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Research overview in the Adli lab

Main Goal: Identify and target key genomic and epigenomic drivers in cancer

Main Tools: CRISPR-based Genome & Epigenome editing, Genome scale CRISPR-screening, Live cell chromatin imaging, ChIP-Seq, ATAC-Seq, RNA-Seq, single cell RNA-Seq

Our ultimate research goals are to understand key drivers of cancer and identify novel therapeutic drug combinations to prevent cancer development and chemotherapy resistance. To achieve these goals, our lab is using and developing genomic and epigenomic mapping, editing and imaging approaches to understand genome regulation in normal and malignant settings. We integrate experimental approaches with large-scale computational data analysis to verify our experimental observations and come up with new testable hypotheses.

Our laboratory is utilizing and also developing cutting-edge functional genomics strategies and developing novel CRISPR based manipulation tools to understand dynamic gene regulation and 3D genome organization in normal and malignant settings. These efforts are based on our previous expertise in genome-wide approaches, and development of novel technologies for cancer research. Our lab has developed particular experitse in utilizing and developing CRISPR based technologies.

Dr. Adli have long standing interest in genome organization and its aberrant regulation in the development of various diseases. During his postdoctoral training at Harvard Medical School and the Broad Institute, Dr. Adli established unique technical and analytical expertise in genomics and epigenomic profiling and computational data analysis. During this process, he developed the Nano-ChIP-Seq technology to map whole gnome level epigenomic mapping in limitedly available cell numbers (Nature Methods, 2010; Nature Protocols, 2011). He played critical roles in multiple large-scale projects including Roadmap Epigenome Mapping Consortium (Cell, 2013) and cancer genome projects (Nature 2012, Cancer Cell 2012, NEJM 2013).

Currently, the Adli lab is combining genome and epigenome mapping expertise with novel CRISPR-based manipulation tools to achieve our ultimate research goals. To this end, we have developed a strong expertise in CRISPR technologies (Nature Communications 2018; Nature Methods 2016; Nature Biotechnology 2014; NAR, 2015). We are actively developing and utilizing novel CRISPR tools to edit genome, manipulate epigenome and image live cells chromatin dynamics in living cells (Nature Methods, 2017, Nature Communications, 2017). These functional genomic tools combined with our capacity to analyze and integrate large-scale data analysis enables us to set ambitious research goals and utilize unbiased CRISPR screening (Nature Communications, 2018) and targeted genome manipulation (Genome Biology, 2018) to achieve our goals faster.

Main research projects in the Adli Lab:

Project #1: Characterizing therapy induced epigenetic alterations that drive chemoresistance in High Grade Serous Ovarian Cancer (HGCOC).

Ovarian cancer is associated with the worst survival of all gynecological cancers. The central obstacle in the treatment of ovarian cancer is the development of chemo-resistance. The vast majority of ovarian cancers are initially chemo-sensitive. However, recurrence and development of chemoresistance is nearly ubiquitous and responsible for the high mortality rate of this disease. We are using unbiased genome and epigenome mapping technologies such as ChIP-Seq, ATAC-Seq and single cell RNA-Seq to understand the molecular basis of chemoresistance. We then utilize our expertise in CRISPR technologies to target aberrant regulatory elements and epigenomic features to overcome chemoresistance and find better therapeutic avenues for this deadly disease.

Project #2: Identifying novel tumor suppressors and combinatorial synthetic lethal drug targets in cancer.

Pancreatic adenocarcinoma (PAC) comprises 95% of pancreatic cancers and remains one of the deadliest cancers; 80% of patients die within the first year and only less than 7% survive past 5 years. Our incomplete understandings of what drives the aggressive proliferation and the chemotherapy resistant state in pancreatic cancer are major roadblocks that impede progress in the development of successful therapeutics. Our long-term research goal in this project is to understand the transcriptional and epigenomic regulatory networks that distinguish normal cellular state from the cancerous one. This knowledge is critical to develop effective therapies for pancreatic cancer. We have major objective in this project. Firstly, we aim to identify novel transcriptional regulators that drive proliferation and progression of pancreatic cancer cells. Secondly, we aim to identify novel and better combinatorial drug treatment strategies for pancreatic cancer.
To this end, we use genome-scale as well targeted sgRNA libraries such as “druggable genome”, “epigenetic regulators” and “nuclear” sgRNA libraries to perform CRISPR KO screening in pancreatic cancer. We perform in vitro as well as in vivo CRISPR screening using patient derived xenograft (PDX) mouse model to study and find novel therapeutics of pancreatic cancer.

Project #3: Develop novel CRISPR-based tools for epigenome editing and chromatin engineering in living cells.

CRISPR is becoming an indispensable tool in biological research. Once known as the bacterial immune system against invading viruses, the programmable capacity of the Cas9 enzyme is now revolutionizing diverse fields of medical research, biotechnology, and agriculture. CRISPR-Cas9 is no longer just a gene-editing tool; the application areas of catalytically impaired inactive Cas9, including gene regulation, epigenetic editing, chromatin engineering, and imaging, now exceed the gene editing functionality of WT Cas9. The major purpose of this project in to continue develop CRISPR based genome and epigenome targeting technologies with improved flexibility and enhanced sensitivity.

Project 4: Identify functional roles and target recurrent non-coding mutations in cancer.

Somatic mutations are the driving force for cancer cell evolution. Large-scale efforts, including The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC), have mapped somatic mutations genome-wide in multiple cancer types. Beyond the protein-coding component of the genome, these whole-genome sequencing (WGS) efforts revealed that somatic mutation burden largely resides within non-coding genomic regions. The mutational processes underlying coding and non-coding cancer mutations and their biological significance in tumor evolution are poorly understood. In this project, we utilize computational tools and CRISPR based genome-editing tool to identify and interrogate the functional role and the molecular process that leads to development of disease associated somatic mutations.