Modeling Immune Cell Recruitment and its Impact on Triple Negative Breast Cancer Recurrence in the Irradiated Microenvironment
模拟免疫细胞募集及其对辐射微环境中三阴性乳腺癌复发的影响
基本信息
- 批准号:10574480
- 负责人:
- 金额:$ 1.34万
- 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:2021-01-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:4T1AmericanBiological AssayBreast Cancer CellBreast Cancer ModelBreast Cancer PatientBreast Cancer therapyBreast conservationCD8-Positive T-LymphocytesCancer EtiologyCell CommunicationCell secretionCellsCessation of lifeChemotaxisCoculture TechniquesDiagnosisFaceFatty acid glycerol estersFlow CytometryGoalsGrowthHumanImmunocompetentImmunocompromised HostImmunological ModelsInfiltrationInvadedLaboratoriesLiteratureMDA MB 231MacrophageMalignant NeoplasmsMediatingModelingMonitorMonoclonal AntibodiesMusNeoplasm Circulating CellsNormal tissue morphologyOperative Surgical ProceduresOrganoidsPatientsPhenotypePlayPrimary NeoplasmProcessPrognosisProliferatingRadiationRadiation induced damageRadiation therapyRecurrenceRecurrent Malignant NeoplasmResearchRoleSiteStudy modelsTestingTissuesTrainingTumor Cell InvasionTumor Cell MigrationTumor PromotionWomanWorkblocking factorcancer recurrencecell behaviorchemotherapycytokineeffective therapyexperiencehigh riskimmune cell infiltrateimmunosuppressive macrophagesimprovedin vitro Modelin vivointerestmalignant breast neoplasmmammarymammary epitheliummigrationmouse modelneoplastic cellorthotopic breast cancerpre-clinicalpreclinical studyradiation responserecruitsmall molecule inhibitortriple-negative invasive breast carcinomatumortumor ablationtumor growthtumor progressionwound healing
项目摘要
PROJECT SUMMARY
Approximately half of triple negative breast cancer (TNBC) patients receive breast conserving therapy, which
includes irradiating the primary tumor site. Although this therapy improves prognosis overall, patients continue
to experience locoregional recurrences at high rates. The mechanisms controlling recurrence following therapy
are poorly understood. Previous research suggests that normal tissue radiation damage may be correlated to
recurrence. Pre-clinical studies have shown that tumor cells migrate into irradiated mammary tissue and that
macrophages play a critical role in the tumor cell recruitment process. While blockade of macrophage infiltration
was shown to eliminate tumor cell migration to irradiated sites, the impact of macrophage phenotype has not
been investigated. Macrophages with a wound healing phenotype (M2) are known to promote tumor growth and
progression, but whether M2 macrophages influence tumor cell recruitment and proliferation in irradiated tissues
is unknown. The central hypothesis of this proposal is that radiation damage in the tissue microenvironment
promotes a pre-metastatic niche through immunosuppressive cell infiltration. I will test this hypothesis using pre-
clinical orthotopic breast cancer models as well as organoids to study the normal tissue response to radiation
and its influence on recurrence.
This project is guided by two specific aims: 1) To characterize macrophage phenotypes associated with RT-
induced recurrence and 2) to identify targetable secreted factors that contribute to tumor cell recruitment in
irradiated tissues. In Aim 1, I will rigorously examine the immune cell infiltrate into irradiated mammary tissue
using flow cytometry. To confirm the importance of M2 macrophages in recurrence, I will develop an M2
macrophage-depleted mouse model by blocking polarization with small molecule inhibitors or monoclonal
antibodies. Finally, I will determine the impact of M2 macrophage depletion on tumor cell recruitment to irradiated
tissues. In Aim 2, I will use an organoid model developed by our laboratory that recapitulates pre-clinical
observations. I will analyze secreted pro-tumor factors by co-culturing organoids with macrophages, tumor cells,
and CD8+ T cells and characterizing secreted cytokines in conditioned media. I will then evaluate how these
factors contribute to tumor cell recruitment in vivo. This study will establish the conditions that lead to recurrence
following radiotherapy, including composition of macrophage infiltrate and mechanisms of tumor regrowth, which
will have significant implications for TNBC patients vulnerable to recurrence.
