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Identification of Differentially Expressed Genes in Actinic Keratosis Samples Treated with Ingenol Mebutate Gel

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PLOS ONE RESEARCH ARTICLE Identification of differentially expressed genes in actinic keratosis samples treated with ingenol mebutate gel Sonia Segura1, Alejandra Gadea2,3, Lara Nonell4, Evelyn Andrades2, Silvia SaÂnchez2, 1 2 5,6 Ramon Pujol , Inmaculada HernaÂndez-Muñoz , Agustõ TollID * 1 Department of Dermatology, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain, 2 Group of Inflamatory and Neoplasic Dermatological Diseases, IMIM (Hospital del Mar Medical Research Institute), Barcelona, a1111111111 Spain, 3 Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Paul Pascal (CRPP), a1111111111 Universite de Bordeaux, Pessac, France, 4 MARGenomics, IMIM (Hospital del Mar Medical Research a1111111111 Institute), Barcelona, Spain, 5 Department of Dermatology, Hospital ClõÂnic de Barcelona, University of a1111111111 Barcelona, Barcelona, Spain, 6 Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain a1111111111 * [email protected] OPEN ACCESS Abstract Citation: Segura S, Gadea A, Nonell L, Andrades E, Actinic keratosis is a common skin disease that may progress to invasive squamous cell car- SaÂnchez S, Pujol R, et al. (2020) Identification of cinoma if left untreated. Ingenol mebutate has demonstrated efficacy in field treatment of differentially expressed genes in actinic keratosis samples treated with ingenol mebutate gel. PLoS actinic keratosis. However, molecular mechanisms on ingenol mebutate response are not ONE 15(5): e0232146. https://doi.org/10.1371/ yet fully understood. In this study, we evaluated the gene expression profiles of actinic kera- journal.pone.0232146 tosis lesions before and after treatment with ingenol mebutate using microarray technology. Editor: Liang Liu, University of Minnesota, UNITED Actinic keratoses on face/scalp of 15 immunocompetent patients were identified and evalu- STATES ated after treatment with topical ingenol mebutate gel 0.015%, applied once daily for 3 con- Received: December 18, 2019 secutive days. Diagnostic and clearance of lesions was determined by clinical, Accepted: April 7, 2020 dermoscopic, and reflectance confocal microscopy criteria. Lesional and non-lesional skin biopsies were subjected to gene expression analysis profiled by Affymetrix microarray. Dif- Published: May 15, 2020 ferentially expressed genes were identified, and enrichment analyses were performed using Copyright: © 2020 Segura et al. This is an open STRING database. At 8 weeks post-treatment, 60% of patients responded to ingenol mebu- access article distributed under the terms of the Creative Commons Attribution License, which tate therapy, achieving complete clearance in 40% of cases. A total of 128 differentially permits unrestricted use, distribution, and expressed genes were identified following treatment, and downregulated genes (114 of reproduction in any medium, provided the original 128) revealed changes in pathways important to epidermal development, keratinocyte dif- author and source are credited. ferentiation and cornification. In responder patients, 388 downregulated genes (of 450 differ- Data Availability Statement: All microarray data entially expressed genes) were also involved in development/differentiation of the files are available from the Gene Expression epidermis, and immune system-related pathways, such as cytokine and interleukin signal- Omnibus database (accession number GSE142108). ing. Cluster analysis revealed two relevant clusters showing upregulated profile patterns in pre-treatment actinic keratoses of responders, as compared to non-responders. Again, dif- Funding: Funding Source: This study was sponsored by LEO Pharma S.A. (http://www.leo- ferentially expressed genes were mainly associated with cornification, keratinization and pharma.es/). The sponsor had no role in study keratinocyte differentiation. Overall, the present study provides insight into the gene expres- design, collection and analysis, decisioÂn to publish, sion profile of actinic keratoses after treatment with ingenol mebutate, as well as identifica- or preparation of the manuscript. tion of genetic signatures that could predict treatment response. Competing interests: Agustõ Toll received research funds from LEO Pharma S.A. for this work. The PLOS ONE | https://doi.org/10.1371/journal.pone.0232146 May 15, 2020 1 / 20 PLOS ONE Gene profiles of ingenol-treated actinic keratoses other authors have indicated they have no financial Introduction relationships or conflicts of interest to disclose. This does not alter our adherence to PLOS ONE Actinic keratosis (AK) is a common skin disease characterized by thick, scaly, cutaneous policies on sharing data and materials. lesions on chronic sun-exposed areas, and histologically by atypical keratinocytes extending to the basal layer of the epidermis, that may progress to invasive squamous cell carcinoma (SCC) if left untreated [1,2]. The risk to develop a cutaneous SCC is approximately 0.03±20% per year for any single lesion [3±6], and the risk of malignant progression for a patient affected by mul- tiple AK lesions has been estimated within a wide range between 0.15% and 80% [7]. The high- est malignant transformation rates are found in males, elderly patients, individuals with phototypes I and II, human papillomavirus infection, a family history of skin cancer, and in immune-suppressed individuals [8±10]. However, despite the advances in the recognition of clinic, dermoscopic and histologic patterns, it is not yet possible to predict which lesions will advance to SCC [11]. For this reason, an early diagnosis and effective treatment are recommended. There are many variables that may influence the therapy choice in an individual, such as the number and location of lesions, age and immunological status of the patient, personal his- tory of previous skin lesions and previous treatments [11]. Nevertheless, since AKs are usually multiple and often subclinical, a field-directed approach is suggested to remove clinically visi- ble as well as non-visible lesions within the treatment area to prevent the development to inva- sive SCC [12]. Among the topical field therapies available, ingenol mebutate (IM) has demonstrated to be an ef-fective and well tolerated option for the treatment of AK, with a simple dosing regimen and a short treating course [13,14]. However, the precise mechanism of action by which the drug induces cell death is not fully understood, neither are the molecular mechanisms involved in the lack of response to IM. Herein, we report the results of a prospective study investigating the transcriptomic profile of AK lesions before and after treatment with IM gel. Our study included clinical and dermo- scopic evaluations together with a monitoring of the histological patterns of AKs by in vivo reflectance confocal microscopy (RCM), a non-invasive imaging technique. We also per- formed a comparative analysis of gene expression profiles of AKs responsive and unresponsive to the study treatment, in order to gain a better understanding of the molecular mechanisms involved and to identify potential genetic signatures of response to IM therapy. Materials and methods Study design and patient population This was a single-center, single-arm, prospective observational study conducted in Hospital del Mar in Barcelona from April 2016 to April 2018, to evaluate the mRNA expression profile of AKs before and after treatment with IM. We prospectively enrolled fifteen immunocompe- tent adult patients aged � 18 years, who were clinically diagnosed with at least one AK (grade I-II, according to Olsen's classification [15]) on the head and/or scalp larger than 8 mm in diameter. All patients were regularly being followed-up for previous history of non-melanoma skin cancer at the Skin Cancer Clinic of the Hospital del Mar. Patients could not have received any pharmacological treatment for AK within 6 months before inclusion. Subjects were excluded if they were pregnant, breastfeeding, or planning on becoming pregnant during the course of the trial. All individual participants received written and verbal information con- cerning the study, provided signed written informed consent, and allowed photographs of the selected treatment areas to be taken. Data confidentiality and anonymity will be ensured, according to the provisions of the Spanish Organic Law 3/2018, of December 5, on Personal PLOS ONE | https://doi.org/10.1371/journal.pone.0232146 May 15, 2020 2 / 20 PLOS ONE Gene profiles of ingenol-treated actinic keratoses Data Protection and Digital Rights, and the provisions of Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016. The study was approved by the local ethics committee (Comite EÂtico de InvestigacioÂn ClõÂnica- Parc de Salut Mar, nÊ 