Extracellular matrix remodelling in breast cancer metastasis

Breast cancer is the most abundant cancer type and the leading cause of cancer-related death in women. One fifth of the diagnosed patients develop metastasis, which correlates with very poor prognosis. The development of novel therapeutic strategies for targeting metastatic disease is still limited by the knowledge gaps about metastatic processes and the involvement of stromal cells. The proposed research project aims to investigate breast cancer metastasis with a focus on tumour:stroma interactions and the functions of Endo180 in these processes. Endo180, a constitutively recycling endocytic collagen receptor, is predominantly expressed in mesenchymal cells. Stromal Endo180 expression has been shown to promote primary tumour growth. However, until now, the impact of Endo180 in the metastatic process has not been investigated. Furthermore, little is known about the regulation of Endo180 expression. The project aims to answer the following questions: (1) What is the impact of Endo180 expression on the tumour progression, and in particular on the metastatic process? (2) How is Endo180 expression regulated within the tumour stroma and are there differences between primary and metastatic tumours and between different metastatic sites? (3) Does targeting Endo180 modulate the response to chemotherapy? To answer these questions, 5 work packages (WPs) are proposed that employ different in vitro and in vivo analyses. In WP1 we will compare metastatic colonisation in Endo180+/+ and Endo180-/- mice in different metastasis models, including spontaneous and experimental metastasis assays. A special focus will be on brain metastasis. Whereas negligible Endo180 expression has been found in normal brain, consistent with the absence of stromal fibroblastic cells, analysis of brain metastases in human breast cancer patients indicated an extensive infiltration of Endo180-positive fibroblast-like stromal cells associated with the brain metastases. Our investigations aim to determine the molecular and cellular nature of these cells. In WP2 we will investigate the regulation of Endo180 expression in normal mammary fibroblasts in contrast to cancer associated fibroblasts (CAFs). In WP3 we will determine the impact of stromal Endo180 expression and collagen internalization on the malignant progression of breast cancer cells. There is growing evidence that stromal cells influence cancer therapy response. Consequently, in WP4 we will also investigate the consequence of Endo180 and stroma modulation on chemotherapy. The applicant will also be involved in a structural biology collaboration (WP5) to identify the precise mechanism of collagen binding to Endo180 that will inform future studies to design Endo180 functional blocking strategies. Finally, in WP5 a number of approaches will be taken to validate and correlate the relevance of our findings to human breast cancers and breast cancer patient outcome. The data generated in this project will provide important new insights into tumour:stroma interplay during breast cancer metastasis and identify new strategies for therapeutic intervention.

The focus of this Erwin Schrödinger fellowship project was to identify novel ways of tackling secondary breast cancer. Breast cancer is one of the most abundant cancer types and is a leading cause of cancer-related death in women worldwide. This is because one fifth of breast cancer patients will develop secondary (metastatic) cancer, which cannot be successfully treated, and eventually spreads out of control. The tumour cells do this by encouraging the normal tissue that they encounter to create a supportive niche that supports their growth. The goal of this project was to identify novel strategies for disrupting the interaction between the tumour cells and the normal tissue surroundings, and to determine whether these strategies can limit the further spread of metastatic disease and increase the responsiveness of tumour cells to chemotherapy without increasing the toxicity to the patient. In this project we demonstrated that the collagen internalisation receptor Endo180 plays a key role in the remodelling of the extracellular matrix surrounding the tumour. Expression of Endo180 by normal healthy cells, such as fibroblasts, is required for efficient metastatic colonisation of the lungs and liver. Inhibition of this collagen receptor reduced primary tumour growth and the burden of metastatic disease in the lungs and liver. We demonstrated that Endo180 is capable of remodelling collagen, a major component of the extracellular matrix and thereby changing the mechanical characteristics of the tumour surrounding. With this work we emphasize the importance of the interaction breast cancer cells with healthy cells at the metastatic site. These data are the basis for the development of novel therapies to target metastatic breast cancer in different secondary sites.