Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer.

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Embargo End Date

ICR Authors

Carreira, Suzanne
 Gurel, Bora
 De Bono, Johann

Authors

Hermanova, I
Zúñiga-García, P
Caro-Maldonado, A
Fernandez-Ruiz, S
Salvador, F
Martín-Martín, N
Zabala-Letona, A
Nuñez-Olle, M
Torrano, V
Camacho, L
Lizcano, JM
Talamillo, A
Carreira, S
Gurel, B
Cortazar, AR
Guiu, M
López, JI
Martinez-Romero, A
Astobiza, I
Valcarcel-Jimenez, L
Lorente, M
Arruabarrena-Aristorena, A
Velasco, G
Gomez-Muñoz, A
Suárez-Cabrera, C
Lodewijk, I
Flores, JM
Sutherland, JD
Barrio, R
de Bono, JS
Paramio, JM
Trka, J
Graupera, M
Gomis, RR
Carracedo, A

Document Type

Journal Article

Date

2020-06-01

Date Accepted

2020-02-06

Abstract

Gene dosage is a key defining factor to understand cancer pathogenesis and progression, which requires the development of experimental models that aid better deconstruction of the disease. Here, we model an aggressive form of prostate cancer and show the unconventional association of LKB1 dosage to prostate tumorigenesis. Whereas loss of Lkb1 alone in the murine prostate epithelium was inconsequential for tumorigenesis, its combination with an oncogenic insult, illustrated by Pten heterozygosity, elicited lethal metastatic prostate cancer. Despite the low frequency of LKB1 deletion in patients, this event was significantly enriched in lung metastasis. Modeling the role of LKB1 in cellular systems revealed that the residual activity retained in a reported kinase-dead form, LKB1K78I, was sufficient to hamper tumor aggressiveness and metastatic dissemination. Our data suggest that prostate cells can function normally with low activity of LKB1, whereas its complete absence influences prostate cancer pathogenesis and dissemination.

Citation

The Journal of experimental medicine, 2020, 217 (6)

DOI

10.1084/jem.20191787

URI

https://repository.icr.ac.uk/handle/internal/3607

Rights

https://www.rioxx.net/licenses/under-embargo-all-rights-reserved

Source Title

Publisher

ROCKEFELLER UNIV PRESS

ISSN

0022-1007

eISSN

1540-9538

Collections

Cancer Therapeutics
Clinical Studies

Research Team

Cancer Biomarkers
Prostate Cancer Targeted Therapy Group

Notes