Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression

Bailey, P. et al. (2023) Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression. Nature Communications, 14, 5211. (doi: 10.1038/s41467-023-40822-9) (PMID:37626054) (PMCID:PMC10457401)

Abstract

The molecular basis of disease progression from UV-induced precancerous actinic keratosis (AK) to malignant invasive cutaneous squamous cell carcinoma (cSCC) and potentially lethal metastatic disease remains unclear. DNA sequencing studies have revealed a massive mutational burden but have yet to illuminate mechanisms of disease progression. Here we perform RNAseq transcriptomic profiling of 110 patient samples representing normal sun-exposed skin, AK, primary and metastatic cSCC and reveal a disease continuum from a differentiated to a progenitor-like state. This is accompanied by the orchestrated suppression of master regulators of epidermal differentiation, dynamic modulation of the epidermal differentiation complex, remodelling of the immune landscape and an increase in the preponderance of tumour specific keratinocytes. Comparative systems analysis of human cSCC coupled with the generation of genetically engineered murine models reveal that combinatorial sequential inactivation of the tumour suppressor genes Tgfbr2, Trp53, and Notch1 coupled with activation of Ras signalling progressively drives cSCC progression along a differentiated to progenitor axis. Taken together we provide a comprehensive map of the cSCC disease continuum and reveal potentially actionable events that promote and accompany disease progression.

• Item Type: Articles
• Additional Information: We thank the Core Services and Advanced Technologies at the Cancer Research UK Beatson Institute (A31287 and C596/A17196) and particularly the Biological Services Unit, Histology Service and Molecular Technologies. G.J.I and members of his laboratory were supported by Cancer Research UK (A29802). O.J.S and members of his laboratory were supported by Cancer Research UK (A21139 and DRCQQRMay21\100002). K.B was supported by Cancer Research UK (A29799). M.T-T was supported by a Cancer Research UK MB-PhD studentship, M.B was supported by a British Skin Foundation PhD studentship and D.S. and P.B were supported by from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie grant agreement No 861196 designated for PRECODE.
• Keywords: Animals, Humans, Mice, Carcinoma, Squamous Cell, Skin Neoplasms, Disease Progression, Gene Expression Profiling, Cell Differentiation, Keratosis, Actinic
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cammareri, Dr Patrizia and Campbell, Dr Andrew and Blyth, Professor Karen and Bailey, Dr Peter and Bailey, Dr Ulla-Maja and Ridgway, Dr Rachel and Schoenherr, Dr Christina and Bone, Mr Max and Inman, Professor Gareth and Sansom, Professor Owen and Treanor-Taylor, Ms Mairi and Schreyer, Mr Daniel
• Authors: Bailey, P., Ridgway, R. L., Cammareri, P., Treanor-Taylor, M., Bailey, U.-M., Schoenherr, C., Bone, M., Schreyer, D., Purdie, K., Thomson, J., Rickaby, W., Jackstadt, R., Campbell, A. D., Dimonitsas, E., Stratigos, A. J., Arron, S. T., Wang, J., Blyth, K., Proby, C. M., Harwood, C. A., Sansom, O. J., Leigh, I. M., and Inman, G. J.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright: © The Author(s) 2023
• First Published: First published in Nature Communications 14: 5211
• Publisher Policy: Reproduced under a Creative Commons licence