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

乳腺癌进展中的转移生态位分析：定义骨桥蛋白在转移和治疗抵抗中的作用

• 批准号: 325305834
• 负责人: Dr. Thordur Oskarsson, Ph.D.
• 金额: --
• 依托单位: Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/325305834?language=en
• 关键词: Analysis; metastatic; niche; breast; cancer

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.

转移是癌细胞从其起源部位扩散，导致继发器官中的恶性生长。转移性进展通常与对治疗干预的抵抗相关，并且是所有癌症相关死亡的90%以上的原因。虽然转移进展仍然很难表征，但干细胞特性在疾病中起着重要作用变得越来越明显。此外，特定的微环境，转移小生境，建议支持和维持这些特征，促进癌细胞生长和转移的发展。转移小生境由许多反应性细胞类型组成，例如成纤维细胞、炎性细胞和内皮细胞。此外，转移性微环境的主要组分是不溶性细胞外基质（ECM）。ECM成分在转移性小生境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蛋白的一个亚组，称为基质细胞蛋白，在小生境中发挥特别重要的作用。基质细胞蛋白是ECM的糖蛋白，其在干细胞龛中表达，并且与胚胎发育和组织重塑相关。重要的是，基质细胞蛋白经常在肿瘤组织中检测到，并且与癌症患者的存活率低相关。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，也是乳腺癌化疗耐药的介导因子。我们的目标是剖析SPP 1在转移进展和耐药过程中的作用。为了能够以有意义的方式追求这些目标，必须使用转移的动物模型。由于SPP1是由癌细胞和肿瘤基质产生的，我们将敲除癌细胞中的SPP1基因，并植入SPP1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如何促进信号通路以支持转移适应性，并深入了解所涉及的机械调节。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乳腺癌患者的原始样本进行。在这项研究中，我们的目标是分析转移性癌细胞及其小生境之间的相互作用，并确定功能性后果。在乳腺癌患者的原发性肿瘤切除后，播散的癌细胞在远处器官中仍然未被检测到，在那里它们依赖于转移性小生境组分来维持生存。小生境的ECM组分，如SPP 1，可能作为未来对抗转移性癌症和治疗抗性的靶点具有重要的前景。

项目成果

28 Stress signalling in breast cancer cells induces matrix components of stem cell niches that promote chemotherapy-resistant metastasis

28â乳腺癌细胞中的应激信号诱导干细胞微环境的基质成分，促进化疗耐药性转移

• DOI: 10.1136/esmoopen-2018-eacr25.28
• 发表时间: 2018
• 期刊: ESMO Open
• 影响因子: 7.3
• 作者: J Insua-Rodríguez;M Pein;T Hongu;J Meier;HP Sinn;S Spaich;M Sütterlin;A Schneeweiss;T Oskarsson
• 通讯作者: T Oskarsson

Abstracts from the EACR seed and soil: in vivo models of metastasis conference

EACR 种子和土壤摘要：体内转移模型会议

• DOI: 10.1007/s10585-018-9885-y
• 发表时间: 2017
• 期刊: Clinical & Experimental Metastasis
• 影响因子: 4
• 作者: Jacob Insua-Rodriguez;Maren Pein;Tsunaki Hongu;Jasmin Meier;Arnaud Descot;Camille M Lowy;Etienne De Braekeleer;Hans-Peter Sinn;Saskia Spaich;Marc Suetterlin;Andreas Schneeweiss;Thordur Oskarsson
• 通讯作者: Thordur Oskarsson

Stress-induced metastatic niches in breast cancer

压力诱导的乳腺癌转移位

• DOI: 10.1080/23723556.2020.1780105
• 发表时间: 2020
• 期刊: Molecular & Cellular Oncology
• 影响因子: 2.1
• 作者: Oskarsson T