TY - JOUR
T1 - Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression
AU - Bailey, Peter
AU - Ridgway, Rachel A.
AU - Cammareri, Patrizia
AU - Treanor-Taylor, Mairi
AU - Bailey, Ulla-Maja
AU - Schoenherr, Christina
AU - Bone, Max
AU - Schreyer, Daniel
AU - Purdie, Karin
AU - Thomson, Jason
AU - Rickaby, William
AU - Jackstadt, Rene
AU - Campbell, Andrew
AU - Dimonitsas, Emmanouil
AU - Stratigos, Alexander J.
AU - Arron, Sarah T.
AU - Wang, Jun
AU - Blyth, Karen
AU - Proby, Charlotte
AU - Harwood, Catherine A.
AU - Sansom, Owen J.
AU - Leigh, Irene
AU - Inman, Gareth
N1 - Funding 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 DRCQQR-May21\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.
Funding 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 DRCQQR-May21\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.
Publisher Copyright:
© 2023, Springer Nature Limited.
PY - 2023/8/25
Y1 - 2023/8/25
N2 - 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.
AB - 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.
KW - Cancer models
KW - Squamous cell carcinoma
UR - http://www.scopus.com/inward/record.url?scp=85168720848&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-40822-9
DO - 10.1038/s41467-023-40822-9
M3 - Article
C2 - 37626054
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
M1 - 5211
ER -
