Pericyte-derived tumor stroma – a target for cancer therapy

Project Information

PERICYTEStroma

Grant agreement ID: 707449

DOI

10.3030/707449

Project closed

EC signature date 17 March 2016

Start date 1 October 2016

End date 30 June 2019

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 185 857,20

EU contribution

€ 185 857,20

Coordinated by

KAROLINSKA INSTITUTET
Sweden

Periodic Reporting for period 1 - PERICYTEStroma (Pericyte-derived tumor stroma – a target for cancer therapy)

Reporting period: 2016-10-01 to 2018-09-30

Summary of the context and overall objectives of the project

Solid tumors develop in tissue microenvironments, which contribute most of the stroma (non-malignant cells) to the tumor. The tumor stroma includes various types of cells such as vascular cells, perivascular cells, and immune cells. During recent years it has become clear that the tumor stroma is important for tumor growth, invasion, and metastasis and hence could be an attractive target for cancer therapy. Glioblastoma multiforme is the most common and highly aggressive primary brain tumor with an extremely poor prognosis. Patients have an average survival rate of 9-18 months upon diagnosis and with the available treatment options. The conventional therapies for glioblastoma are surgical removal of the tumor mass followed by radiotherapy and chemotherapy. A combination of chemo-radiotherapy with other modalities such as targeting tumor blood vessels (Bevacizumab antibody) provides only modest improvement in patient survival rates. Thus, these improved vascular-targeted therapies suggest that targeting perivascular compartments of the tumor has direct translational implications. The overall objective of this project was to study perivascular cell-derived stroma contribution to tumor with the aim to identify novel cellular targets for improving glioblastoma therapy.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In this project, we have investigated the contribution of perivascular cell-derived stroma and assessed its heterogeneity using a mouse model of glioblastoma. To address the heterogeneous contribution of perivascular cells we performed single cell RNA sequencing studies and showed that there are three subpopulations of perivascular stromal cells in glioblastoma. Importantly, these tumor-associated perivascular cells are distinct from perivascular cells of healthy control brain. Furthermore, we could characterize the gene marker profiles and the localization of these previously unknown subpopulations within tumor. This observation implies that targeting perivascular cells, which was thought to be one type of cell population, needs to be reconsidered for efficiently targeting all three subpopulations. The prognostic and diagnostic potential of the identified marker genes of perivascular cells will be exploited further using human tissue samples. These results might pave a way for the development of therapies targeting different perivascular cell-derived stromal compartments for glioblastoma therapy. The results of this project will be published soon and will be available in open access journal within this year. Data obtained in this project has been presented at the Swedish Tumor Microenvironment meeting to researchers from academic and clinical background. The results have also been disseminated to high school students participating in summer school and have been discussed with people visiting Karolinska Institutet during the researcher’s night in Stockholm.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The current therapies for glioblastoma multiforme provide modest improvement in the progression free survival of patients but it still remains to be an incurable cancer. Overall progress is being made in aiming to target the non-malignant, tumor-supporting stromal compartment of tumors with improved clinical outcomes. But to date, perivascular cells surrounding blood vessels remain poorly characterized and their contribution to tumor stroma has not been sufficiently studied especially in the context of glioblastoma. In this project, we studied tumor-associated perivascular cells compared to perivascular cells in healthy brain at the single cell level to show the distinct tumor-associated subpopulations. This study provides a better understanding of perivascular cells and the data are being explored further to design better perivascular cell-targeted therapies for glioblastoma.

Blood vessels and pericytes in Mouse Brain