Cancer immunotherapy research is rapidly advancing, with immune-checkpoint inhibitors showing particular promise. Tumor associated macrophages/microglia (TAMs) are an abundant immune infiltrate, which can be co-opted into a polarized, tumor-supportive state, and contribute significantly to immunosuppression. Status-quo approaches target TAM survival. But, both myeloid-derived macrophages and brain-resident microglia are targeted equally. Current strategies don’t distinguish tumor-supportive TAMs from those that play an anti-tumor role.
Since the advent of next-generation sequencing, there has been an explosion in the number of molecular, genome-wide assays performed in the biomedical sciences. Advances in microfluidics technologies, gene-editing platforms and others, have further increased the amount of data generated by orders of magnitude. Rapidly growing repositories, such as the NIH BRAIN Initiative, ENCODE, TCGA, Roadmap Epigenomics Project and others, enable functional hypotheses to be tested via large-scale meta-analysis.
Glioblastoma (GBM) is the most aggressive, and most common, malignant primary brain tumor. We are mapping intra-tumor heterogeneity, via high-throughput single-cell sequencing of matched cohorts of primary and recurrent GBMs. Our goal is to assess the mechanisms with which subclones from primary GBMs evade treatment, and populate secondary tumors. Via a clonal ordering of individual cells, we are constructing high-resolution phylogenies to model tumor evolution. This provides a window into the history of the tumor’s origin, growth process and response to treatment.
As part of the President's BRAIN (Brain Research through Advancing Innovative Neuro-technologies) Initiative, we are collaborating with the Kriegstein Lab and Lim Lab of the UCSF Stem Cell Center to classify the diverse cell types in the prefrontal cortex of the developing human brain. Our goal is to capture, sequence and analyze over 100,000 cells from human fetal neocortex.