Project code: PN-III-P1-1.1-TE-2016-1352 (cod proiect)
PI: Imola Wilhelm (director proiect)
Institution: Vasile Goldiş Western University of Arad/Universitatea de Vest “Vasile Goldiş” Arad (instituţie)
Title: Interaction of pericytes with melanoma and breast cancer cells during formation of cerebral metastases/Interacțiunea pericitelor cu celulele de melanom și carcinom mamar în timpul formării metastazelor cerebrale (titlu)
Acronym: PERI_mel_br-c (acronim)

Project summary

Brain tumors are life threatening pathologies with limited therapeutic options. The majority of the tumors of the central nervous system (CNS) are metastases, among which lung cancer, breast cancer and melanoma metastases are the most common. Among these tumors, melanoma is the one which metastasizes to the brain with one of the highest frequencies: brain metastases are diagnosed in 40-50% of the cases, which, after autopsy, increase with an additional 30-40%. In breast cancer patients brain metastases occur with a 30% incidence, triple-negative breast cancers (TNBCs) being more likely to spread to the brain. Unfortunately, present treatment strategies of brain metastases are very ineffective; the prognosis of the disease is extremely poor: the median survival of the patients is less than one year. Since the CNS parenchyma lacks a lymphatic vasculature, the only possibility for cancer cells to reach the brain is via the blood stream. Metastatic cells invading the CNS parenchyma, however, have to pass the blood-brain barrier (BBB).
Cellular elements of the neurovascular unit have a great importance in the formation and progression of brain metastases. Interaction between metastatic tumor cells and several cell types of the neurovascular unit (endothelial cells, astrocytes and microglia) has been extensively studied, except for pericytes.
Pericytes are contractile cells located in the duplication of the basement membrane, in close contact with endothelial cells. In the brain, pericyte coverage of the capillaries is very high (80%). Pericytes can participate in the regulation of blood flow, endothelial proliferation, angiogenesis or inflammatory processes. However, the role of pericytes during metastatic extravasation is largely unexplored. Brain pericytes may have multiple roles in the formation and development of brain metastases. First, by stabilizing the endothelial barrier, they contribute to the formation of a physical obstacle in front of transmigrating tumor cells. Second, proper pericyte function is needed for vascularization of the growing tumor mass. Pericytes are involved in the co-option of pre-existing vessels, which is an important form of tumor blood supply, characteristic to highly vascularized tissues, as the brain. In addition, pericytes may directly interact with tumor cells. After transmigration, melanoma and breast cancer cells adhere to the extraluminal surface of capillaries and proliferate in close proximity of the vessels, ensheathing endothelial cells and pericytes, and detaching astrocytic endfeet. However, molecular details of the direct interaction of pericytes and tumor cells are largely unexplored.

Hypothesis, key questions

By stabilizing the vessel wall, pericytes are able to inhibit extravasation of tumor cells. On the other hand, pericytes have a key role in tumor angiogenesis. However, it is not known how pericytes directly act on tumor cells. Our hypothesis is that pericytes are not only important in transmigration and tumor vascularization, but directly influence the fate of tumor cells. The main goal of the present project is to understand the mechanisms of direct interactions of pericytes with melanoma and triple negative breast cancer cells during metastatic colonization of the brain, focusing on the following specific aims:
-to evaluate the signaling pathways activated during pericyte-tumor cell interaction,
-to understand the possible protective impact of pericytes on brain metastatic cells,
-to determine the morphological basis of pericyte-tumor cell interaction.

Impact

The present project aims at understanding the role of pericytes in the metastatic colonization of the brain. Our experiments will be focused on two relevant brain metastatic tumor cells: melanoma and triple negativ breast cancer cells. These two cell types are among those which have the highest propensity to metastasize to the brain. Prognosis of brain metastases is extremely poor, therapeutic options are almost limited to surgical resection of single lesions and palliative treatments. Therefore, understanding the mechanisms of brain metastasis formation may be indispensable for the development of new therapeutic and preventive strategies. The brain microenvironment has a great impact on the fate of the metastases; and the role of pericytes in this process is poorly understood. Results of the present project proposal may expand our knowledge on the formation of melanoma and breast cancer metastases in the brain. Data acquired from the experiments of this grant proposal should provide a rationale for the development of new therapeutic strategies targeting brain pericytes.