Analysis of the metastatic niche in breast cancer progression: Defining the role of osteopontin in metastasis and therapy resistance

转移是癌细胞从其起源部位扩散，导致二次器官的恶性生长。转移性进展通常与治疗干预的耐药性有关，90%以上的癌症相关死亡是由转移性进展造成的。虽然转移进展的特征仍然很差，但干细胞特性在该疾病中发挥重要作用越来越明显。此外，特定的微环境，即转移生态位，支持和维持这些特征，促进癌细胞生长和转移的发生。转移性壁龛由许多反应性细胞类型组成，如成纤维细胞、炎症细胞和内皮细胞。此外，转移性微环境的主要组成部分是不溶性细胞外基质（ECM）。ECM成分在转移性生态位中的功能作用越来越被认识到，我们和其他人最近的工作表明，ECM蛋白的一个亚群，称为基质细胞蛋白，在转移性生态位中起着特别重要的作用。基质细胞蛋白是ECM的糖蛋白，在干细胞壁龛中表达，与胚胎发育和组织重塑有关。重要的是，基质细胞蛋白经常在肿瘤组织中检测到，并与癌症患者的低生存率相关。我们小组的早期证据表明基质细胞蛋白骨桥蛋白（SPP1）可能是乳腺癌肺转移的重要调节因子和化疗耐药的介质。我们的目的是剖析SPP1在转移进展和治疗耐药中的作用。为了能够以有意义的方式追求这些目标，使用转移的动物模型是必不可少的。由于SPP1是由癌细胞和肿瘤基质产生的，我们将在癌细胞中敲除SPP1基因并植入SPP1基因敲除小鼠。这使我们能够从转移中消除SPP1，并解决SPP1抑制是否可以使癌细胞对化疗敏感。我们将分析SPP1如何促进支持转移适应度的信号通路，并深入了解其中的机械调控。临床验证将通过组织微阵列、转录组数据集的计算机分析和使用来自乳腺癌患者的原始样本进行。在这项研究中，我们的目的是分析转移癌细胞与其生态位之间的相互作用，并确定功能后果。乳腺癌患者原发肿瘤切除后，弥散性癌细胞在远端器官中仍未被发现，它们依靠转移性生态位成分维持生存。该生态位的ECM成分，如SPP1，可能有望成为未来治疗转移性癌症和治疗耐药的靶点。

Metastasis is the spread of cancer cells from their site of origin leading to malignant growth in secondary organs. Metastatic progression is frequently associated with resistance to therapeutic intervention and is responsible for over 90% of all cancer related deaths. While metastatic progression is still poorly characterized, it is becoming evident that stem cell properties play an important role in the disease. Moreover, specific microenvironment, a metastatic niche, is suggested to support and maintain these characteristics, furthering cancer cell-growth and development of metastasis. Metastatic niches are composed of a number of reactive cell types such as fibroblasts, inflammatory cells and endothelial cells. Moreover, a major component of the metastatic microenvironment is insoluble extracellular matrix (ECM). The functional role of ECM components within the metastatic niche is increasingly being recognized, and recent work from us and others indicates that a subgroup of ECM proteins, called matricellular proteins, play a particularly important role in the niche. Matricellular proteins are glycoproteins of the ECM that are expressed in stem cell niches and have been associated with embryonic development and tissue remodeling. Importantly, matricellular proteins are frequently detected in tumor tissues and are associated with poor survival in cancer patients. Early evidence from our group indicates that the matricellular protein osteopontin (SPP1) may be an important regulator of lung metastasis and a mediator of resistance to chemotherapy in breast cancer. Our objective is to dissect the role of SPP1 during metastatic progression and therapy resistance. To be able to pursue these goals in a meaningful manner, it is essential to use animal models of metastasis. Since SPP1 is produced by both cancer cells and tumor stroma, we will knockdown the SPP1 gene in cancer cells and implant into SPP1 knockout mice. This allows us to eliminate SPP1 from the metastasis and address if SPP1 inhibition can sensitize cancer cells to chemotherapy. We will analyze how SPP1 may promote signaling pathways in support of metastatic fitness and gain insight into the mechanical regulation involved. Clinical validation will be performed by tissue microarray, in silico analysis of transcriptomic data sets and by the use of primary samples from breast cancer patients. In this study, we aim to analyze the interactions between metastatic cancer cells and their niches and determine functional consequences. After the removal of a primary tumor in breast cancer patients, disseminated cancer cells remain undetected in distant organs where they rely on metastatic niche components for viability. The ECM components of the niche, such as SPP1, may hold significant promise as future targets against metastatic cancer and therapy resistance.