Reprogramming of the stromal microenvironment in melanoma progression and therapeutic escape
黑色素瘤进展和治疗逃避中基质微环境的重新编程
基本信息
- 批准号:10430243
- 负责人:
- 金额:$ 35.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-15 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAutomobile DrivingBRAF geneBiological ProcessBiologyBypassCancer ControlCell LineCoinComplexDataDevelopmentDrug resistanceExtracellular MatrixFibroblastsGenesGeneticGenetic TranscriptionGoalsGrowthHumanImmune checkpoint inhibitorIn VitroKnowledgeMAP Kinase GeneMEK inhibitionMEKsMagicMalignant NeoplasmsMediatingMelanoma CellMetastatic MelanomaModelingMolecularMolecular TargetMusNuclearOutcomePathway interactionsPatient-Focused OutcomesPatientsPenetrationPharmaceutical PreparationsPhenotypePopulationProteinsRecurrenceRelapseResearchResistanceRoleSeriesSignal PathwaySignal TransductionStromal CellsTCF7L2 geneTestingTherapeuticTherapeutic Agentsbasebeta catenincell growthcellular targetingdesigndrug developmentdrug-sensitiveexperimental studyimprovedin vivoinhibitorinhibitor therapyinnovationmelanomamouse modelmultidisciplinarymutantneoplastic cellnew therapeutic targetnovelnovel strategiesnovel therapeuticsperiostinraf Kinasesresilienceresponsetargeted treatmenttherapy outcometranscriptometranscriptome sequencingtreatment optimizationtumortumor microenvironment
项目摘要
Although the approval of novel targeted therapy drugs, such as BRAF inhibitors (BRAFi), MEK inhibitors (MEKi),
and immune checkpoint inhibitors, has revolutionized melanoma treatment, long-term outcomes are still
disappointing for many patients because of the development of drug resistance. A major contributing factor to
tumor resilience and relapse is the presence of a “plastic” microenvironment, which is comprised of
heterogeneous stromal cell populations embedded in a dense and stiff extracellular matrix (ECM). Particularly,
the ECM not only functions as a barrier to drug penetration and distribution and also provides structural and
adaptive signals, which can induce therapeutic escape pathways in melanoma cells. Genetically stable cancer-
associated fibroblasts (CAFs) are known to be a notorious ECM-remodeling machine in the tumor stroma. We
have discovered that the number of CAFs with nuclear β-catenin in the melanoma stroma increases significantly
after the patients are treated with BRAFi/MEKi. We have established that increased nuclear β-catenin in CAFs
is induced by BRAFi but not MEKi. Nevertheless, how BRAFi stimulates CAFs to reprogram their biological
functions via hyperactivated nuclear β-catenin activity remains to be understood. We have obtained compelling
data demonstrating that targeted depletion of β-catenin in CAFs ablates their ability to remodel the tumor
microenvironment, downregulates abnormal BRAF/MAPK/ERK signaling in melanoma cells, and suppresses
melanoma cell drug resistance in vitro and in vivo. RNA-Seq data show that β-catenin is essential for CAF to
remodel the ECM by coining the CAF transcriptome. We have identified the β-catenin/TCF4 target gene periostin
(POSTN) as an important matricellular protein secreted by CAFs to promote BRAFi resistance. The central
hypothesis is that decoding and targeting the ECM-remodeling CAFs has the potential to create a drug-sensitive
microenvironment that sensitizes melanoma cells to therapeutic agents and increase their response rate. In Aim
1, we will elucidate the pro-activation pathway(s) by which BRAFi stimulates CAFs to mediate melanoma drug
resistance phenotypes. We will assess the role of hyperactivated nuclear β-catenin in the function of CAFs in
melanoma. In Aim 2, we will determine whether the β-catenin-TCF4 transcriptional complex is the signaling hub
that controls CAF-driven ECM remodeling and BRAFi/MEKi resistance. We will evaluate whether disrupting the
β-catenin-TCF4 interaction in CAFs will sensitize BRAF-mutant melanoma cells to BRAFi/MEKi in vivo. In Aim
3, we will determine the roles of CAF-derived POSTN in melanoma cell growth and resistance to BRAFi/MEKi.
We will investigate signaling pathways that are activated by POSTN in melanoma cells to promote their
proliferation and resistance to BRAFi. The expected outcomes are to be an in-depth mechanistic characterization
of the complex interactions among CAFs, BRAFi, and the ECM microenvironment that promote the growth and
drug resistance in BRAF-mutant melanoma cells. The knowledge obtained will open the possibility of developing
a “magic bullet” that could destroy the tumor niche to improve targeted therapy and optimize patient outcomes.
