Raymond Konger, MD
Phone: (317) 274-4154
Phone: (317) 944-0920, Patient issues/appointments
975 W. Walnut St.
Indianapolis, IN 46202
- Professor of Pathology & Laboratory Medicine, Department of Pathology and Laboratory Medicine, IU School of Medicine
- Professor of Dermatology, Department of Dermatology, IU School of Medicine
- Medical Director, Clinical Chemistry Laboratory, Richard L. Roudebush Veterans Affairs Medical Center
- Full member
Indiana University Melvin and Bren Simon Cancer Center, Tumor Microenvironment and Metastasis
Current Research (funded): In work that is funded by my VA Merit award, my laboratory is focused on examining whether peroxisome proliferator recetor gamma agonists suppress skin cancer formation through their ability to suppress inflammation and promote antigen-specific anti-tumor immune responses. Skin cancer is primarily caused by environmental ultraviolet (UV) exposure from sunlight. UV suppresses T-cell mediated contact hypersensitivity (CHS) responses as well as anti-tumor immune responses (termed UV-induced immunosuppression (UV-IS)). UV-IS likely promotes skin cancer formation by promoting tolerance to tumor-specific antigens. We have shown that loss of peroxisome proliferator activated receptor gamma (PPAR¿) in the epidermis of mice (Pparg-/-epi mice) promotes UV-induced skin cancer formation . Pparg-/-epi mice are also markedly immune suppressed as shown by a roughly 70% reduction in contact hypersensitivity (CHS) responses . In addition, we have also shown that the PPAR¿ agonist rosiglitazone (Rosig) protects mice against skin cancer formation, reverses the ability of UV to suppress CHS responses, and reverses the ability of UV to promote melanoma tumor growth in mice ( & unpublished observations). In addition, PPAR¿ agonists can activate two mechanistically distinct pathways leading to transcriptional regulation. Full PPAR¿ ligands, such as the anti-diabetic agents rosiglitazone & pioglitazone, can activate both pathways. The first pathway results in ligand induced transactivation of selective target genes. This results in upregulation of PPAR¿-dependent genes that are associated with the negative side effects of rosiglitazone & pioglitazone use (e.g. adipogenesis). In the second pathway, ligand interaction with a different site in the PPAR¿ ligand-binding pocket results in PPAR¿ sumoylation and subsequent transrepression of genes under the control of NF-¿B, STAT, and AP-1 transcription factors. Our current work is focused on our hypothesis that PPAR¿ ligand-dependent transrepression, rather than transactivation, is key to the anti-tumor activity of PPAR¿. We have currently identified two PPAR¿ agonists (SR202 & resveratrol-4-glucuronide (Resv-Gluc)) that have potent transrepressive activity, but lack transactivating activity (unpublished observations). An additional PPAR¿ agonist (FMOC-L-Leu) has potent transactivating activity and no transrepressive activity (unpublished). These ligands, combined with the appropriate genetic models, should allow us to rigorously examine whether transrepressive signaling is necessary for the ability of PPAR¿ ligands to reverse UV-IS. In particular, we show that Pparg-/-epi mice exhibit a robust increase in the full-length transmembrane form of tumor necrosis factor a (TNF-a). Our studies & work by others suggests that the transmembrane form (tmTNF-a) is primarily involved in immune suppression. Finally, recent studies have shown that radiation therapy, like UV, also promotes systemic immunosuppression through its ability to induce oxidative stress. We propose that transrepressive PPAR¿ ligands will reverse this immune suppression and promote the so-called abscopal effect. This abscopal effect results in anti-tumor responses in tumors that are outside the field of radiation treatment. Although spontaneous abscopal effects occur rarely, evidence exists that efforts to promote immune responses can make this response commonplace. We propose that transrepressive PPAR¿ ligands will act in concert with radiotherapy to promote the abscopal effect. Our identification of selective transrepressive (SR202 & Resv-Gluc) and selective transactivating (FMOC-L-Leu) ligands will aid in establishing this relationship. The funded studies are divided into the following three specific aims (SA): SA#1: Determine whether epidermal PPAR¿ regulates CHS responses through transmembrane TNF-a (tmTNF-a) rather than soluble TNF-a (solTNF-a). SA#2: Determine the capacity of diverse PPAR¿ ligands to induce PPAR¿-specific transrepression of UVB-induced NF-¿B activation and TNF-a production in vitro and in vivo. We will correlate this transrepressive activity with the ability to reverse UV-induced suppression of CHS responses. SA#3: Determine whether transrepressive PPAR¿ ligands promote anti-tumor immune responses either alone or following external beam radiation therapy. Future research (un-funded studies): In a second line of ongoing research, we hypothesize that chronic ultraviolet A &/or B (UVA & B) exposure results in a multifocal dermal senescent field that promotes overlying epidermal tumorigenesis. We have shown that persistent (remain long after cessation of UVB treatments) hyperemic dermal foci develop in roughly 30% of the treated area of chronically UV treated mice [3,4]. These foci predict the site of UVB-induced tumor formation with 96% sensitivity. We have strong unpublished preliminary data that indicate that these foci have a marked senescent dermal phenotype that precedes tumor formation. These foci also predict reduced UVB-induced T-cell infiltrates and increased numbers of potentially immunosuppressive CD11b+Gr-1+ myeloid cells. Senescence in the epithelial compartment