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

• Applicant: Dr. Thordur Oskarsson, Ph.D.
• Subject Area: Hematology, Oncology ; Cell Biology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 325305834

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.

• DFG Programme: Research Grants