Periodic Reporting for period 1 - PERICYTEStroma (Pericyte-derived tumor stroma – a target for cancer therapy)
Reporting period: 2016-10-01 to 2018-09-30
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.
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.
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.