2016/6597/I) and conducted in accordance with the Declaration of Helsinki (Fortaleza, Brazil, October 2013). Study assessments At the initial screening visit (visit 0), participants provided informed consent, and study der- matologists collected demographic data and performed a clinical evaluation of the lesions on the head suggestive of AK. AK lesions larger than 8 mm in diameter were identified, evaluated, and subsequently monitored at the pre-treatment visit (visit 1), at 4±2 days after treatment (visit 2), and at 8±1 weeks after treatment (visit 3). Clinical assessment of AKs and photographs with a digital camera (Canon Powershot G101, OÅ ita, Japan) were made at each study visit. At visits 1 and 3, dermoscopic images (DermliteFoto1, 3Gen, San Juan
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    xO GENE PANEL 1714 gene comprehensive cancer panel enriched for clinically actionable genes with additional biologically relevant genes 400-500x average coverage on tumor Genes A-C Genes D-F Genes G-I Genes J-L AATK ATAD2B BTG1 CDH7 CREM DACH1 EPHA1 FES G6PC3 HGF IL18RAP JADE1 LMO1 ABCA1 ATF1 BTG2 CDK1 CRHR1 DACH2 EPHA2 FEV G6PD HIF1A IL1R1 JAK1 LMO2 ABCB1 ATM BTG3 CDK10 CRK DAXX EPHA3 FGF1 GAB1 HIF1AN IL1R2 JAK2 LMO7 ABCB11 ATR BTK CDK11A CRKL DBH EPHA4 FGF10 GAB2 HIST1H1E IL1RAP JAK3 LMTK2 ABCB4 ATRX BTRC CDK11B CRLF2 DCC EPHA5 FGF11 GABPA HIST1H3B IL20RA JARID2 LMTK3 ABCC1 AURKA BUB1 CDK12 CRTC1 DCUN1D1 EPHA6 FGF12 GALNT12 HIST1H4E IL20RB JAZF1 LPHN2 ABCC2 AURKB BUB1B CDK13 CRTC2 DCUN1D2 EPHA7 FGF13 GATA1 HLA-A IL21R JMJD1C LPHN3 ABCG1 AURKC BUB3 CDK14 CRTC3 DDB2 EPHA8 FGF14 GATA2 HLA-B IL22RA1 JMJD4 LPP ABCG2 AXIN1 C11orf30 CDK15 CSF1 DDIT3 EPHB1 FGF16 GATA3 HLF IL22RA2 JMJD6 LRP1B ABI1 AXIN2 CACNA1C CDK16 CSF1R DDR1 EPHB2 FGF17 GATA5 HLTF IL23R JMJD7 LRP5 ABL1 AXL CACNA1S CDK17 CSF2RA DDR2 EPHB3 FGF18 GATA6 HMGA1 IL2RA JMJD8 LRP6 ABL2 B2M CACNB2 CDK18 CSF2RB DDX3X EPHB4 FGF19 GDNF HMGA2 IL2RB JUN LRRK2 ACE BABAM1 CADM2 CDK19 CSF3R DDX5 EPHB6 FGF2 GFI1 HMGCR IL2RG JUNB LSM1 ACSL6 BACH1 CALR CDK2 CSK DDX6 EPOR FGF20 GFI1B HNF1A IL3 JUND LTK ACTA2 BACH2 CAMTA1 CDK20 CSNK1D DEK ERBB2 FGF21 GFRA4 HNF1B IL3RA JUP LYL1 ACTC1 BAG4 CAPRIN2 CDK3 CSNK1E DHFR ERBB3 FGF22 GGCX HNRNPA3 IL4R KAT2A LYN ACVR1 BAI3 CARD10 CDK4 CTCF DHH ERBB4 FGF23 GHR HOXA10 IL5RA KAT2B LZTR1 ACVR1B BAP1 CARD11 CDK5 CTCFL DIAPH1 ERCC1 FGF3 GID4 HOXA11 IL6R KAT5 ACVR2A
  • Fra-2 Overexpression Upregulates Pro-Metastatic Cell-Adhesion

    Fra-2 Overexpression Upregulates Pro-Metastatic Cell-Adhesion

    Fra-2 Overexpression Upregulates Pro-metastatic Cell-adhesion Molecules, Promotes Pulmonary Metastasis and Reduces Survival in a Spontaneous Xenograft Model of Human Breast Cancer Sabrina Arnold University Medical Center Hamburg-Eppendorf: Universitatsklinikum Hamburg-Eppendorf Jan Kortland University Medical Center Hamburg-Eppendorf: Universitatsklinikum Hamburg-Eppendorf Diana V. Maltseva National Faculty of Biology and Biotechnology, National Research University Higher School of Economics Timur R. Samatov Evotec International GmbH Susanne Lezius University Medical Center Hamburg-Eppendorf: Universitatsklinikum Hamburg-Eppendorf Alexander G. Tonevitsky Far Eastern Federal University Karin Milde-Langosch University Medical Center Hamburg-Eppendorf: Universitatsklinikum Hamburg-Eppendorf Daniel Wicklein University Medical Center Hamburg-Eppendorf: Universitatsklinikum Hamburg-Eppendorf Udo Schumacher University Medical Center Hamburg-Eppendorf: Universitatsklinikum Hamburg-Eppendorf Christine Stürken ( [email protected] ) endorf: Universitatsklinikum Hamburg-Eppendorf https://orcid.org/0000-0003-3997-3304 Research Article Keywords: Breast Cancer, Transcription factor, AP-1, Fra-2, Metastasis Posted Date: June 15th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-592522/v1 Page 1/33 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 2/33 Abstract Purpose: The transcription factor Fra-2 affects the invasive potential of breast cancer cells by dysregulating adhesion molecules in vitro. Previous results suggested that it upregulates the expression of E- and P- selectin ligands. Such selectin ligands are important members of the leukocyte adhesion cascade, which govern the adhesion and transmigration of cancer cells into the stroma of the host organ of metastasis. As so far, no in vivo data are available, this study was designed to elucidate the role of Fra-2 expression in a spontaneous breast cancer metastasis xenograft model.