A novel breast cancer therapy based on secreted protein ligands from CD36+ fibroblasts

基于 CD36 成纤维细胞分泌蛋白配体的新型乳腺癌疗法

• 批准号: 10635290
• 负责人: Bahram A. Parvin
• 金额: $ 45.93万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635290
• 关键词: 3-Dimensional; 3D Print; Address; Agonist; Animals; Apoptotic; Biochemical; Biochemical Markers; Bioinformatics; Biological Assay; Breast Cancer Cell; Breast Cancer Model; Breast Cancer cell line; Breast Cancer therapy; CD36 gene; Cell Death; Cell Line; Cell Surface Receptors; Cell secretion; ChIP-seq; Clinical; Complement; Computing Methodologies; Coupling; Data; Development; Fatty acid glycerol esters; Fibroblasts; Goals; Growth; Heterogeneity; Image; Immunocompetent; Immunocompromised Host; Incubated; Induction of Apoptosis; Ligands; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Microscopy; Modeling; Molecular; Morphology; Multi-Drug Resistance; Mus; Organoids; Pathway interactions; Patients; Pilot Projects; Pre-Clinical Model; Printing; Property; Protein Secretion; Proteins; Proteomics; Public Health; Recombinant Proteins; Regulatory Element; Resected; Signal Pathway; Signal Transduction; Specificity; System; Targeted Research; Techniques; Technology; Testing; Therapeutic; Time; Toxic effect; Transplantation; Tumor Pathology; Tumor Subtype; Tumor Suppression; Tumor Tissue; activin A; cancer cell; cancer subtypes; cancer therapy; deep learning; established cell line; genetic signature; genomic signature; humanized mouse; in vivo Model; innovation; insight; learning strategy; malignant breast neoplasm; mammary; mitochondrial dysfunction; mouse model; neoplastic cell; new technology; next generation; novel; novel therapeutics; overexpression; patient derived xenograft model; physical property; recruit; response; screening; side effect; systemic toxicity; targeted treatment; technology platform; three dimensional cell culture; transcription factor; transcriptomics; translational impact; treatment response; tumor; tumor growth; tumor microenvironment

A novel breast cancer therapy based on secreted protein ligands from CD36+ fibroblasts Cancer cells recruit and alter fibroblasts' biochemical and physical properties (FBs) to benefit their growth. Cancer-associated fibroblasts (CAFs) have emerged as potential targets for reprogramming the tumor microenvironment and for optimizing therapeutic strategies. However, there is a critical gap in research targeting tumors and CAFs simultaneously. Breast cancer tumors have distinct subtypes. And there is a lack of a biochemical marker exclusive to CAFs because of their heterogeneity. In fact, the currently available CAF- targeted therapies succumb to off-target effects, so their applications are limited. We aim to address this conundrum by testing our central hypothesis that factors secreted from non-cancer-associated FBs that express CD36—a cell surface receptor downregulated in CAFs—could be utilized as an alternative strategy to induce growth suppression in subtypes of breast cancer while upregulating CD36 in CAFs. This hypothesis is based on our pilot study showing that co-transplantation of breast cancer cells with CD36+ FBs dramatically suppressed tumor growth in animals. Furthermore, for the first time, we identified three active protein ligands in the secretome of CD36+ FBs and determined the effective concentration of their corresponding recombinant proteins that induce growth suppression in breast cancer cell lines while overexpressing CD36 in at least one CAF model. This study is significant because it will have a positive translational impact on breast cancer therapy with reduced toxicity. We will continue to test our hypothesis through two specific aims and the integration of a novel technological platform: Aim 1a will identify breast cancer subtypes that are sensitive to the three recombinant proteins (RPs). To this end, we will employ 3D cultures of the established cell lines and patient-derived organoids. We will also investigate the overexpression of CD36, by the active ligands, on a panel of CAFs. To facilitate a large number of experimental variables and intrinsic heterogeneity of organoids, we will develop a novel high-throughput imaging and high-content screening by coupling printed 3D cultures or organoids with 3D microscopy and deep learning methods for quantitative profiling of 3D organization and molecular features. Aim 1b will determine the mechanisms by which the three recombinant proteins induce (a) growth suppression in sensitive breast cancer subtypes or (b) upregulate CD36 in CAFs. Mechanistic studies will be anchored by apoptotic pathways, the cis- regulatory networks' prediction, and the application of bioinformatics techniques. It will also include the mechanisms of mitochondrial dysfunction induced by RPs. Aim 2 will use mouse models to investigate tumor suppression in sensitive cell lines, mouse tumors, and PDX models. Resected tumors will also be profiled for tumor morphology and molecular endpoints using advanced computational methods. In addition, in select cases, tumor sections will be complemented with spatial proteomics/transcriptomic for additional mechanistic studies. The study is innovative because it applies, for the first time, factors secreted from CD36+ FBs that confer tumor suppression and could be utilized to treat subtypes of breast cancer with few side effects.

