Associate Dean For Graduate Affairs (Ph.D. Programs)
Director of Pibbs
Dr. Laird-Offringa is Associate Professor of Surgery and of Biochemistry & Molecular Biology at USC Keck School of Medicine. She received her Ph.D. in 1991 from University of Leiden (Netherlands), and she undertook a postdoctoral research fellowship from 1991–1996 at Harvard Medical School (Boston, MA). She joined the USC staff in 1966. Besides her STOP CANCER Award, Dr. Laird-Offringa is the recipient of numerous grants from the National Institutes of Health for research in relation to lung cancer and lung diseases, as well as many other grants from private foundations and from individuals.
The Laird-Offringa lab's studies of small cell lung cancer stimulated their 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 grants from NIH, and by various grants/donations from private foundations or individuals. We have received support from the American Lung Association, 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, Dana Aswad at UCI, radiologists Peter Conti and Chris Lee at USC, clinical oncologsits Barbara Gitlitz and Jorge Nieva at USC, Muller Fabbri at CHLA and Ian Haworth in the USC School of Pharmacy. In our epigenetic work we collaborate with statistician Kim Siegmund, surgeons Jeffrey Hagen and Daniel Oh, clinical oncologist Barbara Gitlitz and members of the USC Genomics Core such as Daniel Weisenberger and Charlie Nicolet, pathologists Michael Koss at USC and Keith Kerr from Aberdeen, Scotland. 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 we can all achieve so much more than alone and we greatly enjoy our collaborative efforts.
Selamat SA, Chung BS, Girard L, Zhang W, Zhang Y, Campan M, Siegmund KD, Koss MN, Hagen JA, Lam WL, Lam S, Gazdar AF, Laird-Offringa IA. Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression. Genome Res. 2012 Jul; 22(7):1197-211. View in: PubMed
Campan M, Moffitt M, Houshdaran S, Shen H, Widschwendter M, Daxenbichler G, Long T, Marth C, Laird-Offringa IA, Press MF, Dubeau L, Siegmund KD, Wu AH, Groshen S, Chandavarkar U, Roman LD, Berchuck A, Pearce CL, Laird PW. Genome-scale screen for DNA methylation-based detection markers for ovarian cancer. PLoS One. 2011; 6(12):e28141. View in: PubMed
Kazarian M, Laird-Offringa IA. Small-cell lung cancer-associated autoantibodies: potential applications to cancer diagnosis, early detection, and therapy. Mol Cancer. 2011; 10:33. View in: PubMed
Selamat SA, Galler JS, Joshi AD, Fyfe MN, Campan M, Siegmund KD, Kerr KM, Laird-Offringa IA. DNA methylation changes in atypical adenomatous hyperplasia, adenocarcinoma in situ, and lung adenocarcinoma. PLoS One. 2011; 6(6):e21443. View in: PubMed
Vázquez-Chantada M, Fernández-Ramos D, Embade N, Martínez-Lopez N, Varela-Rey M, Woodhoo A, Luka Z, Wagner C, Anglim PP, Finnell RH, Caballería J, Laird-Offringa IA, Gorospe M, Lu SC, Mato JM, Martínez-Chantar ML. HuR/methyl-HuR and AUF1 regulate the MAT expressed during liver proliferation, differentiation, and carcinogenesis. Gastroenterology. 2010 May; 138(5):1943-53. View in: PubMed
