The functional relationship of myoepithelial cells and macrophages in DCIS progression

只有50%的导管原位癌(DCIS)会进展为浸润性疾病，但我们目前无法预测哪些病例会进展为浸润性疾病，导致过度诊断和过度治疗。了解DCIS的进展是乳腺癌研究的一个关键领域，被确定为CRUK的一项重大挑战。人们普遍认为，炎症可以在改变乳腺癌细胞的行为和肿瘤进展方面发挥关键作用。在乳腺癌中，通常可以观察到强烈的巨噬细胞浸润，有明显的证据表明这与不良的患者预后有关。虽然巨噬细胞存在于一系列动态和不断演变的激活表型中，但已知促肿瘤生成的巨噬细胞亚群(尽管不受一组标志物的限制)通过直接接触和细胞因子介导的串扰促进血管生成和促进恶性肿瘤细胞的转移。在人类乳腺导管中，肌上皮细胞发挥着重要的保护功能，为易恶性转化的管腔上皮细胞提供生物物理和肿瘤抑制支持。鉴于它们在健康乳腺导管中的保护作用以及在进展为浸润性导管癌过程中的进行性丢失，我们将剖析肌上皮细胞在DCIS进展中的作用及其与巨噬细胞的关系。该项目将使用最先进的3D建模和单细胞RNA测序方法，并结合对患者样本的询问(DCIS与侵袭性疾病或DCIS与匹配的侵袭性疾病)，以确定在DCIS进展过程中介导肌上皮-ECM-巨噬细胞串扰的关键事件。我们将使用我们的遗传易处理的3D模型来更好地了解DCIS相关的肌上皮细胞和巨噬细胞在进展中对微环境的贡献。离开传统的和有些简单化的M1/M2巨噬细胞表型的观点，我们将考虑组织驻留的巨噬细胞与单核细胞来源的巨噬细胞的个体发育和贡献，使用我们的单细胞方法来强调未知和稀有的群体。了解这些微环境特征将使我们能够预测进展，对患者进行分层管理，并确定微环境治疗目标，更重要的是，作为肌上皮-巨噬细胞相互作用的结果，DCIS进展的生物标志物。

Only 50% of Ductal Carcinoma in-situ (DCIS) will progress to invasive disease, but we currently cannot predict which cases will do so, leading to overdiagnosis and overtreatment. Understanding the progression of DCIS is a critical area of breast cancer research, identified as a CRUK Grand Challenge. It is well accepted that inflammation can play a critical role in changing the behaviour of breast cancer cells and tumour progression. In breast cancer, strong macrophage infiltration is commonly observed, with significant evidence to suggest correlation with poor patient outcome. Although macrophages exist within a spectrum of dynamic and evolving activation phenotypes, a subset (albeit not restricted by one set of markers) of pro-tumourigenic macrophages are known to promote angiogenesis and facilitate the metastasis of malignant cells through direct contact and cytokine mediated crosstalk. In the human breast duct myoepithelial cells fulfil a critical protective function, providing biophysical and tumour suppressive support to luminal epithelial cells that are prone to malignant transformation. Given their protective role in the healthy breast duct and progressive loss during progression to invasive ductal carcinoma, we will dissect the role of myoepithelial cells and their relationship with macrophages in the progression of DCIS. This project will use state-of-the-art 3D modelling and single-cell RNA sequencing approaches coupled with interrogation of patient samples (DCIS vs Invasive disease or DCIS with matched invasive disease), to determine the key events that mediate myoepithelial-ECM-macrophage cell cross talk in DCIS progression. We will use our genetically tractable 3D model to better understand the contribution of DCIS associated myoepithelial cells and macrophages to the microenvironment in progression. Moving away from the traditional and somewhat simplistic view of M1/M2 macrophage phenotypes, we will consider the ontogeny and contribution of tissue-resident versus monocyte derived macrophages using our single cell approach to highlight as yet unknown and rare populations. Understanding these microenvironmental features will allow us to predict progression to stratify patient management and identify microenvironmental therapeutic targets and more importantly, biomarkers of DCIS progression as a consequence of myoepithelial-macrophage interactions.