The Showe Laboratory
The Showe laboratory applies a variety of omics approaches to answer complex biomedical questions in the context of the interactions between the immune system and cancer, with the goal of developing novel tools for early diagnosis and markers of therapy response, survival and relapse. Through an extensive network of collaborations with other laboratories at Wistar and several other institutions, the lab’s research addresses a diversified group of diseases, including lung cancer, glioblastoma multiforme and cutaneous T cell lymphoma. They also have several long-term collaborative efforts at Wistar on HIV and influenza, and an international collaboration on multiple sclerosis with the University of Nottingham. The lab’s diverse interests are further evidenced by collaboration with the University of Fairbanks to understand how hibernating black bears and Alaskan ground squirrels modify gene expression in various tissues during hibernation. She developed the first bear transcriptome microarray in collaboration with the Fairbanks group.
Biomarkers for Early Diagnosis of Non-Small Cell Lung Cancer
The Showe lab has been a pioneer in the development of cancer biomarkers from blood. In 2009, they published novel findings showing how mononuclear white blood cells (PBMC) from lung cancer patients contain a 29-gene, tumor-relevant gene signature that accurately predicts whether a lung nodule detected by CT scan is benign or malignant. They also demonstrated that information in blood gene expression patterns could predict patient survival and inform further treatments. In moving these studies forward to a clinical application, the lab has adopted a simplified and standardized blood sample collection using commercially available PAXgene RNA stabilizing tubes and successfully moved their assay from the developmental microarray platform to the to the clinically approved Nanostring nCounter platform, (Kossenkov et al, 2019). The technology has been patented and is in development for commercialization.
Ongoing effort: As part of the NCI Early Detection Network, the lab is developing new methods to detect and diagnose cancers early, when they are more easily and successfully treated, and new methods to predict recurrence/survival after treatment. This is a collaborative study with investigators at The University of Pennsylvania, Roswell Park, NYU, Temple University, The Helen F. Graham Cancer Center, NYU Medical Center, Meridian Health, N.J. and the Barzilai Medical Center, Israel.
Gene Expression in Cutaneous T-Cell Lymphoma
Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin lymphomas with characteristics of “skin-homing” T lymphocytes. The most common forms of CTCL are the skin-associated mycosis fungoides (MF) and a more aggressive leukemic form, Sezary Syndrome (SS). SS has been the focus of the laboratory studies. Early interest in this cancer was based on the observation that patients were severely deficient in the production of interleukin 12, a cytokine originally identified and characterized at The Wistar Institute, and on availability of a unique collection of patients being treated at the University of Pennsylvania Department of Dermatology. Based on initial studies, Showe was awarded one of the first National Cancer Institute Director’s Challenge grants to develop molecular diagnostics for CTCL using microarray platforms. This study led to the identification of a small number of genes that could detect SS by microarray or Q-RTPCR. The lab also identified some new specific cellular defects and a signature of poor prognosis that was independent of stage or circulating malignant cell numbers.
Ongoing studies: in collaboration with clinicians at the University of Pennsylvania (Alain Rook and Ellen Kim), Columbia University (Susan Bates) and NCI (Richard Piekarz), present work focuses on understanding mechanisms of therapeutic response both in vitro and in vivo to combined treatments such as toll-receptor agonists and interferon as well as histone deacetylase inhibitors. Combining data from gene and microRNA expression produced using microarrays and next-generation sequencing, the lab is defining parameters that distinguish responders from non-responders and markers of residual disease that can be monitored to detect potential recurrences before they are clinically evident. Using single cell analysis, the team is probing malignant cell heterogeneity and therapeutic response.
Development of a Gene Expression Signature to Distinguish Glioblastoma Multiforme (GBM) Subtypes
Glioblastoma multiforme (GBM) is the most common and severe form of primary malignant brain cancer. GBM is an aggressive cancer with no effective treatments and the median survival time is only 15 months from diagnosis. GBM is a heterogenous tumor having multiple disease subtypes, so it is important for clinicians to understand how these various GBM subtypes respond to emerging therapies that may one day be useful to glioblastoma patients.
