Laboratory of Genetics, The Salk Institute for Biological Studies/Research Associate-JSPS fellow (with Prof. Inder Verma)
Single-cell analyses of a mouse glioma model to dissect intratumoral heterogeneity and clonal expansion
While cancer is initiated by the accumulation of genetic alterations within a single or a few cells, individual cancer cells in a solid cancer mass often exhibit heterogeneous phenotypes such as morphology, differentiation, growth and motility. Intrinsic and extrinsic factors determine cancer cell states with plasticity, and the created diversity in primary tumors provides the capability to produce cancer clones which resist therapy and invade. Therefore deciphering cellular and molecular mechanisms, at single-cell level, that drive and maintain tumor heterogeneity provides us new approaches to untangle and challenge malignant phenotypes of cancers.
Glioblastoma multiforme (GBM) is the most common and lethal form of brain cancer. Despite optimal treatment and evolving standard of care, due to its heterogeneity and aggressive biological behavior resulting in the recurrence, the median survival of patients diagnosed with GBM is only 12–15 month. With a mouse model of glioma, our study investigates how heterogeneity within a GBM can be generated, and test if altering the developmental process of heterogeneity or turning heterogeneity of established tumors can be beneficial to patients with GBMs. To characterize phenotypic heterogeneity within a tumor, we employ a stochastic multi-color labeling strategy that allows us to visualize 3 dimensional structures and the fate of a single tumor cell in vivo, and single-cell RNA-seq to characterize cellular identities based on gene expression signatures. With these, we find functional and morphological differences between glioma cells, and show that morphologically distinct subclones exhibit clonal growth with different proliferation and invasion index. Our approaches also identify transcriptional factors which are expressed differentiationally in Oligodendrocyte progenitor cells (OPCs) as being inductively and heterogeneously expressed between in glioma subclones during the later stages of tumorigenesis. Induced expression of a key transcriptional factor for OPC development accelerates invasive phenotype and GBM formation. I would like to discuss potential mechanisms of induction of OPC genes to address non-genetic regulation of cellular states in cancer heterogeneity and clonal expansion.