Report
Teaser, summary, work performed and final results
Periodic Reporting for period 1 - META-DORM (Mechanobiology of METAstatic and DORMant cancer cells in bone marrow lesions)
Teaser
While cancer survival rates have improved significantly in recent years, survival decreases dramatically after tumour metastasis. One of the most common sites for metastatic tumours to develop is bone. Intriguingly, evidence suggests that once they have invaded the bone...
Summary
While cancer survival rates have improved significantly in recent years, survival decreases dramatically after tumour metastasis. One of the most common sites for metastatic tumours to develop is bone. Intriguingly, evidence suggests that once they have invaded the bone marrow, individual metastatic cancer cells can persist for years in a quiescent or “dormant†state, and are resistant to both radiation and chemotherapy treatment. These dormant cells can reside for months or years while the cancer is in remission, and then “reactivate†without warning to form new, usually fatal, skeletal lesions. Tumour cells achieve this by “hijacking†the normal bone remodelling cycle, a homeostatic balance between bone formation and resorption, to form a metastatic niche within the marrow. However, the signalling mechanisms that cause metastasis and dormancy, particularly in such a mechanically active environment, are poorly understood.
Therefore, the goal of this project is to investigate the chemical and physical interactions between bone and cancer cells, both during dormancy and mechanical stimulation, to provide new insight into bone metastatic lesions and explore novel therapeutic targets to prevent cancer metastasis. This will be achieved by culturing specific bone and cancer cell types together for the first time to observe changes in their signalling and behaviour. Dormancy will also be induced, to observe its effect on changes in signalling. Mechanical stimulation will be applied to investigate whether the complex mechanical environment of the bone marrow plays a role in cancer metastasis. Finally, a specific cellular mechanosensor, the primary cilium, which has been implicated in the development of cancer and is known to be involved in bone formation, will be investigated. This will shed new light on its chemosensing and mechanobiological roles in cancer metastasis, as well as explore its potential as a novel target for cancer treatment and prevention.
Work performed
A co-culture of osteocytes and breast/prostate cancer cells in vitro has been established, and it has been found that osteocytes induce increased migration, but decreased proliferation and invasion of most breast and prostate cancer cell lines. Interestingly, deeper investigation of this effect has implicated TGF-β as an important mediator and that this signalling may occur via the primary cilium.
Dormancy has been induced in cancer cells, finding decreased proliferation in both breast and prostate cancer cell lines with the additions of GAS6 (which is thought to induce dormancy in vivo). This research will be continued in the second year of the project.
Mechanical stimulation, via fluid shear stress, was applied to osteocytes, with the conditioned media taken from these cells and applied to cancer cells. It was found that loading of osteocytes induces increased proliferation, but decreased migration, of cancer cells. Further studies will investigate if TGF-β plays a role in this effect.
Knockdown of osteocyte primary cilia via siRNA transfection was found to reverse the effects on cancer cell behaviour caused by the presence of osteocytes, resulting in increased proliferation and invasion, but decreased migration. This implies that primary cilia are key to the signalling cross-talk between osteocytes and cancer cells.
Final results
The project thus far as sufficiently advanced our understanding of the interaction between invading tumour cells and bone cells during metastasis. Importantly, our results have implicated the osteocyte primary cilium and TGF-B as key regulators of the metastatic cascade, and are therefore identified as potential therapeutic targets.
Thus, the expected deliverables of this project will have important impacts on European society, by increasing the knowledge base of the European scientific community in the field of cancer research. As cancer metastasis is becoming the greatest health and cost burden of cancer in Europe, the potential therapeutic avenues that have been identified by META-DORM could significantly benefit patients.
Website & more info
More info: https://stefaanverbruggen.com/.