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      WNT ligands control initiation and progression of human papillomavirus-driven squamous cell carcinoma

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          Abstract

          Human papillomavirus (HPV)-driven cutaneous squamous cell carcinoma (cSCC) is the most common cancer in immunosuppressed patients. Despite indications suggesting that HPV promotes genomic instability during cSCC development, the molecular pathways underpinning HPV-driven cSCC development remain unknown. We compared the transcriptome of HPV-driven mouse cSCC with normal skin and observed higher amounts of transcripts for Porcupine and WNT ligands in cSCC, suggesting a role for WNT signaling in cSCC progression. We confirmed increased Porcupine expression in human cSCC samples. Blocking the secretion of WNT ligands by the Porcupine inhibitor LGK974 significantly diminished initiation and progression of HPV-driven cSCC. Administration of LGK974 to mice with established cSCC resulted in differentiation of cancer cells and significant reduction of the cancer stem cell compartment. Thus, WNT/β-catenin signaling is essential for HPV-driven cSCC initiation and progression as well as for maintaining the cancer stem cell niche. Interference with WNT secretion may thus represent a promising approach for therapeutic intervention.

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          Wnt/β-Catenin/Tcf Signaling Induces the Transcription of Axin2, a Negative Regulator of the Signaling Pathway

          Eek-hoon Jho, Tong Zhang, Claire Domon … (2002)
          Axin2/Conductin/Axil and its ortholog Axin are negative regulators of the Wnt signaling pathway, which promote the phosphorylation and degradation of β-catenin. While Axin is expressed ubiquitously, Axin2 mRNA was seen in a restricted pattern during mouse embryogenesis and organogenesis. Because many sites of Axin2 expression overlapped with those of several Wnt genes, we tested whether Axin2 was induced by Wnt signaling. Endogenous Axin2 mRNA and protein expression could be rapidly induced by activation of the Wnt pathway, and Axin2 reporter constructs, containing a 5.6-kb DNA fragment including the promoter and first intron, were also induced. This genomic region contains eight Tcf/LEF consensus binding sites, five of which are located within longer, highly conserved noncoding sequences. The mutation or deletion of these Tcf/LEF sites greatly diminished induction by β-catenin, and mutation of the Tcf/LEF site T2 abolished protein binding in an electrophoretic mobility shift assay. These results strongly suggest that Axin2 is a direct target of the Wnt pathway, mediated through Tcf/LEF factors. The 5.6-kb genomic sequence was sufficient to direct the tissue-specific expression of d2EGFP in transgenic embryos, consistent with a role for the Tcf/LEF sites and surrounding conserved sequences in the in vivo expression pattern of Axin2 . Our results suggest that Axin2 participates in a negative feedback loop, which could serve to limit the duration or intensity of a Wnt-initiated signal.
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            APC mutations occur early during colorectal tumorigenesis.

            S Powell, N Zilz, Y Beazer-Barclay … (1992)
            Human tumorigenesis is associated with the accumulation of mutations both in oncogenes and in tumour suppressor genes. But in no common adult cancer have the mutations that are critical in the early stages of the tumorigenic process been defined. We have attempted to determine if mutations of the APC gene play such a role in human colorectal tumours, which evolve from small benign tumours (adenomas) to larger malignant tumours (carcinomas) over the course of several decades. Here we report that sequence analysis of 41 colorectal tumours revealed that the majority of colorectal carcinomas (60%) and adenomas (63%) contained a mutated APC gene. Furthermore, the APC gene met two criteria of importance for tumour initiation. First, mutations of this gene were found in the earliest tumours that could be analysed, including adenomas as small as 0.5 cm in diameter. Second, the frequency of such mutations remained constant as tumours progressed from benign to malignant stages. These data provide strong evidence that mutations of the APC gene play a major role in the early development of colorectal neoplasms.
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              SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma.

