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Read the Suva Lab 2017-2018 Annual Report
Mario Luca Suvà, MD, PhDAssistant Professor of PathologyMassachusetts General HospitalAssistant Molecular Pathologist Massachusetts General HospitalAssociated Scientist Broad Institute of MIT and Harvard
The Suvà laboratory is focused on developing and applying single-cell genomic technologies to dissect the biology of brain tumors, in particular adult and pediatric gliomas. We study patient samples at single-cell resolution and establish genetically and epigenetically relevant cellular models directly from clinical tumors. We model how brain cancer cells exploit their plasticity to establish phenotypically distinct populations of cells, with a focus on programs governing glioma stem cells. We seek to redefine tumor cell lineages and stem cell programs across all types of gliomas and to leverage the information for renewed therapeutic attempts in gliomas. Through collaborations, the laboratory is invested in similar efforts in other types of tumors and participates in the tumor cell atlas and the human cell atlas initiatives.
Mario Luca Suvà, MD, PhDPrincipal Investigator
Gliomas are heterogeneous disease in which intra-tumoral heterogeneity contributes to disease progression and therapeutic failure. Glioma cells vary in stemness, proliferation, invasion, chemoresistance, apoptosis, and metabolism. Various factors contribute to this heterogeneity: on the one hand, branched genetic evolution of cancer cells generates distinct tumor sub-clones; on the other hand, it is also becoming increasingly clear that gliomas cells display functional properties related to developmental pathways and transcriptional programs, such as those associated with the self-renewal of tissue stem cells and their differentiation into specialized cell types. In order to dissect those influences and obtain a comprehensive view of gliomas biology, my laboratory is leveraging single-cell expression profiling across the spectrum of human gliomas, directly in patient samples. Analysis of transcriptomes of individual cells from human malignancies indeed offers a compelling approach to dissect the cellular state and infer partial genetic information from cancer cells in an unbiased way. We seek to discover novel therapies for gliomas.
Assessing malignant cells heterogeneity at the single-cell level in gliomas.
Tumor heterogeneity poses a major challenge to cancer diagnosis and treatment. It can manifest as variability between tumors, or within cells from the same tumor, that may harbor different mutations or exhibit distinct phenotypic or epigenetic states. Such intra-tumoral heterogeneity is increasingly appreciated as a determinant of treatment failure and disease recurrence. The Suvà Lab is performing large-scale single-cell RNA-seq analyses in IDH-mutant gliomas, histone H3-mutant midline gliomas, IDH-wildtype glioblastoma, and ependymoma to assess tumor cell lineages, stem cell programs and genetic heterogeneity at an unprecedented scale and depth (see figure). Our goal is to identify both lineage-defined and somatically-altered therapeutic targets.
Dissecting the ecosystem of gliomas
The composition of the tumor micro-environment (TME) has an important impact on tumorigenesis and modulation of treatment responses. For example, gliomas contain substantial populations of microglia and macrophages, with putative immunosuppressive functions but whose precise programs remains uncharted at single-cell resolution. In addition, very little is known about the functional state of T cells in human gliomas. As is the case in diverse other conditions, the CNS may create a unique microenvironment that impacts T cell function by distinct mechanisms. The laboratory leverages single-cell analyses in clinical samples to dissect the functional programs of immune cells in gliomas that can be used to elucidate mechanisms relevant to immuno-oncology. We profile both dysfunctional T cells that express multiple inhibitory receptors and T cells that are functional based on expression of multiple genes required for T cell cytotoxicity. We find these modules to be distinct from observations in other types of tumors (such as melanoma), underscoring the necessity to perform these analyses directly in gliomas. By analyzing modules of co-expressed genes in subsets of T cells in patients with glioma we seek to shed light on mechanism of activation and exhaustion in patient tumors and to highlight candidate novel regulatory programs that can exploited for therapeutics.
View a full list of publications by researchers at the Suva Laboratory
Venteicher AS†, Tirosh I†, Hebert C, Yizhak K, Neftel C, Filbin MG, Hovestadt V, Escalante LE, Shaw ML, Rodman C, Gillespie SM, Dionne D, Luo CC, Ravichandran H, Mylvaganam R, Mount C, Onozato ML, Nahed BV, Wakimoto H, Curry WT, Iafrate AJ, Rivera MN, Frosch MP, Golub TR, Brastianos PK, Getz G, Patel AP, Monje M, Cahill DP, Rozenblatt-Rosen O, Louis DN, Bernstein BE, Regev A*, Suvà ML*. Decoupling genetics, lineages and micro-environment in IDH-mutant gliomas by single-cell RNA-seq. Science. 2017 Mar 31; 55(6332)
Tirosh I†, Venteicher AS†, Hebert C, Escalante LE, Patel AP, Yizhak K, Fisher JM, Rodman C, Mount C, Filbin MG, Neftel C, Desai N, Nyman J, Izar B, Luo CC, Francis JM, Onozato ML, Riggi N, Livak KJ, Gennert D, Satija R, Nahed BV, Curry WT, Martuza RL, Mylvaganam R, Iafrate AJ, Frosch MP, Golub T, Rivera MN, Getz G, Rozenblatt-Rosen O, Cahill DP, Monje M, Bernstein BE, Louis DN, Regev A*, Suvà ML*. Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature, 2016 Nov 10;539(7628):309-313.
Flavahan WA, Drier Y, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, Suvà ML, Bernstein BE. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature. 2016 Jan 7;529(7584):110-4.
Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, Cahill DP, Nahed BV, Curry WT, Martuza RL, Louis DN, Rozenblatt- Rosen O, Suvà ML*, Regev A*, Bernstein BE*. Single-cell RNA-seq highlights intra-tumoral heterogeneity in primary glioblastoma. Science. 2014 Jun 20;344(6190):1396-401.
Suvà ML†, Rheinbay E†, Gillespie SM, Patel AP, Wakimoto H, Rabkin SD, Chi AS, Cahill DP, Nahed BV, Curry WT, Martuza RL, Rivera MN, Riggi N, Rossetti N, Kasif S, Beik S, Kadri S, Tirosh I, Wortman I, Shalek A, Rozenblatt-Rosen O, Regev A, Louis DN, Bernstein BE. Reconstructing and reprogramming the tumor propagating potential of glioblastoma stem-like cells. Cell. 2014 Apr 24;157(3):525-7.
*co-senior authorship †co-first authorship
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