Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression.
Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression.
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DOI：
10.1038/s41467-023-40822-9
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发表时间：
2023-08-25
影响因子：
16.6
通讯作者：
Inman, Gareth J.
中科院分区：
文献类型：
--
作者：
Bailey, Peter;Ridgway, Rachel A.;Cammareri, Patrizia;Treanor-Taylor, Mairi;Bailey, Ulla-Maja;Schoenherr, Christina;Bone, Max;Schreyer, Daniel;Purdie, Karin;Thomson, Jason;Rickaby, William;Jackstadt, Rene;Campbell, Andrew D.;Dimonitsas, Emmanouil;Stratigos, Alexander J.;Arron, Sarah T.;Wang, Jun;Blyth, Karen;Proby, Charlotte M.;Harwood, Catherine A.;Sansom, Owen J.;Leigh, Irene M.;Inman, Gareth J.
从紫外线诱导的癌前光化性角化病 (AK) 到恶性侵袭性皮肤鳞状细胞癌 (cSCC) 和潜在致命性转移性疾病的疾病进展的分子基础仍不清楚。 DNA 测序研究揭示了巨大的突变负担，但尚未阐明疾病进展的机制。在这里，我们对代表正常日晒皮肤、AK、原发性和转移性 cSCC 的 110 名患者样本进行 RNAseq 转录组分析，揭示了从分化到祖细胞样状态的疾病连续体。伴随着表皮分化主调节因子的精心策划的抑制、表皮分化复合物的动态调节、免疫景观的重塑以及肿瘤特异性角质形成细胞的优势增加。对人类 cSCC 的比较系统分析以及基因工程小鼠模型的生成表明，肿瘤抑制基因 Tgfbr2、Trp53 和 Notch1 的组合顺序失活与 Ras 信号传导的激活相结合，逐渐驱动 cSCC 沿分化为祖细胞轴发展。总之，我们提供了 cSCC 疾病连续体的全面图谱，并揭示了促进和伴随疾病进展的潜在可操作事件。光化性角化病分化为恶性侵袭性皮肤鳞状细胞癌的过程尚不清楚。在这里，作者使用 RNA-seq 来说明两种状态之间的疾病连续体，并使用体内模型来确认 Tgfbr2、Trp53 和 Notch1 在此过程中的作用。
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. The process by which actinic keratosis differentiates to malignant invasive cutaneous squamous cell carcinoma is unclear. Here, the authors use RNA-seq to illustrate a disease continuum between the two states, and use in vivo models to confirm the role of Tgfbr2, Trp53, and Notch1 in this process.
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影响因子：
12.3
作者：
Fang H;Gough J
通讯作者：
Gough J
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
46.9
作者：
Becht, Etienne;McInnes, Leland;Newell, Evan W.
通讯作者：
Newell, Evan W.
影响因子：
30.8
作者：
Abby, Emilie;Dentro, Stefan C. C.;Hall, Michael W. J.;Fowler, Joanna C. C.;Ong, Swee Hoe;Sood, Roshan;Herms, Albert;Piedrafita, Gabriel;Abnizova, Irina;Siebel, Christian W. W.;Gerstung, Moritz;Hall, Benjamin A. A.;Jones, Philip H. H.
通讯作者：
Jones, Philip H. H.
影响因子：
64.8
作者：
Baslan, Timour;Morris, John P.;Zhao, Zhen;Reyes, Jose;Ho, Yu-Jui;Tsanov, Kaloyan M.;Bermeo, Jonathan;Tian, Sha;Zhang, Sean;Askan, Gokce;Yavas, Aslihan;Lecomte, Nicolas;Erakky, Amanda;Varghese, Anna M.;Zhang, Amy;Kendall, Jude;Ghiban, Elena;Chorbadjiev, Lubomir;Wu, Jie;Dimitrova, Nevenka;Chadalavada, Kalyani;Nanjangud, Gouri J.;Bandlamudi, Chaitanya;Gong, Yixiao;Donoghue, Mark T. A.;Socci, Nicholas D.;Krasnitz, Alex;Notta, Faiyaz;Leach, Steve D.;Iacobuzio-Donahue, Christine A.;Lowe, Scott W.
通讯作者：
Lowe, Scott W.