Kazarian M, Calbo J, Proost N, Carpenter CL, Berns A, Laird-Offringa IA. Immune response in lung cancer mouse model mimics human anti-Hu reactivity. J Neuroimmunol. 2009 Dec 10; 217(1-2):38-45. View in: PubMed
Rich RL, Papalia GA, Flynn PJ, Furneisen J, Quinn J, Klein JS, Katsamba PS, Waddell MB, Scott M, Thompson J, Berlier J, Corry S, Baltzinger M, Zeder-Lutz G, Schoenemann A, Clabbers A, Wieckowski S, Murphy MM, Page P, Ryan TE, Duffner J, Ganguly T, Corbin J, Gautam S, Anderluh G, Bavdek A, Reichmann D, Yadav SP, Hommema E, Pol E, Drake A, Klakamp S, Chapman T, Kernaghan D, Miller K, Schuman J, Lindquist K, Herlihy K, Murphy MB, Bohnsack R, Andrien B, Brandani P, Terwey D, Millican R, Darling RJ, Wang L, Carter Q, Dotzlaf J, Lopez-Sagaseta J, Campbell I, Torreri P, Hoos S, England P, Liu Y, Abdiche Y, Malashock D, Pinkerton A, Wong M, Lafer E, Hinck C, Thompson K, Primo CD, Joyce A, Brooks J, Torta F, Bagge Hagel AB, Krarup J, Pass J, Ferreira M, Shikov S, Mikolajczyk M, Abe Y, Barbato G, Giannetti AM, Krishnamoorthy G, Beusink B, Satpaev D, Tsang T, Fang E, Partridge J, Brohawn S, Horn J, Pritsch O, Obal G, Nilapwar S, Busby B, Gutierrez-Sanchez G, Gupta RD, Canepa S, Witte K, Nikolovska-Coleska Z, Cho YH, D'Agata R, Schlick K, Calvert R, Munoz EM, Hernaiz MJ, Bravman T, Dines M, Yang MH, Puskas A, Boni E, Li J, Wear M, Grinberg A, Baardsnes J, Dolezal O, Gainey M, Anderson H, Peng J, Lewis M, Spies P, Trinh Q, Bibikov S, Raymond J, Yousef M, Chandrasekaran V, Feng Y, Emerick A, Mundodo S, Guimaraes R, McGirr K, Li YJ, Hughes H, Mantz H, Skrabana R, Witmer M, Ballard J, Martin L, Skladal P, Korza G, Laird-Offringa I, Lee CS, Khadir A, Podlaski F, Neuner P, Rothacker J, Rafique A, Dankbar N, Kainz P, Gedig E, Vuyisich M, Boozer C, Ly N, Toews M, Uren A, Kalyuzhniy O, Lewis K, Chomey E, Pak BJ, Myszka DG. A global benchmark study using affinity-based biosensors. Anal Biochem. 2009 Mar 15; 386(2):194-216. View in: PubMed
Tsou JA, Kazarian M, Patel A, Galler JS, Laird-Offringa IA, Carpenter CL, London SJ. Low level anti-Hu reactivity: A risk marker for small cell lung cancer? Cancer Detect Prev. 2009; 32(4):292-9. View in: PubMed
Julien KR, Sumita M, Chen PH, Laird-Offringa IA, Hoogstraten CG. Conformationally restricted nucleotides as a probe of structure-function relationships in RNA. RNA. 2008 Aug; 14(8):1632-43. View in: PubMed
Anglim PP, Alonzo TA, Laird-Offringa IA. DNA methylation-based biomarkers for early detection of non-small cell lung cancer: an update. Mol Cancer. 2008; 7:81. View in: PubMed
Anglim PP, Galler JS, Koss MN, Hagen JA, Turla S, Campan M, Weisenberger DJ, Laird PW, Siegmund KD, Laird-Offringa IA. Identification of a panel of sensitive and specific DNA methylation markers for squamous cell lung cancer. Mol Cancer. 2008; 7:62. View in: PubMed
Tsou JA, Galler JS, Wali A, Ye W, Siegmund KD, Groshen S, Laird PW, Turla S, Koss MN, Pass HI, Laird-Offringa IA. DNA methylation profile of 28 potential marker loci in malignant mesothelioma. Lung Cancer. 2007 Nov; 58(2):220-30. View in: PubMed
