoplasm MetastasisNeuronsOral cavityOrganOutcomePI3 genePIK3CG genePathologicPatientsPopulationProcessPrognostic MarkerPropertyProtein ArrayProtein SecretionRouteSideSiteSkinSpecimenSquamous Cell Lung CarcinomaSquamous cell carcinomaStratified EpitheliumT-LymphocyteTP53 geneTestingTherapeutic InterventionTobacco-Associated CarcinogenTongueTransplantationTravelVeteransbiomarker identificationcancer stem cellcancer typecandidate markerdesigndriver mutationhigh riskhigh throughput screeningin vivoinhibitorinnovationknock-downliquid biopsymelanomamigrationmilitary veteranmolecular markermouse modelnano-stringpharmacologicprognosis biomarkerprotein biomarkersrestorationsingle-cell RNA sequencingskin squamous cell carcinomaspectrographstem cell expansionstem cellstherapeutic evaluationtherapeutic targettooltumor microenvironmenttumor-immune system interactionstwo-photonultraviolet irradiation
项目摘要
Squamous cell carcinomas (SCCs) arise from stratified epithelia, the most relevant organ sites in the veteran
population are the skin and oral cavity where high exposure to UV irradiation and tobacco carcinogens make
the total and high-risk SCCs significantly higher than the civilian population. SCC’s worst outcome is death
through metastasis, most commonly in the lung. SCC deaths exceed melanoma deaths due to the high
number of SCC cases. The lack of spontaneous SCC lung metastasis models has hindered identification of
SCC lung metastasis mechanisms and therapeutic targets. We developed several genetically engineered
mouse models that target driver mutations frequently found in human SCCs to keratin K15+ stem cells. These
models develop spontaneous lung SCC metastasis with different frequencies. Together with their derived cell
lines, they are unique tools to study mechanisms of SCC lung metastasis in different immune tumor
microenvironments (TME). We have shown that a subpopulation of cancer stem cells (CSCs), i.e., the Hoechst
dye excluding side population (SP), have the ability to metastasize, suggesting that CSC properties dictate the
lung metastasis route. Our preliminary data revealed that cancer associated fibroblasts (CAFs) derived from
metastatic SCCs enhanced CSC expansion and invasion in vitro and seeding to the lung in vivo. Further, CAFs
undergo unique changes in gene expression of extracellular matrix (ECM) proteins, and candidate markers for
SCC CAFs are distinctive from other metastatic cancers. Lastly, targeting myeloid cells reduced SCC
metastasis. Taken together, we hypothesize that CSC properties predispose them to travel via blood vessels
and survive in the lung. Additionally, SCC-CAF crosstalk has local and systemic effects preparing the
metastatic TME and premetastatic (prior to metastasis)/metastatic (after SCC cell seeding) niche. Using our
mouse models as well as patients’ SCC specimens, the proposed studies will identify prognostic markers and
therapeutic targets for high risk metastatic SCCs and develop interventional therapies that will be brought into
clinic in the near future. Aim 1 will assess if molecules associated with multipotent CSC properties contribute
to CSCs invasion and intravasation to blood vessels. Aim 2 will identify metastatic SCC-specific CAF ECM
signatures and molecular markers that enhance metastatic CSC properties. Aim 3 will identify systemic effects
of CAF-SCC interactions that establish a metastatic TME in primary SCC and pre-metastatic/metastatic niche
in the lung. Our unique mouse model systems and cross-species comparisons with human SCCs, multiple high
throughput assays and innovative approaches will significantly accelerate discovery of SCC metastasis
mechanisms and simultaneously test therapeutic interventions.
