Research Interests

Regulation of gene expression and signal transduction pathways is key for the survival of all living organisms, from bacteria to humans. My laboratory aims to understand key mechanisms involved in the regulation gene expression and signal transduction pathways in cancer. To this end, we are using unbiased functional genomics approaches and hypothesis-based research. Our long-term goal is to identify new cancer-specific vulnerability pathways that can be targeted to develop improved cancer treatments. Below, I describe five major areas of research of my laboratory and future research directions.

1. Gene silencing mechanisms: Instructive and stochastic mechanisms of gene silencing. Transcriptional regulation of gene expression in cancer cells can occur through many different pathways. One of the foremost mechanisms that has emerged, with direct implications for cancer biology and therapy, is epigenetic regulation. Notably, epigenetic silencing of tumor suppressor genes (TSGs) is a common feature of all human cancers. By definition, epigenetic alterations refer to stable and heritable changes that occur without any change in DNA sequence. One example is the DNA methylation of cytosine [at position 5], typically in the context of a CpG dinucleotide. In fact, epigenetic silencing involving DNA hypermethylation at CpG-rich promoter regions, rather than classical mutation, is the predominant mechanism by which certain TSGs are inactivated during cancer development. There are currently two postulated mechanisms by which a TSG can be epigenetically silenced. The first is a stochastic model in which a TSG is randomly epigenetically silenced, followed by selection of cancer cells harboring epigenetically silenced TSGs due to the resulting growth and/or survival advantages. A second model is referred to as instructive epigenetic silencing. This postulates that genetic alterations, such as the acquisition of an oncogenic mutation in the KRAS gene, can direct the epigenetic silencing of TSGs.
Over the past several years, our research has uncovered significant evidence in favor of the instructive model (Gazin et al., Nature, 2007, Wajapeyee et al., Genes and Development, 2014, Forloni et al., Cell Reports 2016). Collectively, these studies have shown that epigenetic silencing of TSGs in cancer cells is largely a non-random, complex, and highly orchestrated process, which has direct implications for the understanding cancer biology and therapy development. We are currently studying other oncogenes to determine if similar candidate factors and pathways are also required for epigenetic gene silencing of TSGs. Furthermore, using large-scale CRISPR/CAS9, shRNA-based and ORFome screening, we are in the process of identifying new factors that are necessary for TSG silencing and imprinting in a variety of physiological and pathological conditions. 

2. Discovering new regulators of RAS/BRAF pathways and receptor tyrosine kinase (RTK) signaling. The second main focus of research in my laboratory is to identify new regulators of key signal transduction pathways of significance to human disease, cancer in particular. To this end, we are focusing our efforts on the RAS/RAF, EGFR, and insulin signaling pathways. Using large-scale genomic screening and transcriptomic approaches, we have identified several new regulators of the RAS/RAF pathway and are in the process of characterizing their roles in human cancers with RAS/RAF mutations, in particular in melanoma, lung cancer and pancreatic cancer. These studies have revealed previously unexpected aspects of RAS mutant melanoma (Forloni et al., eLife, 2014, Gupta et al., eLife, 2017) that are of biological and clinical significance. Similarly, using an E3 ubiquitin ligase-targeting short-hairpin library, we have identified several new repressors of the insulin signaling pathway. We have also utilized in vivo approaches, such as antisense oligonucleotide (ASO)-based liver gene knockdown and adeno-associated virus-based liver-specific ectopic gene expression in mice, and gene expression analysis in primary samples from lean and obese human subjects, to establish the physiological significance a number of genes in the emergence of insulin resistance. In particular, we showed that MARCH1, an E3 ubiquitin ligase, acts as a repressor of insulin signaling (Nagarajan et al., Nature Communications, 2017). Based on the success of this screening approach, we have also conducted similar screens and have identified new insulin signaling modifiers that have not previously been implicated in the regulation of insulin signaling. We are currently working towards understanding their mechanism-of-action and establishing their physiological significance and relevance to type 2 diabetes and cancer. 

3. Identifying novel drivers of tumor growth and metastasis. One of my major research interests is to identify and characterize oncogenic and tumor suppressor pathways that promotes tumor growth and metastasis in cancer, in particular in melanoma and lung cancer. Specifically, we are interested in genes and pathway that are druggable and promote tumor growth and metastasis. In this direction, we have used both hypothesis-driven experimental approaches as well as large-scale unbiased approached of genome-wide CRISPR/CAS9 and RNA interference screening and deep sequencing methods to identify novel genes and pathways that can promote cancer growth and metastasis . These studies have led to several major discoveries, including discovery of new oncogenic drivers of melanoma initiation and progression and discovery and characterization of several novel lung cancer tumor suppressors and oncogenes (see Lin et al., Cancer Discovery, 2014 and Forloni et al., 2014, eLife, Janostiak et al., Cell Reports, 2017). We are continuing our effort using functional genomics approaches in several cancers, including pancreatic cancer, hepatocellular carcinoma and breast cancer, in addition to melanoma and lung cancer.

4. Metabolic dependencies in cancer. A new area of research that my laboratory has recently initiated involves investigating the transcriptional alterations that shape cancer metabolism. In this regard, using the integrative approach of combining transcriptional profiling of cancer cells with functional genomic methods, we have identified specific metabolic vulnerability pathways in ovarian and pancreatic cancer (Gupta et al., Oncogene, 2017 and Nagarajan et al., Molecular Cell, 2017). Similar studies are currently underway in other cancer types, with the overall goal of identifying distinct metabolic needs of different cancer types in order to develop more precise, cancer type-selective therapies. 

5. Regulation of Innate immune system and its role in cancer. We are also investigating the genetic and non-genetic mechanisms that dictate immune response against cancer cells. In particular, we are interested in studying the effect of epigenetic regulation in the context of the natural killer (NK) cells of innate immune system. These cells are the first line of defense against pathogen-infected and transformed cancer cells; however, NK cell-based immunotherapies are still in the early stages of development. We have recently found that inhibition of a polycomb repressive complex 2 (PRC2) protein, EZH2, enhances NK cell-mediated eradication of hepatocellular carcinoma (HCC) cells (Bugide et al., PNAS, 2018). We are now testing this as an approach for treating HCC using a variety of complementary mouse models of HCC, including a highly relevant IL-15 transgenic mouse containing an implanted human immune system with human NK cells. Other ongoing projects have also identified new regulators of NK cell function against HCC and other cancer types and makes the basis of other projects in my laboratory.

Honors

• Research Scholar Grant, American Cancer Society, 2016
• Yale Cancer Center Translational Cancer Research Excellence Prize, Yale Cancer Center, Yale University, 2014
• IASLC Young Investigator Award, International Association for the Study of Lung Cancer, 2013
• Young Investigator Award Melanoma Research Alliance, 2013
• Kimmel Scholar for Translational Cancer Research. Sidney Kimmel Foundation for Cancer Research, 2012
• Hollis Brownstein Award for Leukemia Research, Leukemia Research Foundation, 2011
• AACR Centennial Cancer Research Award for Childhood Cancer Research American Association for Cancer Research, 2010

Education

Graduate School
PhD: Indian Institute of Science

Postdoctoral Training: University of Massachusettes Medical School

Contact

Office
Kaul Human Genetics Building
Room 540A
720 20th Street South
Birmingham, AL 35294-0024

Phone
(205) 934-5331

Email
nwajapey@uab.edu