Functional Determinants of Metastatic Dormancy

转移休眠的功能决定因素

基本信息

项目摘要

SUMMARY. The majority of cancer patients die of metastases originating from disseminated cancer cells (DCCs), years and decades after treatment. This has been linked to the ability of DCCs to survive in a dormant state and evade therapies. Our long-term goal is to understand dormancy of DCCs as a systemic disease mechanism to target them and prevent relapse. Our overarching hypothesis is that complementary mechanism between gene programs in primary lesions and target organs niche signals, converge to instruct DCCs in target organs to enter dormancy via quiescence, pluripotency and survival programs. We further hypothesize that such signals can be manipulated to suppress metastasis. Using epithelial cancer models we have discovered that early dissemination spawns mesenchymal-like (M-Like) dormant breast cancer (BC) DCCs. We also discovered that hypoxia in advanced primary tumors can prime DCC precursors to activate quiescence programs and enter dormancy in target organs. Importantly, M-like early DCC precursors also display a strong hypoxia response. Both early and late DCCs were found to respond to retinoic acid, WNT5A, BMP7 and TGF2 signals derived from stromal target organ niches. These activate transcriptional programs integrated by ZFP281 (a novel early DCC dormancy regulator) and NR2F1 to induce dormancy. Our new aims build on these findings and explore three significant new discoveries: 1) Hypoxia signals in early and late primary lesions turn on quiescence programs that epigenetically imprint DCC precursors to enter dormancy when they arrive to target organs, 2) early or late DCCs that arrive to the bone marrow (BM) enter dormancy in response to TGF2 and BMP7 produced by Nestin+/NG2+ mesenchymal stem cells (N+MSCs), which control hematopoietic stem cells (HSCs) dormancy; loss of N+MSCs or TGF2 expression in these MSCs led to bone metastasis and 3), in lungs, early and late DCCs reside in pro-dormancy niches orchestrated by alveolar macrophages (AMs), which when depleted awaken dormant DCCs. We propose to study how signals from primary lesion hypoxia along with BM and lung homeostatic niches are integrated to keep DCCs dormant. The specific aims are: AIM 1. Determine how hypoxia primes DCCs for dormancy. AIM 2. Determine how NG2+/Nestin+ MSCs orchestrate dormancy niches and how aging affects these mechanisms. AIM 3. Determine how tissue resident lung alveolar macrophages (AMs) dictate DCC fate and how aging impacts the function of these niches. Our proposal will integrate how primary lesions (early or late) may pre-program DCCs for dormancy in defined target organ niches which further reinforce dormancy via specific cues, which may be affected by aging. This approach will aid the design of rational methods to predict dormancy onset, monitor residual cancer and develop therapies to induce and maintain dormancy or eradicate minimal residual cancer.
总结。大多数癌症患者死于源自播散性癌细胞的转移

项目成果

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Julio A. Aguirre-Ghiso其他文献

Models, mechanisms and clinical evidence for cancer dormancy
癌症休眠的模型、机制和临床证据
  • DOI:
    10.1038/nrc2256
  • 发表时间:
    2007-11-01
  • 期刊:
  • 影响因子:
    66.800
  • 作者:
    Julio A. Aguirre-Ghiso
  • 通讯作者:
    Julio A. Aguirre-Ghiso
Targeting PERK Arm of Unfolded Protein Response Helps to Eliminate Therapy-Induced Residual Senescent-like Acute Myeloid Leukemia Cells
  • DOI:
    10.1182/blood-2024-203451
  • 发表时间:
    2024-11-05
  • 期刊:
  • 影响因子:
  • 作者:
    Gowri Poigaialwar;Sumiko Takao;Sovira Chaudhry;Laura K. Schmalbrock;Varun Gupta;Alex Kentsis;Julio A. Aguirre-Ghiso;Marina Konopleva;Maria S. Sosa;Anna Skwarska
  • 通讯作者:
    Anna Skwarska

Julio A. Aguirre-Ghiso的其他文献

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{{ truncateString('Julio A. Aguirre-Ghiso', 18)}}的其他基金

Epigenetic and microenvironmental regulation of dormant disseminated cancer
休眠播散性癌症的表观遗传学和微环境调控
  • 批准号:
    10525056
  • 财政年份:
    2022
  • 资助金额:
    $ 61.06万
  • 项目类别:
Functional Determinants of Metastatic Dormancy
转移休眠的功能决定因素
  • 批准号:
    10516864
  • 财政年份:
    2022
  • 资助金额:
    $ 61.06万
  • 项目类别:
Functional Determinants of Metastatic Dormancy
转移休眠的功能决定因素
  • 批准号:
    10678829
  • 财政年份:
    2022
  • 资助金额:
    $ 61.06万
  • 项目类别:
Immune Regulation of Disseminated Cancer Cell Dormancy
播散性癌细胞休眠的免疫调节
  • 批准号:
    10201082
  • 财政年份:
    2021
  • 资助金额:
    $ 61.06万
  • 项目类别:
Immune Regulation of Disseminated Cancer Cell Dormancy
播散性癌细胞休眠的免疫调节
  • 批准号:
    10513907
  • 财政年份:
    2021
  • 资助金额:
    $ 61.06万
  • 项目类别:
Mechanisms of uveal melanoma dormancy and targeted therapy tolerance
葡萄膜黑色素瘤休眠机制及靶向治疗耐受性
  • 批准号:
    10645058
  • 财政年份:
    2020
  • 资助金额:
    $ 61.06万
  • 项目类别:
Mechanisms of uveal melanoma dormancy and targeted therapy tolerance
葡萄膜黑色素瘤休眠机制及靶向治疗耐受性
  • 批准号:
    10226338
  • 财政年份:
    2020
  • 资助金额:
    $ 61.06万
  • 项目类别:
Mechanisms of uveal melanoma dormancy and targeted therapy tolerance
葡萄膜黑色素瘤休眠机制及靶向治疗耐受性
  • 批准号:
    10414811
  • 财政年份:
    2020
  • 资助金额:
    $ 61.06万
  • 项目类别:
Epigenetic and microenvironmental regulation of dormant disseminated cancer
休眠播散性癌症的表观遗传学和微环境调控
  • 批准号:
    9924485
  • 财政年份:
    2017
  • 资助金额:
    $ 61.06万
  • 项目类别:
Epigenetic and microenvironmental regulation of dormant disseminated cancer
休眠播散性癌症的表观遗传学和微环境调控
  • 批准号:
    9502259
  • 财政年份:
    2017
  • 资助金额:
    $ 61.06万
  • 项目类别:

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