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）和细胞组分之间具有复杂的相互作用。Clarke实验室已经在免疫缺陷小鼠中使用患者来源的异种移植物（PDX）肿瘤模型来重现复杂的微环境，包括骨转移小生境（Eyre et al.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，迫切需要一种上级体外替代方案。“异种患者”群组是癌症药物发现中最临床相关的动物模型（Byrne等人，Nature Reviews Cancer，2017）。即使有其局限性，乳腺癌领域也常规使用异种移植模型。一种替代方案是使用从患者来源的乳腺癌细胞或异种移植物体外生长的乳腺类器官（Sachs等人，Cell，2018; Guillen等人，BioRxiv，2021）。类器官将被封装在肽水凝胶中，我们预计这将上级基质胶（金标准），因为它的刚度可以调整，以匹配乳腺癌ECM的物理状态。肽凝胶技术将在有或没有成骨因子的情况下进行修改，以模拟骨转移灶。此外，人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，以创建用于多种应用的功能性和顺从性体外平台。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，为精准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.