基于CD 36+成纤维细胞分泌蛋白配体的乳腺癌新疗法 癌细胞招募并改变成纤维细胞的生化和物理特性（FB）以利于其生长。 癌症相关成纤维细胞（CAF）已成为肿瘤重编程的潜在靶点 微环境和优化治疗策略。然而，在研究目标方面存在着一个关键的差距， 肿瘤和CAF同时发生。乳腺癌肿瘤有不同的亚型。而且缺乏一个 由于其异质性，CAF特有的生物化学标记物。事实上，目前可用的CAF- 靶向治疗屈服于脱靶效应，因此其应用受到限制。我们的目标是解决这个问题 通过测试我们的中心假设，即从表达非癌症相关FB分泌的因子， CD 36--CAFs中下调的细胞表面受体--可用作诱导CAFs表达的替代策略。 乳腺癌亚型中的生长抑制，同时上调CAF中的CD 36。这个假设是基于 我们的初步研究表明，乳腺癌细胞与CD 36 + FB的共移植显著抑制了乳腺癌细胞的增殖。 肿瘤在动物体内生长。此外，我们还首次在分泌蛋白组中鉴定了三种活性蛋白配体 的CD 36 + FB，并确定其相应的重组蛋白的有效浓度， 在至少一种CAF模型中，在乳腺癌细胞系中过表达CD 36的同时抑制肿瘤生长。本研究 是重要的，因为它将对乳腺癌治疗产生积极的转化影响，同时降低毒性。 我们将继续通过两个具体的目标和一个新的技术整合来测试我们的假设。 平台：目标1a将确定对三种重组蛋白（RP）敏感的乳腺癌亚型。 为此，我们将采用已建立的细胞系和患者来源的类器官的3D培养物。我们还将 研究一组CAFs上活性配体对CD 36的过度表达。为了方便大量的 实验变量和类器官的内在异质性，我们将开发一种新的高通量 通过将打印的3D培养物或类器官与3D显微镜和深度成像相结合， 学习3D组织和分子特征的定量分析方法。目标1b将决定 三种重组蛋白诱导（a）敏感性乳腺癌中生长抑制的机制 亚型或（B）上调CAF中的CD 36。机制研究将通过凋亡途径，顺式- 调控网络的预测和生物信息学技术的应用。它还将包括 RP诱导的线粒体功能障碍的机制。目标2将使用小鼠模型研究肿瘤 在敏感细胞系、小鼠肿瘤和PDX模型中的抑制。切除的肿瘤也将进行分析， 肿瘤形态学和分子终点。此外，在某些情况下， 肿瘤切片将用空间蛋白质组学/转录组学进行补充，用于额外的机制研究。 这项研究具有创新性，因为它首次应用了从CD 36 + FB分泌的因子，这些因子赋予肿瘤细胞 抑制，并可用于治疗乳腺癌的亚型，副作用少。