Elucidating the role and regulation of periostin in therapy-induced chemoresistance in metastatic breast cancer

阐明骨膜素在转移性乳腺癌化疗耐药中的作用和调节

基本信息

  • 批准号:
    10408263
  • 负责人:
  • 金额:
    $ 10.3万
  • 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:
    2021-04-01 至 2022-03-31
  • 项目状态:
    已结题

项目摘要

Project Summary Approximately 450,000 women succumb to breast cancer each year, making it the most common cause of female cancer mortality globally, with the majority of these deaths resulting from metastatic disease. In the treatment of metastases, the initial drug response rate is only about 50%, as compared to 90% observed in the treatment of primary tumors. Furthermore, resistance to these systemic therapies typically develops more quickly in the metastatic setting. While numerous studies have focused on tumor cell intrinsic mechanisms of metastasis and drug resistance, there have been very few investigations into how non- malignant host cells of the metastatic tumor microenvironment extrinsically promote these processes. Fibroblasts are one cell type present in the tumor microenvironment which have been linked to several tumor growth and metastasis promoting activities. Despite this emerging paradigm, very few studies have evaluated the contributions of lung fibroblasts to extrinsic mechanisms of cancer cell survival and chemo-resistance, a reflection of the difficulty of conducting these investigations in vivo, and the paucity of in vitro models which reliably recapitulate in vivo tumor-stroma interactions. Our laboratory has fully optimized a 3D lung-like organotypic co-culture model which effectively incorporates both tumor cells and primary resident stromal cells from secondary sites of metastasis. Utilizing this model, our preliminary data demonstrate that lung fibroblasts modulate significant phenotypic differences in human breast cancer cell proliferation and drug response, in a breast cancer molecular-subtype dependent manner. Based on these data, we hypothesize that we can identify tumor cell specific genes whose function is essential for their attainment of pro-survival and drug resistant phenotypes upon interaction with lung fibroblasts. To investigate this, we propose to conduct a genome-wide CRISPR “stromal synthetic lethal” screen against human breast cancer cells cultured in the presence or absence of primary human lung fibroblasts. Results of these studies will fill a critical knowledge gap regarding lung fibroblast mediated promotion of breast cancer survival and will uncover novel genes whose function/proteins can be targeted for assessment as potential novel anti-metastatic therapies for breast cancer.
项目概要 每年约有 450,000 名女性死于乳腺癌,使其成为最常见的癌症 是全球女性癌症死亡的原因,其中大部分死亡是由转移性疾病造成的。 在转移瘤的治疗中,初始药物反应率仅为 50% 左右,而观察到的药物反应率为 90% 在原发性肿瘤的治疗中。此外,通常会对这些全身疗法产生耐药性 在转移环境中更快。虽然许多研究都集中在肿瘤细胞内在 转移和耐药机制,但很少有人研究非 转移性肿瘤微环境的恶性宿主细胞从外部促进这些过程。 成纤维细胞是肿瘤微环境中存在的一种细胞类型,与多种肿瘤有关 生长和转移促进活动。尽管存在这种新兴范式,但很少有研究评估 肺成纤维细胞对癌细胞存活和化疗耐药的外在机制的贡献 反映出在体内进行这些研究的难度以及体外模型的缺乏 可靠地重现体内肿瘤-基质相互作用。我们的实验室已经全面优化了3D类肺 器官型共培养模型,有效整合肿瘤细胞和原代基质细胞 来自继发性转移部位。利用该模型,我们的初步数据表明肺成纤维细胞 调节人乳腺癌细胞增殖和药物反应的显着表型差异 乳腺癌分子亚型依赖方式。根据这些数据,我们假设我们可以 识别肿瘤细胞特异性基因,其功能对于实现促生存和药物至关重要 与肺成纤维细胞相互作用后产生耐药表型。为了调查这一点,我们建议进行一次 针对在培养皿中培养的人类乳腺癌细胞进行全基因组 CRISPR“基质合成致死”筛选 存在或不存在原代人肺成纤维细胞。这些研究的结果将填补关键知识 关于肺成纤维细胞介导的乳腺癌生存促进的差距并将发现新的基因 其功能/蛋白质可以作为潜在的新型乳腺抗转移疗法进行评估 癌症。

项目成果

期刊论文数量(19)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Rotator cuff repair using a bioresorbable nanofiber interposition scaffold: a biomechanical and histologic analysis in sheep.
  • DOI:
    10.1016/j.jse.2021.07.018
  • 发表时间:
    2022-03
  • 期刊:
  • 影响因子:
    3
  • 作者:
    Romeo, Anthony;Easley, Jeremiah;Regan, Dan;Hackett, Eileen;Johnson, James;Johnson, Jed;Puttlitz, Christian;McGilvray, Kirk
  • 通讯作者:
    McGilvray, Kirk
Canine tonsillar neoplasia and tonsillar metastasis from various primary neoplasms.
  • DOI:
    10.1111/vco.12604
  • 发表时间:
    2020-12
  • 期刊:
  • 影响因子:
    2.1
  • 作者:
    Mickelson MA;Regan D;Randall EK;Worley D;Seguin B
  • 通讯作者:
    Seguin B
Immunization against full-length protein and peptides from the Lutzomyia longipalpis sand fly salivary component maxadilan protects against Leishmania major infection in a murine model.
  • DOI:
    10.1016/j.vaccine.2017.10.039
  • 发表时间:
    2017-12-04
  • 期刊:
  • 影响因子:
    5.5
  • 作者:
    Wheat WH;Arthun EN;Spencer JS;Regan DP;Titus RG;Dow SW
  • 通讯作者:
    Dow SW
Evaluation of lumbar spinal fusion utilizing recombinant human platelet derived growth factor-B chain homodimer (rhPDGF-BB) combined with a bovine collagen/β-tricalcium phosphate (β-TCP) matrix in an ovine model.
  • DOI:
    10.1002/jsp2.1166
  • 发表时间:
    2021-09
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Gadomski BC;Labus KM;Puttlitz CM;McGilvray KC;Regan DP;Nelson B;Seim HB 3rd;Easley JT
  • 通讯作者:
    Easley JT
Bony ingrowth potential of 3D-printed porous titanium alloy: a direct comparison of interbody cage materials in an in vivo ovine lumbar fusion model.
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Daniel Patrick Regan其他文献

Daniel Patrick Regan的其他文献

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{{ truncateString('Daniel Patrick Regan', 18)}}的其他基金

Elucidating the role and regulation of periostin in therapy-induced chemoresistance in metastatic breast cancer
阐明骨膜素在转移性乳腺癌化疗耐药中的作用和调节
  • 批准号:
    9164338
  • 财政年份:
    2016
  • 资助金额:
    $ 10.3万
  • 项目类别:
Elucidating the role and regulation of periostin in therapy-induced chemoresistance in metastatic breast cancer
阐明骨膜素在转移性乳腺癌化疗耐药中的作用和调节
  • 批准号:
    9926128
  • 财政年份:
    2016
  • 资助金额:
    $ 10.3万
  • 项目类别:

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