Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression

Peter Bailey (), Rachel A. Ridgway, Patrizia Cammareri, Mairi Treanor-Taylor, Ulla-Maja Bailey, Christina Schoenherr, Max Bone, Daniel Schreyer, Karin Purdie, Jason Thomson, William Rickaby, Rene Jackstadt, Andrew D. Campbell, Emmanouil Dimonitsas, Alexander J. Stratigos, Sarah T. Arron, Jun Wang, Karen Blyth, Charlotte M. Proby, Catherine A. Harwood, Owen J. Sansom, Irene M. Leigh () and Gareth J. Inman ()
Additional contact information
Peter Bailey: University of Glasgow
Rachel A. Ridgway: Cancer Research UK Beatson Institute
Patrizia Cammareri: Cancer Research UK Beatson Institute
Mairi Treanor-Taylor: Cancer Research UK Beatson Institute
Ulla-Maja Bailey: Cancer Research UK Beatson Institute
Christina Schoenherr: Cancer Research UK Beatson Institute
Max Bone: University of Glasgow
Daniel Schreyer: University of Glasgow
Karin Purdie: Queen Mary University of London
Jason Thomson: Queen Mary University of London
William Rickaby: St John’s Institute of Dermatology, St Thomas’s Hospital
Rene Jackstadt: Cancer Research UK Beatson Institute
Andrew D. Campbell: Cancer Research UK Beatson Institute
Emmanouil Dimonitsas: 1st Department of Dermatology and Venereology, Andreas Sygros Hospital, Medical School, National and Kapodistrian University of Athens
Alexander J. Stratigos: 1st Department of Dermatology and Venereology, Andreas Sygros Hospital, Medical School, National and Kapodistrian University of Athens
Sarah T. Arron: University of of California at San Francisco
Jun Wang: Queen Mary University of London
Karen Blyth: University of Glasgow
Charlotte M. Proby: University of Dundee
Catherine A. Harwood: Queen Mary University of London
Owen J. Sansom: University of Glasgow
Irene M. Leigh: Queen Mary University of London
Gareth J. Inman: University of Glasgow

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40822-9

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