3D spheroids derived from single cells for discovering stochastic patterns behind metastasis

癌症中10例死亡中有9例是由转移引起的。然而，控制转移发生的机制远未完全理解。值得注意的是，转移主要是克隆性的，并且来自单个细胞。3DSecret将从一个全新的角度研究转移，其总体目标是在单细胞水平上揭示具有预测和预后能力的随机模式。重要的是，从单个循环肿瘤细胞（CTC）的整体研究中定义转移的标志，从而解剖肿瘤异质性，有能力彻底改变癌症治疗和诊断。这将为现代临床科学的圣杯之一的改变游戏规则的发现铺平道路。为了实现我们的目标，3DSecret将使用一系列关键的使能技术，包括微流体、纳米传感器、基因组学和人工智能（AI）。微流体技术将推动从60多名转移性乳腺癌患者的全血样本中分离单个CTC。这些将在芯片上生长以形成3D球状体，从而允许对单细胞起源进行全面的基因组和转录组学研究，同时绕过通常由单细胞基因组扩增引入的错误。基因组和转录组数据将与临床信息，单细胞生长概况和通过使用纳米传感器和Sers获得的动态代谢组学分析相结合，以开发能够识别未知模式的多模式AI分析工具。大胆的假设，可能有随机模式驱动转移，癌症演变和恶性肿瘤，使得3DSecret的方法异常高风险，高收益。我们相信，这一突破将导致重大的范式转变，对生物学、物理学、人工智能等颠覆性技术，以及医学竞技场和患者护理产生重大影响。

Metastasis remains accountable for 9 out of 10 fatalities within cancer disease. However, the mechanisms governing the onset of metastasis are far from being fully understood. Notably, metastases are predominantly clonal and arise from a single cell. 3DSecret will investigate metastasis from a radically new perspective, with the overarching goal of unravelling stochastic patterns at the single-cell level with predictive and prognostic capacity. Critically, defining the hallmarks of metastasis from holistic studies of single circulating tumour cells (CTCs), thus dissecting tumour heterogeneity, has the power to revolutionise cancer treatment and diagnosis. This will pave the way for game-changing discoveries in what is one of the holy grails of modern clinical science. To achieve our goal, 3DSecret will use a set of key enabling technologies including microfluidics, nanosensors, genomics, and artificial intelligence (AI). Microfluidics will drive the isolation of single CTCs from whole blood samples of 60+ metastatic breast cancer patients. These will be grown on chip to form 3D spheroids, thus allowing comprehensive genomic and transcriptomic studies of single-cell origin while bypassing the errors typically introduced by single-cell genome amplification. The genomic and transcriptomic data will be combined with clinical information, single-cell growth profiles and dynamic metabolomic analyses obtained by the use of nanosensors and SERS, to develop a multimodal AI analytical tool capable of identifying unknown patterns driving metastasis. The bold assumption that there could be stochastic patterns driving metastasis, cancer evolution and malignancy, makes the approach of 3DSecret exceptionally high-risk, high gain. We are confident that such a breakthrough would lead to a major paradigm shift with significant implications in biology, physics, disruptive technologies such as AI, and critically, in the medical arena and patient care.