The Golub lab brings together a multi-disciplinary scientific community focused on understanding the molecular mechanisms of cancer and applying this knowledge to impact the future of cancer medicine. The work includes systematic and comprehensive elucidation of cancers in terms of their molecular profiles, analysis of responses to genetic and drug perturbation, and the development of novel approaches to therapeutic discovery. Scientists in the lab share ideas and launch collaborative projects to tackle key challenges by partnering with scientists across the Broad Institute and beyond.
Major areas of focus include:
Cancer is a complex disease of genomic alteration, exploiting many different molecular mechanisms. Fighting cancer will ultimately require a comprehensive classification of cancers according to their genomic basis. Projects include: systematic studies of genome-wide loss and amplification; sequencing to identify mutant genes in key pathways; and discovery of cancer-specific biomarkers. Projects also include efforts to discover “hidden” proteins encoded by the genome, efforts to capture the gene expression profiles of tumors using spatial transcriptomics, and efforts to understand the earliest steps in cancer pathogenesis.
A number of the projects in the lab relate to the Cancer Dependency Map, or DepMap -- a large-scale collaborative project within the Broad Cancer Program aimed at discovering all the genetic vulnerabilities (“Achilles Heels”) of cancer using genome editing methods, as well as discovering patterns of drug sensitivity and resistance for all known drugs using a novel molecular barcoding method developed in the Golub lab called PRISM. The current DepMap contains over 800 human cancer cell lines that have been subjected to systematic perturbation. Follow-up studies by members of the lab have revealed highly novel mechanisms of action of chemical compounds -- elucidated using modern functional genomic, proteomic and computational methods. These projects have the potential to lay a foundation for a new set of therapeutics for cancer.
Bringing physiological and clinical relevance to high-throughput biology
Studies using cell lines growing on plastic can be powerful because of their high throughput nature. But they are limited by their inability to recapitulate aspects of the tumor microenvironment and of in vivo metabolism. Several projects in the lab are thus utilizing advanced 3D organoid or in vivo cancer models, and developing methods that allow for powerful high throughput approaches to be brought to bear on these more physiologically relevant models. Such projects include the discovery of patterns of in vivo metastatic spread, projects aimed at discovering cancer dependencies that are unique to the in vivo or organoid setting, and projects aimed at discovering the factors that allow for cancer cells to survive in vitro in the absence of a supporting tumor microenvironment.