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.

项目总结/摘要 乳腺癌是女性最常见的恶性肿瘤，衰老是乳腺癌的最大危险因素之一。 乳腺癌的发展。早期肿瘤细胞内致癌突变的积累和年龄- 基质隔室中的相关变化可共同影响肿瘤进展。一个变化发生在 肿瘤微环境是p16 INKA 4（p16）阳性衰老细胞的积累，这些细胞表达各种 细胞因子、趋化因子和酶，它们一起被认为是衰老相关的分泌性细胞因子。 表型（SASP）因子。虽然来自不同细胞来源的SASP可以对肿瘤发生发挥不同的作用， 衰老基质细胞分泌的SASP因子不仅能直接促进肿瘤细胞增殖， 而且还创造了一个免疫抑制的微环境，最终导致更强大的肿瘤生长。的 乳腺癌患者对免疫治疗的反应不太理想， 基质细胞可能是保护乳腺肿瘤细胞免受当前免疫检查点阻断的屏障之一 并且当与衰老细胞消除相结合时，可以提高免疫疗法的功效 战略布局由于免疫抑制SASP因子在人乳腺癌间质中是可检测的，我假设 衰老的基质细胞通过调节调节性T细胞（TCFs）促进乳腺肿瘤的发生。 首先，我已经证明，衰老的基质细胞的耗竭可以导致乳腺癌的显著延迟， 转基因小鼠模型中的肿瘤发作。另外，我发现原位乳腺肿瘤 用衰老成纤维细胞移植导致更高的肿瘤负荷和更多的TCFs浸润。最后我 对鼠和人乳腺肿瘤/乳腺癌数据集进行单细胞RNA测序（scRNA-seq）分析 显示衰老特征高度局限于特定的癌症相关成纤维细胞（CAF） 亚群，并且该群体表达升高水平的几种Treg诱导因子。因此，我提议 进行进一步的scRNA-seq分析，以鉴定整个乳腺中衰老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，我将在 对转基因和原位注射小鼠模型进行深入的肿瘤免疫分析，以讨论肿瘤如何 免疫环境是由衰老的CAF形成的，并且是否耗尽衰老的基质细胞，使用 遗传和药理学工具，当与免疫检查点结合时可以发挥协同作用 封锁疗法这些目标不仅将提供一个全面的图片之间的关系 衰老间质和乳腺癌的发展，而且还帮助我追求我在免疫学的兴趣， 转化医学通过这项建议接受的培训也将加强我的研究技能， 免疫学和癌症生物学。这些技能将使我能够推进我的职业目标，促进板凳- 癌症治疗的临床研究