Biochemistry & Molecular Biology, Surgery
Keck School of Medicine
USC / Norris Comprehensive Cancer Center
Associate Dean for Graduate Affairs (Doctoral Programs)
- Lung Cancer
- Cancer Genetics, Epigenetics
- DNA Methylation
- RNA/DNA-protein interaction
- Immune Response in Cancer
Research OverviewLung Cancer
Our studies of small cell lung cancer stimulated our interest in developing tools for early diagnosis of lung cancer, which is the cancer that kills the most Americans every year. More people die of lung cancer than from breast, prostate, and colon cancer combined. The high death rate is largely a result of the absence of accurate early detection tools. To develop markers for molecular diagnosis of lung cancer, we are taking two approaches. On the one hand, we are analyzing the expression of specific antibodies in the blood of lung cancer patients. We have recently shown that autoantibodies known to arise in a fraction of human SCLC patients also appear in a mouse model of SCLC and will be using this mouse model to dissect the mechanism of the SCLC-related immune response.
On the other hand, we are studying DNA methylation patterns in lung cancer and other neoplasms found in or near the lung (such as mesothelioma). This work is carried out in collaboration with a multidisciplinary team of investigators inside and outside USC. We have concentrated most on lung adenocarcinoma, the most commonly diagnosed type of lung cancer, arising in the lung periphery. We have recently uncovered numerous candidate epigenetic driver genes (Selamat et al., 2012) and are further investigating the role of these genes in lung adenocarcinoma development and progression.
Lastly, to understand how lung epithelium can become abnormal during cancer development, it is key to understand how normal lung epithelium differentiates and responds to injury. Thus, in collaboration with the laboratory of Dr. Zea Borok and Dr. Beiyun Zhou, we have initiated research on the epigenetic basis for normal alveolar epithelial cell differentiation. This new collaboration recently led to a collaborative $3.5 million grant from the NIH/NHLBI
DNA methylation is and ‘epigenetic’ modification of DNA that is reversible. It does not change the DNA sequence, but it can change the level at which genes are expressed and it can be inherited from one cell to the next. In mammals, DNA methylation occurs on cytosines that are followed by guanosines (so-called CpG dinucleotides). The methylation of CpG-rich regions (“CpG islands”) in the promoter regions of genes is associated with gene silencing, and is now known to be a key mechanism for the inactivation of tumor suppressor genes in cancer. CpG island hypermethylation has been seen in many kinds of cancer, and it appears that distinct profiles of methylated genes are present in different types of cancer. As mentioned above, our research is aimed at identifying genes that are specifically methylated in lung cancer and mesothelioma. This information will be applied towards our most urgent goal: the development of tools for early cancer detection, so that the tumor could be removed before it spreads. However, DNA methylation information will also be applicable to 1) the development of tools for accurate diagnosis, through identification of panels of genes that are specifically methylated in different types of thoracic cancer, 2) development of predictors of patient outcome, by correlating methylation profiles to clinicopathological characteristics of patients such as response to therapy and survival, and 3) gaining insight into the molecular pathways altered in lung cancer, with the objective of developing targeted drugs.
RNA/DNA-Protein Interaction Analysis
Another area of research in the Laird-Offringa lab is aimed at analyzing the interaction between proteins and DNA/RNA. Our specialty is analyzing the dynamic interaction between proteins and DNA/RNA in real time, using a surface plasmon resonance-based biosensor (Biacore). We are currently investigating the kinetics of the interaction between the methyl-binding domain and methylated DNA and, in collaboration with several labs, the binding of transcription factors to their DNA targets.
Research in the Laird-Offringa lab is funded by various grants/donations from NIH, foundations, research institutes and philanthropists. We have received support from the Wright Foundation, the Whittier Translational Research Fund, the Mesothelioma Applied Research Foundation, Joan's Legacy, the Thomas G. Labrecque Foundation, the Canary Foundation, the Kazan Foundation, and the Hoag Family Foundation. We also have a number of wonderful donors, such as Wally and Conya Pembroke, Michelle and Paul Zygielbaum, Steven Schwatrz, Sharon Binder, Bonnie and Tony Addario, Larry Auerbach and others. We deeply appreciate all their contributions, large and small, as well as those of the patients who participate in our research studies by anonymously donating remnants of clinical samples or blood. Our work would not be possible without such fabulous support.
Most of our projects are interdisciplinary collaborations with faculty inside and outside of USC. In the SCLC immune response project, we collaborate with the lab of Anton Berns and Jan Verschuuren and colleagues in the Netherlands, USC immunologists Martin Kast and Omid Akbari at USC, Dana Aswad at UCI, USC radiologist Peter Conti, USC clinical oncologist Barbara Gitlitz, USC pathologist Lina Wang and Ian Haworth in the USC School of Pharmacy. In our epigenetic work we collaborate with statisticians/bioinformaticists Kim Siegmund and Juan Pablo Lewinger, surgeons Jeffrey Hagen and Daniel Oh, clinical oncologist Barbara Gitlitz, members of the USC Genomic Sequencing Core such as Charlie Nicolet and Daniel Weisenberger, pathologists Michael Koss at USC and Keith Kerr from Aberdeen, Scotland, geneticist and biostatistician Maria Theresa Landi and Jianxin Shi from NIEHS. We are also involved in a large collaboration with members of the Canary Foundation and the Early Detection Research Network at NIH. In our kinetic work we collaborate with Ian Haworth from the School of Pharmacy and Lin Chen at USC. Most recently, we started an exciting collaboration with the groups of Dr. Zea Borok and Dr. Beiyun Zhou, on epigenetic analysis of alveolar epithelium. We believe that together all of us can achieve so much more and we greatly enjoy our collaborative efforts.
Please click the PubMed link for our latest papers!