Developing preclinical peptide hydrogel models of breast cancer metastasis to bone using patient-derived tumour cells and xenografts

人类肿瘤在细胞外基质(ECM)和细胞成分之间有着复杂的相互作用。Clarke实验室使用了免疫缺陷小鼠的患者衍生异种移植(PDX)肿瘤模型来概括复杂的微环境，包括骨转移生态位(Eyre等人，《自然通讯》，2019年)。然而，PDX模型受到限制，包括缺乏免疫功能和人类肿瘤与小鼠微环境的相互作用。考虑到PDX模型作为个性化治疗工具的主导地位，对更好的体外替代方案的需求迫在眉睫。“异种患者”队列是癌症药物发现中最具临床相关性的动物模型(Byrne等人，《自然评论癌症》，2017)。即使有其局限性，乳腺癌领域也经常使用异种移植模型。另一种选择是使用从患者来源的乳腺癌细胞或异种移植体外培养的乳房有机化合物(Sachs等人，Cell，2018；Guillen等人，BioRxiv，2021)。有机类物质将被包裹在多肽水凝胶中，我们预计这种水凝胶将优于Matrigel(黄金标准)，因为它的硬度可以调整以匹配乳腺癌ECM的物理状态。多肽凝胶技术，将在有或没有成骨因子的情况下进行修饰，以模拟骨转移的生态位。此外，人类细胞和细胞外基质成分将与患者来源的乳腺癌细胞一起引入，以创建一个功能强大、可用于多种应用的体外平台。这些应用包括研究骨转移性乳腺癌生物学和在临床相关患者样本中筛选靶向治疗，为精确医学和个性化治疗测试提供平台。

Human tumours have complex interplay between the extracellular matrix (ECM) and cellular components. The Clarke lab has used patient-derived xenograft (PDX) tumour models in immune-deficient mice to recapitulate complex microenvironments, including the bone metastatic niche (Eyre et al., Nature Comm., 2019). However, PDX models are subject to limitations including a lack of immune function and human tumour interaction with a mouse microenvironment. The need for a superior in vitro alternative is pressing considering the dominance of PDX models as a tool for personalized therapy. 'Xeno-patient' cohorts are the most clinically relevant animal models in cancer drug discovery (Byrne et al., Nature Reviews Cancer, 2017). Even with its limitations, the breast cancer field uses xenograft models routinely. An alternative is to use breast organoids grown in vitro from patient-derived breast cancer cells or xenografts (Sachs et al., Cell, 2018; Guillen et al., BioRxiv, 2021). The organoids will be encapsulated in peptide hydrogels, which we anticipate will be superior to matrigel (gold standard) since its stiffness can be tuned to match breast cancer ECM physical states. The peptide gel technology, will be modified with or without osteogenic factors to model the bone metastatic niche. In addition, human cellular and extracellular matrix components will be introduced with patient-derived breast cancer cells to create a functional and amenable in vitro platform for multiple applications. These applications include investigating bone metastatic breast cancer biology and screening of targeted therapies in clinically relevant patient samples, providing a platform for precision medicine and testing of personalised treatments.