Project Details
Projekt
Dissecting the role of ECM-producing stromal cells in bone metastatic progression
Applicant
Hind Medyouf, Ph.D.
Subject Area
Hematology, Oncology
Term
since 2018
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 401242005
Despite substantial progress in the treatment of primary tumors, metastases remain a major clinical hurdle and are responsible for most cancer-related deaths in patients with solid tumors. In breast cancer, bone is one of the major sites of metastasis, along with brain and lung. Because effective metastatic potential is defined by both intrinsic features and extrinsic requirements, research efforts aiming to tackle disseminated tumor cells (DTCs) have to incorporate the study of the extrinsic microenvironment. In bone, age-related changes in the niche are suspected to contribute to the significant increase in incidence of bone metastasis with age. However, the cellular and molecular mechanisms that locally modulate the behavior of disseminated tumor cells in the bone, remain poorly understood. In the first funding period, we found that ablation of the matricellular glycoprotein Secreted Protein Acidic and Rich in Cysteine (SPARC), which is one of the most abundant non-collagenous protein in the bone, leads to the acquisition of vascular and bone phenotypes that are reminiscent of aging, including a drastic loss in bone volume and predominant accumulation of adipocytes. Notably, SPARC deficiency significantly accelerated the growth of overt bone metastasis from breast cancer in vivo. The “vicious cycle” concept supports the idea that specialized niches modulate the behavior of DTCs, which in turn trigger reciprocal niche changes that reinforce their metastatic potential. The outcome of such reciprocal interactions is likely to be impacted by the differential niche state in young versus aged individuals. In this project we will use state-of-the-art experimental and computational approaches to dissect the dynamic and multifaceted interaction between tumor and niche cells, using newly established experimental models of young versus aged bone environments. This holistic approach will allow us to explore the dynamically evolving niche landscape in bone metastases in a temporally and spatially resolved fashion. Our overarching goal is to explore the reciprocal interactions between tumor cells and their proximal niche environment at distinct disease stages and exploit the gained knowledge to help define common versus disease-stage specific therapeutic targets.
DFG Programme
Priority Programmes
