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.
Highlights
These authors contributed : Dario Zimmerli, Virginia Cecconi, Tomas Valenta.These authors are shared last authors: Konrad Basler, Maries van den Broek.Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Cutaneous squamous cell carcinoma develops from basal keratinocytes in sunlight-exposed skin and is the second most frequent cancer in fair-skinned individuals
We used the Krt14HPV8(E6) transgenic mouse model for Cutaneous squamous cell carcinoma (cSCC) in which tumor induction can be triggered by UV-irradiation [13]
We found a putative population of cancer stem cells (CSC) that were CD34+ at the tumor–stroma interface in Human papillomavirus (HPV)-driven cSCCs (Supplementary Figure 1d)
Summary
These authors contributed : Dario Zimmerli, Virginia Cecconi, Tomas Valenta. These authors are shared last authors: Konrad Basler, Maries van den Broek.
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