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| Status |
Public on Apr 15, 2020 |
| Title |
Oncogenic ALKF1174L drives tumorigenesis in cutaneous squamous cell carcinoma |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer characterized by increased mortality. Here, we show for the first time that anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase of the insulin receptor superfamily, plays a pivotal role in the pathogenesis of cSCC. Our data demonstrate that the overexpression of the constitutively active, mutated ALK, ALKF1174L is sufficient to initiate the development of cSCC and is 100% penetrant. Moreover, we show that cSCC development upon ALKF1174L overexpression is independent of the cell-of-origin. Molecularly, our data demonstrate that ALKF1174L cooperates with oncogenic KrasG12D and loss of p53, well established events in the biology of cSCC. This cooperation results in a more aggressive cSCC type associated with a higher-grade histological morphology. Finally, we demonstrate that Stat3 is a key downstream effector of ALKF1174L and is indispensable for ALKF1174L-driven cSCC tumorigenesis. In sum, these findings reveal that ALK can exert its tumorigenic potential via cooperation with multiple pathways crucial in the pathogenesis of cSCC. Finally, we show that human cSCCs contain mutations in the ALK gene. Taken together, our data identify ALK as a new key player in the pathogenesis of cSCC and this knowledge suggests that oncogenic ALK signaling can be a target for future clinical trials.
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| Overall design |
mRNA profiles of FACS-sorted tumor cells from ear cSCC from ALKF1174L Lgr5-CreERT2 mice, ALKF1174LKrasG12D Lgr5-CreERT2 mice and from sorted normal ear skin keratinocytes of cre negative siblings were produced in triplicate.
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| Contributor(s) |
Gualandi M, Iorio M, Engeler O, Serra-Roma A, Gasparre G, Schulte J, Hohl D, Shakhova O |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Mar 27, 2020 |
| Last update date |
Apr 17, 2020 |
| Contact name |
giancarlo russo |
| E-mail(s) |
giancarlo.russo@fgcz.ethz.ch
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| Organization name |
ETH/University of Zurich
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| Department |
Functional Genomics Center Zurich
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| Street address |
winterthurerstrasse 190
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| City |
Zurich |
| State/province |
Schweiz |
| ZIP/Postal code |
8057 |
| Country |
Switzerland |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (9)
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| Relations |
| BioProject |
PRJNA615866 |
| SRA |
SRP254328 |
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