Understanding how senescent stromal cells contribute to mammary gland tumorigenesis

了解衰老基质细胞如何促进乳腺肿瘤发生

• 批准号: 10634562
• 负责人: Jiayu Ye
• 金额: $ 3.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634562
• 关键词: AP20187; Aging; American; Bioinformatics; Breast Cancer Cell; Breast Cancer Patient; Cancer Biology; Cell Aging; Cell Proliferation; Cells; Data Set; Development; Diagnosis; Environment; Enzymes; Fibroblasts; Gene Expression Profile; Genetic; Goals; Heterogeneity; Human; Immune; Immunohistochemistry; Immunologic Surveillance; Immunology; Immunotherapy; Infiltration; Injections; Ink; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediating; Modeling; Mouse Mammary Tumor Virus; Mus; Mutation; Neoplasm Transplantation; Oncogenic; Partner in relationship; Penetrance; Phenotype; Population; Proliferating; Refractory; Regulatory T-Lymphocyte; Research; Risk; Risk Factors; Role; Shapes; Stromal Cells; T cell infiltration; Tissues; Training; Transgenic Mice; Transgenic Organisms; Tumor Burden; Tumor Immunity; Tumor Promotion; Woman; Work; age related; bench to bedside; cancer subtypes; cancer therapy; career; cellular targeting; chemokine; cytokine; immune cell infiltrate; immune checkpoint blockade; improved; interest; malignant breast neoplasm; mammary; molecular subtypes; mouse model; neoplastic cell; novel therapeutic intervention; pharmacologic; polyoma middle tumor antigen; response; senescence; single cell analysis; single-cell RNA sequencing; skills; suicide gene; tool; training opportunity; translational medicine; transplant model; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor immunology; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenesis

Project Summary/Abstract Breast cancer is the most frequent malignancy in women and aging is one of the largest risk factors for the development of breast cancer. The accumulation of oncogenic mutations within incipient tumor cells and age- related changes in the stromal compartment may together impact tumor progression. One change that occurs in the tumor microenvironment is the accumulation of p16INKA4 (p16) positive senescent cells which express various cytokines, chemokines, and enzymes that all together recognized as senescence-associated secretory phenotype (SASP) factors. While SASPs from different cell origins can exert different effects on tumorigenesis, SASP factors secreted by senescent stromal cells can not only directly promote the proliferation of tumor cells, but also create an immunosuppressive microenvironment that ultimately leads to more robust tumor growth. The less ideal response to immunotherapy among breast cancer patients raises the possibilities that senescent stromal cells could be one of the barriers protecting breast tumor cells from current immune checkpoint blockade therapies and that the efficacy of immunotherapy can be boosted when combined with senescent cell elimination strategies. Since immunosuppressive SASP factors are detectable in human breast cancer stroma, I hypothesize that senescent stromal cells contribute to mammary gland tumorigenesis by modulating regulatory T cells (Tregs). Preliminarily, I have shown that depletion of senescent stromal cells can lead to significantly delayed mammary tumor onset in a transgenic mouse model. In addition, I have found that orthotopic mammary tumor transplantation with senescent fibroblasts results in higher tumor burden and more Tregs infiltration. Finally, my single cell RNA-sequencing (scRNA-seq) analysis on murine and human mammary tumor/breast cancer dataset reveals that senescence signature is highly restricted to a specific cancer associated fibroblasts (CAFs) subpopulation and this population expresses elevated levels of several Treg-inducing factors. I thus propose to perform further scRNA-seq analysis to identify gene expression signatures of senescent CAFs across breast cancer subtypes and understand these CAFs’ impact on tumor microenvironment. Furthermore, I will conduct in depth tumor immunity analysis on both transgenic and orthotopic injection mouse models to discuss how tumor immune environment is shaped by the senescent CAFs and whether depletion of senescent stromal cells, using both genetic and pharmacological tools, can exert synergistic effect when combined with immune checkpoint blockade therapies. These aims will not only provide a comprehensive picture of the relationship between senescent stroma and breast cancer development, but also help me pursue my interests in immunology and translational medicine. The training received through this proposal will also strengthen my research skills in immunology and cancer biology. These skills will allow me to push forward my career goals of facilitating bench- to-bedside research in cancer therapy.

项目摘要/摘要 乳腺癌是女性中最常见的恶性肿瘤，衰老是该女性的最大风险因素之一 乳腺癌的发展。在初期肿瘤细胞和年龄内的致癌突变的积累 基质区室的相关变化可能会影响肿瘤进展。发生的一种变化 肿瘤微环境是p16inka4（p16）阳性感觉细胞的积累，这些细胞表达各种 细胞因子，趋化因子和酶，这些因子和酶都被识别为感应相关分泌 表型（SASP）因素。虽然来自不同细胞起源的SASP可以对肿瘤发生不同，但 SASP因素因素细胞分泌的SASP因子不仅可以直接促进肿瘤细胞的增殖，还可以直接促进 但也创造了一种免疫抑制微环境，最终导致肿瘤的增长更加健壮。 乳腺癌患者对免疫疗法的理想反应不太理想的反应增加了感觉的可能性 基质细胞可能是保护乳腺肿瘤细胞免受当前免疫障碍封锁的障碍之一 疗法和免疫疗法的效率与Senscent Cell紧急情况结合起来可以提高 策略。由于在人类乳腺癌基质中可以检测到免疫抑制性SASP因子，因此我假设 这种感觉基质细胞通过调节调节T细胞（Tregs）来促进乳腺肿瘤发生。 初步的，我已经表明，感觉基质细胞的耗竭会导致乳腺明显延迟 转基因小鼠模型中的肿瘤发作。此外，我发现原位乳腺肿瘤 带有感觉成纤维细胞的移植会导致肿瘤较高的肿瘤和更多的Treg浸润。最后，我的 关于鼠和人类乳腺肿瘤/乳腺癌数据集的单细胞RNA - 序列（SCRNA-SEQ）分析 表明，感应特征高度限于特定癌症相关的成纤维细胞（CAF） 亚种群和该人群表达了几种Treg诱导因素的水平升高。我因此建议 进行进一步的SCRNA-SEQ分析以识别跨乳房的感觉CAF的基因表达特征 癌症亚型并了解这些CAF对肿瘤微环境的影响。此外，我将进行 对转基因和原位注射小鼠模型的深度肿瘤免疫学分析，以讨论肿瘤如何 免疫环境是由感觉CAF和感觉基质细胞耗尽的形状的 遗传和药物工具都可以与免疫检查点结合使用协同作用 blocade疗法。这些目的不仅可以为 感觉基质和乳腺癌的发展，但也有助于我追求我对免疫学和 翻译医学。通过此提案获得的培训也将增强我的研究技能 免疫学和癌症生物学。这些技能将使我能够推动促进替补席的职业目标 - 癌症疗法的卧式研究。