项目摘要
大约一半的三阴性乳腺癌(TNBC)患者接受保乳治疗,
包括照射原发肿瘤部位。虽然这种治疗总体上改善了预后,但患者继续
局部复发率很高控制治疗后复发的机制
我们对此知之甚少。先前的研究表明,正常组织的辐射损伤可能与
复发临床前研究表明,肿瘤细胞迁移到照射的乳腺组织中,
巨噬细胞在肿瘤细胞募集过程中起关键作用。同时阻断巨噬细胞浸润
显示消除了肿瘤细胞向照射部位的迁移,但对巨噬细胞表型的影响没有
被调查了已知具有伤口愈合表型的巨噬细胞(M2)促进肿瘤生长,
进展,但M2巨噬细胞是否影响照射组织中的肿瘤细胞募集和增殖
不明该建议的中心假设是,组织微环境中的辐射损伤
通过免疫抑制细胞浸润促进转移前小生境。我将使用预测试来测试这个假设
临床原位乳腺癌模型以及类器官,以研究正常组织对辐射的反应
及其对复发的影响。
该项目有两个具体目标:1)表征与RT相关的巨噬细胞表型-
诱导复发和2)鉴定有助于肿瘤细胞募集的靶向分泌因子,
辐照组织。在目标1中,我将严格检查免疫细胞浸润到辐照的乳腺组织中
使用流式细胞术。为了证实M2巨噬细胞在复发中的重要性,我将开发一个M2
通过用小分子抑制剂或单克隆抗体阻断极化的巨噬细胞耗竭小鼠模型
抗体的最后,我将确定M2巨噬细胞耗竭对肿瘤细胞募集到辐射的
组织中在目标2中,我将使用我们实验室开发的类器官模型,该模型概括了临床前
意见。我将通过将类器官与巨噬细胞,肿瘤细胞,
和CD 8 + T细胞,并表征条件培养基中分泌的细胞因子。然后我将评估这些
因子有助于肿瘤细胞在体内募集。这项研究将确定导致复发的条件
包括巨噬细胞浸润的组成和肿瘤再生长的机制,
将对易复发的TNBC患者产生重大影响。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Benjamin Christian Hacker其他文献
Benjamin Christian Hacker的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Benjamin Christian Hacker', 18)}}的其他基金
Modeling Immune Cell Recruitment and its Impact on Triple Negative Breast Cancer Recurrence in the Irradiated Microenvironment
模拟免疫细胞募集及其对辐射微环境中三阴性乳腺癌复发的影响
- 批准号:
10321214 - 财政年份:2021
- 资助金额:
$ 1.34万 - 项目类别:
Modeling Immune Cell Recruitment and its Impact on Triple Negative Breast Cancer Recurrence in the Irradiated Microenvironment
模拟免疫细胞募集及其对辐射微环境中三阴性乳腺癌复发的影响
- 批准号:
10157580 - 财政年份:2021
- 资助金额:
$ 1.34万 - 项目类别:
相似海外基金
Collaborative Research: REU Site: Earth and Planetary Science and Astrophysics REU at the American Museum of Natural History in Collaboration with the City University of New York
合作研究:REU 地点:地球与行星科学和天体物理学 REU 与纽约市立大学合作,位于美国自然历史博物馆
- 批准号:
2348998 - 财政年份:2025
- 资助金额:
$ 1.34万 - 项目类别:
Standard Grant
Collaborative Research: REU Site: Earth and Planetary Science and Astrophysics REU at the American Museum of Natural History in Collaboration with the City University of New York
合作研究:REU 地点:地球与行星科学和天体物理学 REU 与纽约市立大学合作,位于美国自然历史博物馆
- 批准号:
2348999 - 财政年份:2025
- 资助金额:
$ 1.34万 - 项目类别:
Standard Grant
Collaborative Research: Ionospheric Density Response to American Solar Eclipses Using Coordinated Radio Observations with Modeling Support
合作研究:利用协调射电观测和建模支持对美国日食的电离层密度响应
- 批准号:
2412294 - 财政年份:2024
- 资助金额:
$ 1.34万 - 项目类别:
Standard Grant
Conference: Doctoral Consortium at Student Research Workshop at the Annual Conference of the North American Chapter of the Association for Computational Linguistics (NAACL)
会议:计算语言学协会 (NAACL) 北美分会年会学生研究研讨会上的博士联盟
- 批准号:
2415059 - 财政年份:2024
- 资助金额:
$ 1.34万 - 项目类别:
Standard Grant
Conference: Polymeric Materials: Science and Engineering Division Centennial Celebration at the Spring 2024 American Chemical Society Meeting
会议:高分子材料:美国化学会 2024 年春季会议科学与工程部百年庆典
- 批准号:
2415569 - 财政年份:2024
- 资助金额:
$ 1.34万 - 项目类别:
Standard Grant
Collaborative Research: RUI: Continental-Scale Study of Jura-Cretaceous Basins and Melanges along the Backbone of the North American Cordillera-A Test of Mesozoic Subduction Models
合作研究:RUI:北美科迪勒拉山脊沿线汝拉-白垩纪盆地和混杂岩的大陆尺度研究——中生代俯冲模型的检验
- 批准号:
2346565 - 财政年份:2024
- 资助金额:
$ 1.34万 - 项目类别:
Standard Grant
REU Site: Research Experiences for American Leadership of Industry with Zero Emissions by 2050 (REALIZE-2050)
REU 网站:2050 年美国零排放工业领先地位的研究经验 (REALIZE-2050)
- 批准号:
2349580 - 财政年份:2024
- 资助金额:
$ 1.34万 - 项目类别:
Standard Grant
Collaborative Research: RUI: Continental-Scale Study of Jura-Cretaceous Basins and Melanges along the Backbone of the North American Cordillera-A Test of Mesozoic Subduction Models
合作研究:RUI:北美科迪勒拉山脊沿线汝拉-白垩纪盆地和混杂岩的大陆尺度研究——中生代俯冲模型的检验
- 批准号:
2346564 - 财政年份:2024
- 资助金额:
$ 1.34万 - 项目类别:
Standard Grant
Conference: Latin American School of Algebraic Geometry
会议:拉丁美洲代数几何学院
- 批准号:
2401164 - 财政年份:2024
- 资助金额:
$ 1.34万 - 项目类别:
Standard Grant
Conference: North American High Order Methods Con (NAHOMCon)
会议:北美高阶方法大会 (NAHOMCon)
- 批准号:
2333724 - 财政年份:2024
- 资助金额:
$ 1.34万 - 项目类别:
Standard Grant