is proposed to act as a tumor suppressing signal. Others have proposed that senescence in the dermal compartment can act as a tumor promoting signal. Senolytic agents or agents that selectively kill senescent cells are being developed to suppress chronic diseases of aging. However, non-selective killing of epithelial and stromal senescent cells may have unforeseen negative effects on tumorigenesis. In October 2016, I submitted an R01 grant application (1R01 CA216223: “Senescence as a driver of persistent premalignant field formation”). The proposal received an encouraging initial impact score of 37. Summary statement comments included, “The strengths of this application include the significance of the area as clearly defined in the application, the experience of the investigator and the well-crafted plan that studies the relationships of senescence in specific cellular compartments in transgenic mice and the translation of a novel technology for use in humans. These studies focus on an important, yet controversial area related to senescence and immune recognition in the field defect related to cutaneous carcinogenesis… Other strengths are that the approach will employ elegant genetic mouse models to ablate senescent cells.” A key weakness of the proposal was also articulated: “The phenotyping and characterization of the mouse models is at a premature stage, making it difficult to judge how effective these models will actually be (although their potential is high). Thus, the absence of a validated model was a major factor in driving down the impact score. Unfortunately, using random insertion, our initial 8 transgenic mouse founders failed to express target gene transcripts due to either chimerism or gene silencing. We are currently modifying the approach by inserting a revised targeting vector flanked by genetic insulators (to prevent silencing and to suppress background promoter influences) into a safe harbor genetic locus through a recombinase-based strategy (TARGATTTM mice; Applied Stem Cell). The targeting vector will take advantage of the fact that senescent cells express high levels of the cyclin dependent kinase inhibitor (p16INK, CDKN2A). Senescent cells can be induced to undergo apoptosis when mice expressing a p16INK promoter driven FKBP-Caspase 8 fusion protein are treated with the FKBP dimerization agent (AP20187) [5,6]. AP20187 treated mice exhibit reduced aging and tumor formation and a reduction in senescent cells in all compartments. We will utilize the floxed mCherry-Stop cassette to prevent AP20187-induced killing of cells expressing the transgene that lack Cre recombinase. Once developed, these mice can be crossed with transgenic mice containing stromal specific or epidermal specific Cre recombinase to allow for the tissue-specific expression of the FKBP-Casp 8 fusion suicide protein in senescent cells. This will allow us to directly confirm that a stromal senescent phenotype promotes tumorigenesis, while an epithelial senescent phenotype suppresses tumorigenesis. An advantage of our approach is the ability to verify transgene expression in founders by assessing p16-driven expression of mCherry. It can also be used to verify that AP20187-induced senescence cell killing is specific to the targeted tissue (AP20187 will kill cells with p16-driven luciferase reporter in the targeted Cre-expressing tissue, but will not kill cells with p16-induced mCherry expression in tissues not expressing the Cre transgene). Thus, upon treatment of mice with AP20187, mice can be followed by intravital fluorescence and luciferase imaging to verify treatment efficacy and specificity. Once the targeting vector is completed, we will verify functional protein expression following insertion into a TARGATT cell line containing an attP insertion site within the Rosa26 safe harbor genetic locus. The targeting vector will then be sent to Applied Stem Cell, Inc for pronuclear injection. Alternatively, TARGATT mice can be purchased and the pronuclear injection can be done by the IU transgenic mouse facility. We feel that having these mice on hand will markedly improve the funding prospects for this project. This mouse line would likely be useful for other investigators at IU and elsewhere who are interested in aging and cancer research. Citations. 1. Sahu RP, DaSilva SC, Rashid B, Martel KC, Jernigan D, et al. (2012) Mice lacking epidermal PPAR¿ exhibit a marked augmentation in photocarcinogenesis associated with increased UVB-induced apoptosis, inflammation and barrier dysfunction. Int J Cancer 131: E1055-E1066 2. Konger RL, Derr-Yellin E, Travers JB, Ocana JA, Sahu RP (2017) Epidermal PPARg influences subcutaneous tumor growth and acts through TNF-a to regulate contact hypersensitivity and the acute photoresponse. Oncotarget 8: 98184-98199. 3. Konger R, Xu Z, Sahu R, Rashid B, Mehta SR, et al. (2013) Spatiotemporal assessments of dermal hyperemia enable accurate prediction of experimental cutaneous carcinogenesis as well as chemopreventive activity. Cancer Res 73: 150-159. 4. Konger RL, Xu Z, Sahu RP, Kim YL. Tumor site prediction using spatiotemporal detection of subclinical hyperemia in experimental photocarcinogenesis; 2014. pp. 89260Z-89260Z-89268. 5. Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, et al. (2016) Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530: 184-189. 6. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, et al. (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479: 232–236.
Post-doctoral Fellowship - University of Rochester, Rochester, NY 1997-1999
Residency - Wshington University School of Medicine, St. Louis, MO 1992-1997
M.D. - Indiana University School of Medicine, Indianapolis, IN 1988-1992