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Oncogenic ALK$^{ F1174L }$ drives tumorigenesis in cutaneous squamous cell carcinoma


Gualandi, Marco; Iorio, Maria; Engeler, Olivia; Serra-Roma, André; Gasparre, Giuseppe; Schulte, Johannes H; Hohl, Daniel; Shakhova, Olga (2020). Oncogenic ALK$^{ F1174L }$ drives tumorigenesis in cutaneous squamous cell carcinoma. Life Science Alliance, 3(6):e201900601.

Abstract

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, ALK$^{
F1174L
}$ , is sufficient to initiate the development of cSCC and is 100% penetrant. Moreover, we show that cSCC development upon ALK$^{
F1174L
}$ overexpression is independent of the cell-of-origin. Molecularly, our data demonstrate that ALK$^{
F1174L
}$ cooperates with oncogenic Kras$^{
G12D
}$ 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 ALK$^{
F1174L
}$ and likely plays a role in ALK$^{
F1174L
}$ -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.

Abstract

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, ALK$^{
F1174L
}$ , is sufficient to initiate the development of cSCC and is 100% penetrant. Moreover, we show that cSCC development upon ALK$^{
F1174L
}$ overexpression is independent of the cell-of-origin. Molecularly, our data demonstrate that ALK$^{
F1174L
}$ cooperates with oncogenic Kras$^{
G12D
}$ 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 ALK$^{
F1174L
}$ and likely plays a role in ALK$^{
F1174L
}$ -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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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Oncology and Hematology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Physical Sciences > Ecology
Life Sciences > Biochemistry, Genetics and Molecular Biology (miscellaneous)
Life Sciences > Plant Science
Physical Sciences > Health, Toxicology and Mutagenesis
Language:English
Date:June 2020
Deposited On:04 Feb 2021 15:29
Last Modified:06 Feb 2021 04:34
Publisher:Life Science Alliance
ISSN:2575-1077
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.26508/lsa.201900601
PubMed ID:32312912

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