WNT ligands control initiation and progression of human papillomavirus-driven squamous cell carcinoma.
Dario ZimmerliVirginia CecconiTomas ValentaGeorge HausmannClaudio CantùGaetana RestivoJürg HafnerKonrad BaslerMaries van den BroekPublished in: Oncogene (2018)
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.
Keyphrases
- high grade
- squamous cell carcinoma
- cell proliferation
- cancer stem cells
- stem cells
- end stage renal disease
- cervical cancer screening
- endothelial cells
- chronic kidney disease
- ejection fraction
- poor prognosis
- genome wide
- metabolic syndrome
- adipose tissue
- dna methylation
- radiation therapy
- peritoneal dialysis
- locally advanced
- wound healing
- insulin resistance
- childhood cancer