Modelling triple negative breast cancer with stem cells-derived organoids for the development of targeted therapy

本研究项目的目的是开发一种新的体外干细胞模型来研究三阴性乳腺癌（TNBC）的发生和进展。TNBC代表了一个真实的临床挑战，因为这种类型的乳腺癌是侵袭性的，它往往会影响年轻女性，不能用目前的疗法治疗。TNBC是高度转移性的，并且与较差的临床结果和存活率相关。因此，我们认为，该项目通过对TNBC进行建模，研究致癌突变如何驱动TNBC的发展，以及它们如何合作指导肿瘤微环境，以允许转移，从而解决了这一未满足的临床需求。传播.为此，我们将创建一个复杂的体外模型，将携带原发性和转移性TNBC中发现的基因突变的正常乳腺细胞重新编程为诱导多能干细胞（iPSC），然后定向分化为3D乳腺类器官。这些TBNBC类器官将类似于体内突变的肿瘤，并且独特地允许对疾病的早期阶段进行遗传定义的建模，这是使用患者来源的肿瘤无法获得的，以及对肿瘤演变中特定突变的影响进行标准化分析。通过将表观遗传重编程策略与引入特定突变相结合，该模型是研究分化期间由特定突变诱导的肿瘤发生所需的发育背景的理想平台。我们的愿景也是通过领导癌症iPSC领域并提供用于乳腺癌建模的无动物等基因平台来解决3R问题以及癌症研究中未满足的临床需求，这将有助于发现癌症生物标志物以开发新型靶向疗法。

The aim of this research project is to develop a novel in vitro stem cell model to study triple negative breast cancer (TNBC) initiation and progression. TNBC represents a real clinical challenge as this type of breast cancer is aggressive, it tends to affect young women and cannot be treated with current therapies. TNBC is highly metastatic and associated with poor clinical outcome and survival. Therefore, it is critical to dissect the molecular mechanisms responsible for the origin and progression of this breast cancer subtype in order to progress the discovery of novel biomarkers for early detection and effective treatment.This project addressed this unmet clinical need by focusing on modelling TNBC to study how oncogenic mutations can drive the development of TNBC and how they cooperate to instruct the tumour microenvironment to allow metastatic spread. To this end, we will create a complex in vitro model by reprogramming normal breast cells harbouring genetic mutations found in primary and metastatic TNBC into induced pluripotent stem cells (iPSCs) followed by directed differentiation into 3D mammary organoids. These TBNBC organoids will resemble mutated tumours in vivo and uniquely allow a genetically-defined modelling of early stages of the disease, that is not accessible using patient-derived tumours, as well as standardized analysis of the effect of specific mutations in tumour evolution. By combining the epigenetic reprogramming strategy with the introduction of specific mutations, the model is an ideal platform to study the developmental contexts that are required for tumorigenesis induced by specific mutations during differentiation. Our vision is also to address 3Rs concerns together with unmet clinical needs in cancer research by leading the field of cancer iPSC and delivering an animal-free isogenic platform for breast cancer modelling which will be instrumental for the discovery of cancer biomarkers for the development of novel targeted therapies.