              Soufiane Boumahdi, Gregory Driessens, Gaëlle Lapouge … (2014)
              Cancer stem cells (CSCs) have been reported in various cancers, including in skin squamous-cell carcinoma (SCC). The molecular mechanisms regulating tumour initiation and stemness are still poorly characterized. Here we find that Sox2, a transcription factor expressed in various types of embryonic and adult stem cells, was the most upregulated transcription factor in the CSCs of squamous skin tumours in mice. SOX2 is absent in normal epidermis but begins to be expressed in the vast majority of mouse and human pre-neoplastic skin tumours, and continues to be expressed in a heterogeneous manner in invasive mouse and human SCCs. In contrast to other SCCs, in which SOX2 is frequently genetically amplified, the expression of SOX2 in mouse and human skin SCCs is transcriptionally regulated. Conditional deletion of Sox2 in the mouse epidermis markedly decreases skin tumour formation after chemical-induced carcinogenesis. Using green fluorescent protein (GFP) as a reporter of Sox2 transcriptional expression (SOX2-GFP knock-in mice), we showed that SOX2-expressing cells in invasive SCC are greatly enriched in tumour-propagating cells, which further increase upon serial transplantations. Lineage ablation of SOX2-expressing cells within primary benign and malignant SCCs leads to tumour regression, consistent with the critical role of SOX2-expressing cells in tumour maintenance. Conditional Sox2 deletion in pre-existing skin papilloma and SCC leads to tumour regression and decreases the ability of cancer cells to be propagated upon transplantation into immunodeficient mice, supporting the essential role of SOX2 in regulating CSC functions. Transcriptional profiling of SOX2-GFP-expressing CSCs and of tumour epithelial cells upon Sox2 deletion uncovered a gene network regulated by SOX2 in primary tumour cells in vivo. Chromatin immunoprecipitation identified several direct SOX2 target genes controlling tumour stemness, survival, proliferation, adhesion, invasion and paraneoplastic syndrome. We demonstrate that SOX2, by marking and regulating the functions of skin tumour-initiating cells and CSCs, establishes a continuum between tumour initiation and progression in primary skin tumours.
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                Author and article information

                Contributors
                Konrad Basler: kb@imls.uzh.ch
                Maries van den Broek:
                ORCID: http://orcid.org/0000-0002-9489-3692
                vandenbroek@immunology.uzh.ch
                Journal
                Journal ID (nlm-ta): Oncogene
                Journal ID (iso-abbrev): Oncogene
                Title: Oncogene
                Publisher: Nature Publishing Group UK (London )
                ISSN (Print): 0950-9232
                ISSN (Electronic): 1476-5594
                Publication date (Electronic): 17 April 2018
                Publication date PMC-release: 17 April 2018
                Publication date (Print): 2018
                Volume: 37
                Issue: 27
                Pages: 3753-3762
                Affiliations
                [1 ]ISNI 0000 0004 1937 0650, GRID grid.7400.3, Institute of Molecular Life Sciences, , University of Zürich, ; 8057 Zurich, Switzerland
                [2 ]ISNI 0000 0004 1937 0650, GRID grid.7400.3, Institute of Experimental Immunology, , University of Zürich, ; 8057 Zurich, Switzerland
                [3 ]ISNI 0000 0004 0478 9977, GRID grid.412004.3, Department of Dermatology, , University Hospital Zürich, ; 8091 Zürich, Switzerland
                [4 ]ISNI 0000 0001 2162 9922, GRID grid.5640.7, Present Address: Department of Clinical and Experimental Medicine (IKE), Faculty of Health Sciences, , Wallenberg Center for Molecular Medicine (WCMM); Linköping University, ; S-58185 Linköping, Sweden
                Author information
                http://orcid.org/0000-0002-3043-1835
                http://orcid.org/0000-0002-9489-3692
                Article
                Publisher ID: 244
                DOI: 10.1038/s41388-018-0244-x
                PMC ID: 6033839
                PubMed ID: 29662191
                SO-VID: 39c7cc52-f216-478d-adf2-79636b94d3ce
                Copyright © © The Author(s) 2018
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 7 September 2017
                Date revision received : 1 March 2018
                Date accepted : 6 March 2018
                Categories
                Subject: Brief Communication
                Custom metadata
                issue-copyright-statement © Macmillan Publishers Limited, part of Springer Nature 2018

                ScienceOpen disciplines: Oncology & Radiotherapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy

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