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

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

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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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