虽然新型靶向治疗药物,如BRAF抑制剂(BRAFi),MEK抑制剂(MEKi),
和免疫检查点抑制剂,彻底改变了黑色素瘤的治疗,长期结果仍然是
由于耐药性的发展,许多患者感到失望。的一个主要因素
肿瘤恢复力和复发是一个“塑料”微环境的存在,它由以下组成:
异质基质细胞群包埋在致密和坚硬的细胞外基质(ECM)中。特别地,
ECM不仅作为药物渗透和分布的屏障,
适应性信号,这可以诱导黑色素瘤细胞的治疗逃逸途径。基因稳定的癌症-
已知相关成纤维细胞(CAF)是肿瘤间质中臭名昭著的ECM重塑机器。我们
发现黑色素瘤间质中具有核β-连环蛋白的CAF的数量显著增加
在患者接受BRAFi/MEKi治疗后。我们已经确定CAFs中细胞核β-catenin的增加
是由BRAFi而不是MEKi诱导的。然而,BRAFi如何刺激CAFs重新编程其生物学功能,
通过过度激活的核β-连环蛋白活性的功能仍有待了解。我们已经获得了令人信服的
数据表明,靶向清除CAF中的β-连环蛋白会消除其重塑肿瘤的能力,
微环境,下调黑色素瘤细胞中异常的BRAF/MAPK/ERK信号传导,并抑制
黑色素瘤细胞的体外和体内耐药性。RNA-Seq数据显示,β-连环蛋白对于CAF是必需的,
通过铸造CAF转录组来重塑ECM。我们已经鉴定了β-catenin/TCF 4靶基因periostin,
(POSTN)是CAF分泌的一种重要的基质细胞蛋白,可促进BRAFi抗性。中央
有一种假设是,解码和靶向ECM重塑CAFs有可能产生药物敏感的CAFs。
微环境,使黑色素瘤细胞对治疗剂敏感并增加其反应率。在Aim中
1,我们将阐明BRAFi刺激CAFs介导黑色素瘤药物治疗的前活化途径。
抗性表型我们将评估过度活化的核β-连环蛋白在CAFs功能中的作用,
黑素瘤在目标2中,我们将确定β-catenin-TCF 4转录复合物是否是信号中枢
控制CAF驱动的ECM重塑和BRAFi/MEKi抗性。我们将评估是否破坏
CAF中的β-连环蛋白-TCF 4相互作用将使BRAF突变型黑素瘤细胞在体内对BRAFi/MEKi敏感。在Aim中
3,我们将确定CAF衍生的POR 4在黑色素瘤细胞生长和对BRAFi/MEKi的抗性中的作用。
我们将研究黑色素瘤细胞中由POR 4激活的信号通路,
增殖和对BRAFi的抗性。预期的结果将是一个深入的机械特性
CAFs,BRAFi和ECM微环境之间的复杂相互作用促进了生长,
BRAF突变黑色素瘤细胞的耐药性。所获得的知识将为开发
这是一颗“神奇子弹”,可以摧毁肿瘤生态位,以改善靶向治疗并优化患者预后。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Yuhang Zhang其他文献
Yuhang Zhang的其他文献
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{{ truncateString('Yuhang Zhang', 18)}}的其他基金
Multiscale modeling of an inductive hair follicle microenvironment in engineered skin substitute
工程皮肤替代品中诱导毛囊微环境的多尺度建模
- 批准号:
10531266 - 财政年份:2021
- 资助金额:
$ 35.77万 - 项目类别:
Reprogramming of the stromal microenvironment in melanoma progression and therapeutic escape
黑色素瘤进展和治疗逃避中基质微环境的重新编程
- 批准号:
10656454 - 财政年份:2021
- 资助金额:
$ 35.77万 - 项目类别:
Reprogramming of human dermal fibroblasts into inductive dermal papilla cells
将人真皮成纤维细胞重编程为诱导性真皮乳头细胞
- 批准号:
10391555 - 财政年份:2021
- 资助金额:
$ 35.77万 - 项目类别:
Reprogramming of human dermal fibroblasts into inductive dermal papilla cells
将人真皮成纤维细胞重编程为诱导性真皮乳头细胞
- 批准号:
10189163 - 财政年份:2021
- 资助金额:
$ 35.77万 - 项目类别:
Reprogramming of the stromal microenvironment in melanoma progression and therapeutic escape
黑色素瘤进展和治疗逃避中基质微环境的重新编程
- 批准号:
10296843 - 财政年份:2021
- 资助金额:
$ 35.77万 - 项目类别:
Multiscale modeling of an inductive hair follicle microenvironment in engineered skin substitute
工程皮肤替代品中诱导毛囊微环境的多尺度建模
- 批准号:
10341124 - 财政年份:2021
- 资助金额:
$ 35.77万 - 项目类别:
Coordinated Regulation of Hair Growth and Pigmentation by Dermal Papilla Cells
真皮乳头细胞对毛发生长和色素沉着的协调调节
- 批准号:
8518166 - 财政年份:2012
- 资助金额:
$ 35.77万 - 项目类别:
Coordinated Regulation of Hair Growth and Pigmentation by Dermal Papilla Cells
真皮乳头细胞对毛发生长和色素沉着的协调调节
- 批准号:
8288505 - 财政年份:2012
- 资助金额:
$ 35.77万 - 项目类别:
Coordinated Regulation of Hair Growth and Pigmentation by Dermal Papilla Cells
真皮乳头细胞对毛发生长和色素沉着的协调调节
- 批准号:
8708497 - 财政年份:2012
- 资助金额:
$ 35.77万 - 项目类别:
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