Research
Our laboratory's expertise is in synthetic biology, functional genomics and cancer biology. We are interested in new ways to model and overcome drug resistance in cancer. We use genome scale screens, genetic interaction mapping and genome engineering to model and map the genetic and epigenetic causes underlying why some patients are cured and others are not in cancer therapy.
We have special interest in prostate cancer, hematopoietic malignancy and non-small cell lung cancer. We use human cell based models and mouse models of cancer in our research. We are working on innovative new anti-cancer drugs for treating these diseases. We are also mapping strategies for next generation polytherapies that will anticipate and circumvent drug resistance or that have synthetic lethal activity against cancer cells.
Below are three examples of how we use next generation CRISPR tools to study cancer…
Activation of CXCR4 expression by CRISPRa (blue signal)
Editing the epigenome and transcriptome with CRISPR:
We have pioneered the use of a nuclease inactivated version of CRISPR/dCas9 in human cells to edit the epigenome or control transcription of protein coding or non-coding genes. We use dCas9 as a general RNA-guided DNA binding platform to recruit enzyme activities or protein complexes to specific target sites in the genome to execute a desired program. We have shown we can turn on (CRISPRa) and off (CRISPRi) expression of most genes encoded by the human genome.
These tools allow us to mechanistically determine how epigenetic or transcriptional states determine cancer cell behavior and response to anti-cancer interventions. We will continue to use synthetic biology to build new innovative tools for editing the epigenome!
CRISPRi/a functional genomics:
We have developed genome scale CRISPRi/a sgRNA libraries targeting protein coding and non-coding genes encoded by the human and mouse genome. We are using CRISPRi and CRISPRa screens to elucidate genes that dictate response to anti-cancer drugs or determine cancer cell properties such as metastasis or developmental plasticity. We have shown that genome scale CRISPRi/a screens reveal complementary principles of oncogene and non-oncogene addictions.
Genetic interaction mapping:
Genetic interaction maps are pairwise perturbations that measure gene epistasis relationships. We are building genetic interaction maps to search for synthetic lethal gene relationships in cancer, map signaling networks and determine the functions of poorly characterized genes encoded by the human genome.