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

本研究项目旨在建立一种新的体外干细胞模型来研究三阴性乳腺癌（TNBC）的发生和发展。TNBC代表了一个真正的临床挑战，因为这种类型的乳腺癌具有侵袭性，它往往影响年轻女性，目前的治疗方法无法治疗。TNBC是高度转移的，与不良的临床结果和生存有关。因此，解剖这种乳腺癌亚型的起源和发展的分子机制是至关重要的，以便发现新的生物标志物，用于早期发现和有效治疗。该项目通过对TNBC进行建模来研究致癌突变如何驱动TNBC的发展，以及它们如何协同指导肿瘤微环境允许转移扩散，从而解决了这一未满足的临床需求。为此，我们将创建一个复杂的体外模型，通过将原发和转移性TNBC中含有基因突变的正常乳腺细胞重编程为诱导多能干细胞（iPSCs），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建模，这是无法使用患者来源的肿瘤获得的，以及对肿瘤进化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特定突变的引入相结合，该模型是研究分化过程中特定突变诱导肿瘤发生所需的发育环境的理想平台。我们的愿景是通过引领癌症iPSC领域，并提供一个用于乳腺癌建模的无动物等基因平台，解决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，开发新的靶向治疗方法。

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.