The role of lipids in melanoma progression via induction of ER stress and lipid droplet formation

脂质通过诱导内质网应激和脂滴形成在黑色素瘤进展中的作用

基本信息

  • 批准号:
    10431879
  • 负责人:
  • 金额:
    $ 5.18万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-01 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Melanoma is the most lethal skin cancer, and progression to metastatic disease leads to severe reduction in patient survival. The tumor microenvironment (TME) plays a significant role in supporting tumor growth and promoting cancer metastasis. Our laboratory recently discovered that TME adipocytes can directly transfer fatty acids into melanoma cells and promote invasion. Fatty acids can serve as a multipurpose building block to benefit cells, but excess fatty acids can also trigger endoplasmic reticulum (ER) stress. Growing evidence suggests that ER stress can induce cancer cell invasion and survival programs leading to metastasis, but the mechanism by which this occurs remains unclear. Our preliminary data suggests that adipocyte-derived lipids induce ER stress which promotes invasion gene programs. In Aim 1, we will investigate the role of lipid induced ER stress in metastasis. We will mechanistically dissect which ER stress pathways are induced by adipocyte derived lipids, and characterize how ER stress upregulates canonical melanoma invasion genes to facilitate metastasis. We hypothesize that lipids induce IRE and PERK, two branches of ER stress previously linked with cancer metastasis, and promotes melanoma invasion through AXL, a potential melanoma invasion gene. While ER stress can upregulate cell survival programs that can benefit cancer, persistent ER stress leads to cell death. To combat ER stress due to lipid overload, cells can form lipid droplets (LD) which are cytosolic organelles containing a neutral lipid core. LDs can protect cells from toxic side effects of lipids and act a regulated source of lipid accessibility. In Aim 2, we will examine how LDs protect cancer cells against lipid mediated stress. We will investigate the mechanism by which LDs can alleviate ER stress and determine their role in promoting cancer metastasis. We hypothesize that LDs reduce ER stress by sequestering lipids out of the ER lumen and compartmentalize lipids to be used as fuel for cancer progression. We will utilize both human and zebrafish melanoma cells to generate genetic perturbations within ER stress and LD formation pathways in order to understand how these two mechanisms support melanoma progression. We will perform tumor transplants in zebrafish and apply computational image analysis to investigate the role of these pathways in promoting metastasis in vivo. These combined approaches will lead to novel insights into ER stress and LD formation as mechanisms of cancer metastasis, which can identify new strategies to block melanoma progression.
项目摘要 黑色素瘤是最致命的皮肤癌,并且进展为转移性疾病导致黑色素瘤的严重减少。 患者生存率。肿瘤微环境(TME)在支持肿瘤生长和肿瘤转移中起着重要作用。 促进癌症转移。我们实验室最近发现TME脂肪细胞可以直接将脂肪 酸进入黑色素瘤细胞并促进侵袭。脂肪酸可以作为一个多用途的积木, 细胞,但过量的脂肪酸也可以触发内质网(ER)应激。越来越多的证据表明, ER应激可诱导癌细胞侵袭和存活,导致转移,但其机制尚不清楚。 这种情况发生的原因尚不清楚。我们的初步数据表明,脂肪细胞来源的脂质诱导ER应激 它促进了入侵基因程序。在目的1中,我们将研究脂质诱导的ER应激在 转移我们将从机制上剖析哪些ER应激途径是由脂肪细胞衍生的脂质诱导的, 并表征ER应激如何上调典型黑色素瘤侵袭基因以促进转移。我们 假设脂质诱导IRE和PERK,这是先前与癌症相关ER应激的两个分支 转移,并通过AXL(一种潜在的黑色素瘤侵袭基因)促进黑色素瘤侵袭。当ER 应激可以上调细胞存活程序,这可以有益于癌症,持续的ER应激导致细胞死亡。到 对抗由于脂质过载引起的ER应激,细胞可以形成脂滴(LD),其是胞质细胞器 含有中性脂质核心。LD可以保护细胞免受脂质的毒副作用,并充当调节来源 脂质的可及性。在目标2中,我们将研究LD如何保护癌细胞免受脂质介导的应激。 我们将研究LD缓解ER应激的机制,并确定它们在促进ER应激中的作用。 癌症转移我们假设LD通过将脂质隔离出ER腔来减少ER应激, 将脂质区室化以用作癌症进展的燃料。我们将利用人类和斑马鱼 黑色素瘤细胞在ER应激和LD形成途径内产生遗传扰动, 了解这两种机制如何支持黑色素瘤进展。我们将在美国进行肿瘤移植 斑马鱼,并应用计算机图像分析来研究这些途径在促进 体内转移。这些结合的方法将导致对ER应激和LD形成的新见解, 癌症转移的机制,这可以确定新的策略,以阻止黑色素瘤的进展。

项目成果

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Dianne Lumaquin其他文献

Dianne Lumaquin的其他文献

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{{ truncateString('Dianne Lumaquin', 18)}}的其他基金

The role of lipids in melanoma progression via induction of ER stress and lipid droplet formation
脂质通过诱导内质网应激和脂滴形成在黑色素瘤进展中的作用
  • 批准号:
    10066637
  • 财政年份:
    2020
  • 资助金额:
    $ 5.18万
  • 项目类别:
The role of lipids in melanoma progression via induction of ER stress and lipid droplet formation
脂质通过诱导内质网应激和脂滴形成在黑色素瘤进展中的作用
  • 批准号:
    10652471
  • 财政年份:
    2020
  • 资助金额:
    $ 5.18万
  • 项目类别:
The role of lipids in melanoma progression via induction of ER stress and lipid droplet formation
脂质通过诱导内质网应激和脂滴形成在黑色素瘤进展中的作用
  • 批准号:
    10208720
  • 财政年份:
    2020
  • 资助金额:
    $ 5.18万
  • 项目类别:

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