Building on collaborative studies initiated with Ramana Davuluri and Donald O’Rourke, the Showe lab is developing a diagnostic platform to help classify GBM tumor subtypes to match to more efficacious treatments.
Functional Genomics of HIV
In a long-term collaboration with the lab of Luis J. Montaner at Wistar, the Showe lab applies functional genomic approaches to understand mechanisms of immune evasion in HIV infections and explore new ways to manage current HIV-1 infections, including the possibility of using immune-mediated control of virus infection upon interrupting drug therapy. Additional studies have focused on developing biomarkers to assess secondary infections, such as tuberculosis, in the presence of an active HIV infection. Showe is a co-Investigator on the BEAT-HIV Delaney Collaboratory grant to continue these studies.
Gene Expression in Multiple Sclerosis
In collaboration with Cris Constantinescu at The University of Nottingham, UK, the Showe laboratory is examining gene expression profiles in blood and tissue samples from multiple sclerosis patients involved in clinical trials with immuno-modulatory drugs. The aim is to determine whether it is possible to identify gene expression patterns that correlate with responsiveness and non-responsiveness to therapy and to better understand disease initiation and progression.
Gene Expression and Vaccines
Studies in collaboration with Hildegund C.J. Ertl at Wistar have examined gene expression changes in young and aged populations as a function of flu vaccination to try to understand the poorer responses to vaccinations in general and in the elderly population in particular. In addition, potential effects of race and timing of repeated vaccination on response were examined. Additional studies using mouse models have explored protocols that increase vaccine response with the potential benefit of improving vaccine efficacy in the growing elderly population.
Kelich, J., Aramburu, T., van der Vis, J.J., Showe, L., Kossenkov, A., van der Smagt , J., Massink, M., Schoemaker, A., Hennekam, E., Veltkamp, M., et al. “Telomere Dysfunction Implicates POT1 in Patients With Idiopathic Pulmonary Fibrosis.” J Exp Med. 2022 May 2;219(5):e20211681. doi: 10.1084/jem.20211681. Epub 2022 Apr 14.
Lamontagne, R.J., Soldan, S.S., Su, C., Wiedmer, A., Won, K.J., Lu, F., Goldman, A.R., Wickramasinghe, J., Tang, H.Y., Speicher, D.W., et al. “A Multi-omics Approach to Epstein-Barr Virus Immortalization of B-cells Reveals EBNA1 Chromatin Pioneering Activities Targeting Nucleotide Metabolism.” PLoS Pathog. 2021 Jan 26;17(1):e1009208. doi: 10.1371/journal.ppat.1009208. eCollection 2021 Jan.
Midgley, A., Barakat, D., Braitch, M., Nichols, C., Nebozhyn, M., Edwards, L.J., Fox, S.C., Gran, B., Robins, R.A., Showe, L.C., et al. “PAF-R on activated T cells: Role in the IL-23/Th17 pathway and relevance to multiple sclerosis.” Immunobiology. 2021 Jan;226(1):152023. doi: 10.1016/j.imbio.2020.152023. Epub 2020 Nov 13.
Kossenkov, A.V., Qureshi, R., Dawany, N.B., Wickramasinghe, J., Liu, Q., Majumdar, R.S., Chang, C., Widura, S., Kumar, T., Horng, W.H., et al. “A Gene Expression Classifier from Whole Blood Distinguishes Benign from Malignant Lung Nodules Detected by Low-Dose CT.”Cancer Res. 2019 Jan 1;79(1):263-273. doi: 10.1158/0008-5472.CAN-18-2032. Epub 2018 Nov 28.
Iwasaki, O., Tanizawa, H., Kim, KD., Kossenkov, A., Nacarelli, T., Tashiro, S., Majumdar, S., Showe, L.C., et al. “Involvement of condensin in cellular senescence through gene regulation and compartmental reorganization.” Nat Commun. 2019 Dec 12;10(1):5688. doi: 10.1038/s41467-019-13604-5.