Tsou JA, Galler JS, Siegmund KD, Laird PW, Turla S, Cozen W, Hagen JA, Koss MN, Laird-Offringa IA. Identification of a panel of sensitive and specific DNA methylation markers for lung adenocarcinoma. Mol Cancer. 2007; 6:70. View in: PubMed
Kerr KM, Galler JS, Hagen JA, Laird PW, Laird-Offringa IA. The role of DNA methylation in the development and progression of lung adenocarcinoma. Dis Markers. 2007; 23(1-2):5-30. View in: PubMed
Law MJ, Rice AJ, Lin P, Laird-Offringa IA. The role of RNA structure in the interaction of U1A protein with U1 hairpin II RNA. RNA. 2006 Jul; 12(7):1168-78. View in: PubMed
Katsamba PS, Navratilova I, Calderon-Cacia M, Fan L, Thornton K, Zhu M, Bos TV, Forte C, Friend D, Laird-Offringa I, Tavares G, Whatley J, Shi E, Widom A, Lindquist KC, Klakamp S, Drake A, Bohmann D, Roell M, Rose L, Dorocke J, Roth B, Luginbühl B, Myszka DG. Kinetic analysis of a high-affinity antibody/antigen interaction performed by multiple Biacore users. Anal Biochem. 2006 May 15; 352(2):208-21. View in: PubMed
Law MJ, Linde ME, Chambers EJ, Oubridge C, Katsamba PS, Nilsson L, Haworth IS, Laird-Offringa IA. The role of positively charged amino acids and electrostatic interactions in the complex of U1A protein and U1 hairpin II RNA. Nucleic Acids Res. 2006; 34(1):275-85. View in: PubMed
Tsou JA, Shen LY, Siegmund KD, Long TI, Laird PW, Seneviratne CK, Koss MN, Pass HI, Hagen JA, Laird-Offringa IA. Distinct DNA methylation profiles in malignant mesothelioma, lung adenocarcinoma, and non-tumor lung. Lung Cancer. 2005 Feb; 47(2):193-204. View in: PubMed
Law MJ, Chambers EJ, Katsamba PS, Haworth IS, Laird-Offringa IA. Kinetic analysis of the role of the tyrosine 13, phenylalanine 56 and glutamine 54 network in the U1A/U1 hairpin II interaction. Nucleic Acids Res. 2005; 33(9):2917-28. View in: PubMed
Siegmund KD, Laird PW, Laird-Offringa IA. A comparison of cluster analysis methods using DNA methylation data. Bioinformatics. 2004 Aug 12; 20(12):1896-904. View in: PubMed
Johansson C, Finger LD, Trantirek L, Mueller TD, Kim S, Laird-Offringa IA, Feigon J. Solution structure of the complex formed by the two N-terminal RNA-binding domains of nucleolin and a pre-rRNA target. J Mol Biol. 2004 Apr 2; 337(4):799-816. View in: PubMed
Marchevsky AM, Tsou JA, Laird-Offringa IA. Classification of individual lung cancer cell lines based on DNA methylation markers: use of linear discriminant analysis and artificial neural networks. J Mol Diagn. 2004 Feb; 6(1):28-36. View in: PubMed
Park-Lee S, Kim S, Laird-Offringa IA. Characterization of the interaction between neuronal RNA-binding protein HuD and AU-rich RNA. J Biol Chem. 2003 Oct 10; 278(41):39801-8. View in: PubMed
Li H, Park S, Kilburn B, Jelinek MA, Henschen-Edman A, Aswad DW, Stallcup MR, Laird-Offringa IA. Lipopolysaccharide-induced methylation of HuR, an mRNA-stabilizing protein, by CARM1. Coactivator-associated arginine methyltransferase. J Biol Chem. 2002 Nov 22; 277(47):44623-30. View in: PubMed
