Spatiotemporal modeling of cancer-niche interactions in breast cancer bone metastasis

乳腺癌骨转移中癌症-生态位相互作用的时空模型

• 批准号: 10056730
• 负责人: STEPHEN TC WONG
• 金额: $ 54.91万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10056730
• 关键词: Adopted; Algorithms; Animal Model; Autocrine Communication; Bioinformatics; Biological; Biological Assay; Biology; Bone Marrow; Breast Cancer Cell; Breast Cancer Patient; Breast cancer metastasis; CSPG4 gene; Cancer Model; Cell Differentiation process; Cells; Clinical; Clinical Research; Computational algorithm; Computer Assisted; Computer Models; Data; Development; Diagnosis; Disease; Endothelial Cells; Excision; Exhibits; Foundations; Frequencies; Genetically Engineered Mouse; Goals; Homeostasis; Image; In Situ; Indolent; Knowledge; Laboratories; Lead; Malignant Neoplasms; Maps; Mediating; Mesenchymal Stem Cells; Metastatic Neoplasm to the Bone; Micrometastasis; Microscopic; Microscopy; Modeling; Molecular; Molecular Profiling; Neoplasm Metastasis; Osteogenesis; Osteolysis; Osteolytic; Outcome; Ovarian; Paracrine Communication; Patients; Pharmaceutical Preparations; Play; Primary Neoplasm; Process; Quality of life; Resolution; Role; Seeds; Series; Signal Pathway; Signal Transduction; Stromal Cells; Symptoms; Therapeutic; Transforming Growth Factor beta; base; bioimaging; bisphosphonate; bone; bone cell; cancer cell; cell type; clinical translation; design; drug efficacy; improved; laser capture microdissection; malignant breast neoplasm; multi-photon; neoplastic cell; osteogenic; predictive modeling; prevent; recruit; repaired; response; spatiotemporal; success; therapeutic target; tool; transcriptome; transcriptomics; tumor; tumor microenvironment

ABSTRACT About 20-40% of breast cancer patients develop metastasis to the bone, years to even decades after surgical removal of primary tumors. Little is known about the biology of the latent, microscopic bone metastases before they outgrow to overt osteolytic macrometastases. This represents a significant gap in our understanding of bone metastasis. Targeting cancer cells that have not fully adapted to the bone microenvironment might provide therapeutic benefit and prevent the occurrence of overt metastases. Bone and bone marrow comprise of several highly distinctive microenvironment niches. Dormant, single disseminated tumor cells (DTCs) reside in the perivascular niche, whereas proliferative, multi-cell bone micrometastases (BMMs) are found in the osteogenic niche that exhibits features of active osteogenesis. Mechanisms through which the transition of different niches occurs to switch fates of metastatic seeds remain elusive. The overall objectives of this project are to investigate the spatiotemporal dynamics, the molecular crosstalk, and the therapeutic targets underlying the interaction between breast cancer cells and different microenvironment niches in bone. We will pursue three specific aims. First, we will dissect the spatiotemporal dynamics of the perivascular and osteogenic niches and the cancer-niche interactions in bone micrometastasis models. We will use high-resolution, whole- bone, multi-photon microscopy and laser-captured microdissection (LCM) followed by transcriptome profiling (LCM-seq) to obtain relative localization and mutual impacts between cancer cells and niche cells in situ. Second, we will integrate transcriptomic and imaging data and develop computational models for discovery of new mechanisms and therapies toward blockade of cancer-niche interactions. Established and new algorithms will be used to uncover the microenvironment molecules, and autocrine and paracrine signaling pathways mediating niche-tumor interactions. Drug-repurposing analyses will be carried out to identify potential therapies that have already been used for other diseases. We will achieve a systematic understanding of early-stage bone colonization and generate testable mechanistic and therapeutic hypotheses. Third, we will validate the discovered mechanisms and predicted drug efficacies in animal models. The Zhang laboratory has adopted and established a series of genetically engineered mouse models and bone metastasis assays, which will be utilized to validate computational predictions generated by computational modeling by the Wong group. Both metastatic burden and frequency/distribution of DTCs and BMMs will be examined as endpoints. This study will unbiasedly profile the molecular process of early stage metastasis progression in the bone from DTCs to BMMs at single-to-few cell resolutions. This knowledge is unprecedented and critical for the ultimate understanding of metastasis latency, a long-standing clinical challenge. The modeling tool developed through this study will likely be applicable to other biological contexts involving highly spatiotemporally specific cancer- niche interaction. The computer-aided drug repurposing will likely lead to fast clinical translation.

抽象的 大约20-40％ 去除原发性肿瘤。关于潜在的，微观骨转移的生物学知之甚少 它们长于明显的溶性大量变体。这代表了我们对 骨转移。靶向尚未完全适应骨微环境的癌细胞可能 提供治疗益处并防止发生明显的转移。骨髓和骨髓 在几个高度独特的微环境生态位。休眠的单个散布肿瘤细胞（DTC）居住在 在血管周期的小裂中，而增殖性多细胞骨微晶（BMM）则在 成骨的生态位，表现出活性成骨的特征。过渡的机制 发生不同的壁ni以切换转移种子的命运仍然难以捉摸。该项目的总体目标 正在研究时空动力学，分子串扰和治疗目标 乳腺癌细胞与骨骼中不同微环境壁ni之间的相互作用。我们将追求 三个具体目标。首先，我们将剖析周围和成骨的时空动力学 壁细分和骨骼微量症模型中的癌症相互作用。我们将使用高分辨率，整个 骨，多光子显微镜和激光捕获显微解剖（LCM），然后进行转录组分析 （LCM-SEQ）获得相对定位和癌细胞和生态位细胞之间的相互影响。 其次，我们将集成转录组和成像数据，并开发用于发现的计算模型 新的机制和疗法，以阻断癌症之间的相互作用。建立和新算法 将用于揭示微环境分子，以及自分泌和旁分泌信号通路 介导利基 - 肿瘤相互作用。将进行药物替代分析以识别潜在的疗法 已经用于其他疾病。我们将系统地了解早期 骨定殖并产生可检验的机械和治疗假设。第三，我们将验证 发现了动物模型中的机制和预测药物功效。张实验室已经采用了 并建立了一系列基因工程的小鼠模型和骨转移测定法，这将是 用于验证Wong组通过计算建模产生的计算预测。两个都 DTC和BMM的转移负担和频率/分布将被检查为终点。这项研究会 公正地介绍了从DTC到骨骼的早期转移进展的分子过程 BMM在单一触发细胞分辨率下。这些知识是前所未有的，对于最终而言至关重要 了解转移潜伏期，这是一个长期的临床挑战。通过 这项研究可能适用于涉及高度时空特异性癌症的其他生物环境 利基相互作用。计算机辅助的药物重新利用可能会导致快速的临床翻译。