In this interview, Oncology Central spoke with Mario Suva (Massachusetts General Hospital) to find out a little more about his work looking into the biology of brain tumors and recent work his lab has carried out in oligodendroglioma; a study that represents the largest effort ever undertaken to characterize brain tumors at the single-cell level.
Could you please introduce yourself and tell us a little about your career to date? How did you become involved in researching the biology of brain tumors?
What are oligodenrogliomas? What are the current treatment options and associated outcomes for patients with the disease?
Your recent study investigated the role of cancer stem cells in oligodendrogliomas – could you summarize the key results/conclusions from the study?
While we have a good understanding of the genetics of low-grade gliomas, we have a limited knowledge of the cell types and programs driving their growth. Our goal was to obtain a completely unbiased view of these tumors in patients and dissect both genetic events and nongenetic determinants of tumor heterogeneity.
Studying human tumors at single-cell resolution with RNA sequencing provided us with an incredible depth of information that cannot be done with ‘bulk’ sequencing approaches or with functional assays that have intrinsic limitations and are not available for this tumor type. Our study is the first that (i) identifies cancer stem cell and their differentiated progeny in a human tumor in a completely unbiased way, based on a genome-wide expression signature in situ; (ii) relates developmental programs to genetic evolution, demonstrating that a similar hierarchy is identifiable in distinct genetic clones; (iii) shows that neural stem cells are the main source of proliferating cells in gliomas in patients, early in their pathogenesis.
This work also highlights the power of strong collaborations to tackle important questions; this work was done by clinicians and cancer biologists working hand in hand with computer scientists and technologists, primarily the group of Aviv Regev at the Broad Institute (both MA, USA).
Could you comment on the next steps for this research and the possible implications of this work on the field?
Is there evidence for cancer stem cells playing a role in the progression of other malignancies?
Despite the abundant evidence, there still is quite a lot of controversy, as human cancer stem cells are typically demonstrated by their capacity to initiate tumors in mice; while the assay is very valuable, it has a lot of limitations that are difficult to overcome, such as the fact that mice are a different species, and in these assays are typically immunocompromised; also when these assays are done, scientists generally have limited genetic information on the fractions of cells they compare.
Despite these caveats, there is good evidence for stem cell programs in glioblastoma. Yet, because we do not know how to successfully grow low-grade gliomas in vitro or in mice, we have very limited understanding of how this literature on glioblastoma applies to less aggressive brain tumors. As such our study in oligodendroglioma, a slow growing and less-aggressive form of brain tumor, is the first one to highlight a cancer stem cell model in these tumors.
Very importantly, our analysis relies on single-cell RNA sequencing in patients and as such reconstructs programs on a genome-wide scale and does not rely on any given specific functional assay. I think that a lot of the existing literature on cancer stem cells needs to be re-explored with single-cell genomic approaches to better understand the programs that are involved.