Katsamba PS, Bayramyan M, Haworth IS, Myszka DG, Laird-Offringa IA. Complex role of the beta 2-beta 3 loop in the interaction of U1A with U1 hairpin II RNA. J Biol Chem. 2002 Sep 6; 277(36):33267-74. View in: PubMed
Tsou JA, Hagen JA, Carpenter CL, Laird-Offringa IA. DNA methylation analysis: a powerful new tool for lung cancer diagnosis. Oncogene. 2002 Aug 12; 21(35):5450-61. View in: PubMed
Virmani AK, Tsou JA, Siegmund KD, Shen LY, Long TI, Laird PW, Gazdar AF, Laird-Offringa IA. Hierarchical clustering of lung cancer cell lines using DNA methylation markers. Cancer Epidemiol Biomarkers Prev. 2002 Mar; 11(3):291-7. View in: PubMed
Katsamba PS, Park S, Laird-Offringa IA. Kinetic studies of RNA-protein interactions using surface plasmon resonance. Methods. 2002 Feb; 26(2):95-104. View in: PubMed
Katsamba PS, Myszka DG, Laird-Offringa IA. Two functionally distinct steps mediate high affinity binding of U1A protein to U1 hairpin II RNA. J Biol Chem. 2001 Jun 15; 276(24):21476-81. View in: PubMed
Bernasconi NL, Wormhoudt TA, Laird-Offringa IA. Post-transcriptional deregulation of myc genes in lung cancer cell lines. Am J Respir Cell Mol Biol. 2000 Oct; 23(4):560-5. View in: PubMed
Park S, Myszka DG, Yu M, Littler SJ, Laird-Offringa IA. HuD RNA recognition motifs play distinct roles in the formation of a stable complex with AU-rich RNA. Mol Cell Biol. 2000 Jul; 20(13):4765-72. View in: PubMed
Laird-Offringa IA. In vitro genetic analysis of RNA-binding proteins using phage display. Methods Mol Biol. 1999; 118:189-216. View in: PubMed
Laird-Offringa IA, Belasco JG. RNA-binding proteins tamed. Nat Struct Biol. 1998 Aug; 5(8):665-8. View in: PubMed
Laird-Offringa IA, Belasco JG. In vitro genetic analysis of RNA-binding proteins using phage display libraries. Methods Enzymol. 1996; 267:149-68. View in: PubMed
Laird-Offringa IA, Belasco JG. Analysis of RNA-binding proteins by in vitro genetic selection: identification of an amino acid residue important for locking U1A onto its RNA target. Proc Natl Acad Sci U S A. 1995 Dec 5; 92(25):11859-63. View in: PubMed
Laird-Offringa IA. What determines the instability of c-myc proto-oncogene mRNA? Bioessays. 1992 Feb; 14(2):119-24. View in: PubMed
Laird-Offringa IA, Elfferich P, van der Eb AJ. Rapid c-myc mRNA degradation does not require (A + U)-rich sequences or complete translation of the mRNA. Nucleic Acids Res. 1991 May 11; 19(9):2387-94. View in: PubMed
Laird-Offringa IA, de Wit CL, Elfferich P, van der Eb AJ. Poly(A) tail shortening is the translation-dependent step in c-myc mRNA degradation. Mol Cell Biol. 1990 Dec; 10(12):6132-40. View in: PubMed
Laird-Offringa IA, Elfferich P, Knaken HJ, de Ruiter J, van der Eb AJ. Analysis of polyadenylation site usage of the c-myc oncogene. Nucleic Acids Res. 1989 Aug 25; 17(16):6499-514. View in: PubMed
Offringa IA, Melchers LS, Regensburg-Tuink AJ, Costantino P, Schilperoort RA, Hooykaas PJ. Complementation of Agrobacterium tumefaciens tumor-inducing aux mutants by genes from the T(R)-region of the Ri plasmid of Agrobacterium rhizogenes. Proc Natl Acad Sci U S A. 1986 Sep; 83(18):6935-9. View in: PubMed