鳞状细胞癌 (SCC) 起源于复层上皮,这是退伍军人最相关的器官部位
人口是皮肤和口腔,高度暴露于紫外线照射和烟草致癌物会使
SCC 总数和高危人群明显高于平民。 SCC最坏的结果是死亡
通过转移,最常见于肺部。鳞状细胞癌死亡人数超过黑色素瘤死亡人数,原因是
SCC 病例数。缺乏自发性 SCC 肺转移模型阻碍了
SCC肺转移机制和治疗靶点。我们开发了多种基因工程
将人类鳞状细胞癌中常见的驱动突变靶向角蛋白 K15+ 干细胞的小鼠模型。这些
模型以不同的频率发生自发性肺 SCC 转移。连同它们的衍生细胞
线,它们是研究不同免疫肿瘤中 SCC 肺转移机制的独特工具
微环境(TME)。我们已经证明,癌症干细胞 (CSC) 的一个亚群,即 Hoechst
排除侧群 (SP) 的染料具有转移能力,表明 CSC 特性决定了
肺转移途径。我们的初步数据显示,癌症相关成纤维细胞(CAF)源自
转移性鳞状细胞癌在体外增强了鳞状细胞癌的扩张和侵袭,并在体内增强了鳞状细胞癌向肺部的种植。此外,CAF
细胞外基质(ECM)蛋白的基因表达发生独特的变化,以及候选标记物
SCC CAF 与其他转移性癌症不同。最后,靶向骨髓细胞可减少鳞状细胞癌
转移。综上所述,我们假设 CSC 特性使它们易于通过血管传播
并在肺中存活。此外,SCC-CAF 串扰具有局部和系统效应,可以为
转移性 TME 和转移前(转移前)/转移性(SCC 细胞接种后)生态位。使用我们的
小鼠模型以及患者的鳞状细胞癌标本,拟议的研究将确定预后标志物和
高风险转移性鳞状细胞癌的治疗靶点并开发介入疗法,并将其引入
在不久的将来的诊所。目标 1 将评估与多能 CSC 特性相关的分子是否有贡献
CSCs 侵袭和血管内渗。目标 2 将识别转移性 SCC 特异性 CAF ECM
增强转移性 CSC 特性的特征和分子标记。目标 3 将确定系统性影响
CAF-SCC 相互作用在原发性 SCC 和转移前/转移生态位中建立转移性 TME
在肺里。我们独特的小鼠模型系统以及与人类 SCC 的跨物种比较,多个高
通量测定和创新方法将显着加速 SCC 转移的发现
机制并同时测试治疗干预措施。
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)
Setting up clinical trials for success: Applying preclinical advances in combined TGFβ/PD-L1 inhibition to ongoing clinical studies.
建立成功的临床试验:在持续的临床研究中应用临床前的TGFβ/PD-L1抑制作用。
- DOI:10.1002/mc.23373
- 发表时间:2022-03
- 期刊:
- 影响因子:4.6
- 作者:Strait AA;Wang XJ
- 通讯作者:Wang XJ
Revisiting laminin and extracellular matrix remodeling in metastatic squamous cell carcinoma: What have we learned after more than four decades of research?
- DOI:10.1002/mc.23417
- 发表时间:2022-05-21
- 期刊:
- 影响因子:4.6
- 作者:Aleman,John D.;Young,Christian D.;Wang,Xiao-Jing
- 通讯作者:Wang,Xiao-Jing
Transforming Growth Factor-β Signaling in Fibrotic Diseases and Cancer-Associated Fibroblasts.
纤维化疾病和癌症相关成纤维细胞中的转化生长因子-β 信号转导
- DOI:10.3390/biom10121666
- 发表时间:2020-12-12
- 期刊:
- 影响因子:5.5
- 作者:Shi X;Young CD;Zhou H;Wang X
- 通讯作者:Wang X
TGFβ Signaling in Photoaging and UV-Induced Skin Cancer.
- DOI:10.1016/j.jid.2020.11.007
- 发表时间:2021-04
- 期刊:
- 影响因子:0
- 作者:Ke Y;Wang XJ
- 通讯作者:Wang XJ
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Xiao-Jing Wang其他文献
Xiao-Jing Wang的其他文献
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{{ truncateString('Xiao-Jing Wang', 18)}}的其他基金
Treating recurrent HNSCC with radiation and dual TGF-Beta/PD-L1.
使用放射和双重 TGF-Beta/PD-L1 治疗复发性 HNSCC。
- 批准号:
10477461 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Treating recurrent HNSCC with radiation and dual TGF-Beta/PD-L1.
使用放射和双重 TGF-Beta/PD-L1 治疗复发性 HNSCC。
- 批准号:
10704598 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Treating recurrent HNSCC with radiation and dual TGF-Beta/PD-L1.
使用放射和双重 TGF-Beta/PD-L1 治疗复发性 HNSCC。
- 批准号:
10268846 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Mechanisms of Breaking Indolence in Squamous Cell Carcinoma
打破鳞状细胞癌惰性的机制
- 批准号:
9137250 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Mechanisms and Therapeutic Targets of SCC Metastasis
SCC转移的机制和治疗靶点
- 批准号:
10356069 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Testing Smad7-based biologics for treating chronic wounds
测试基于 Smad7 的生物制剂治疗慢性伤口
- 批准号:
8779367 - 财政年份:2014
- 资助金额:
-- - 项目类别:
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