Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer

被引：22

作者：

Hermanova, Ivana ^{[1
]}

Zuniga-Garcia, Patricia ^{[1
]}

Caro-Maldonado, Alfredo ^{[1
]}

Fernandez-Ruiz, Sonia ^{[1
,2
]}

Salvador, Fernando ^{[2
,3
]}

Martin-Martin, Natalia ^{[1
,2
]}

Zabala-Letona, Amaia ^{[1
,2
]}

Nunez-Olle, Marc ^{[3
]}

Torrano, Veronica ^{[1
,2
,4
]}

Camacho, Laura ^{[1
,4
]}

Lizcano, Jose M. ^{[5
,6
]}

Talamillo, Ana ^{[1
]}

Carreira, Suzanne ^{[7
]}

Gurel, Bora ^{[7
]}

Cortazar, Ana R. ^{[1
,2
]}

Guiu, Marc ^{[3
]}

Lopez, Jose, I ^{[8
]}

Martinez-Romero, Anabel ^{[2
,9
]}

Astobiza, Ianire ^{[1
,2
]}

Valcarcel-Jimenez, Lorea ^{[1
]}

Lorente, Mar ^{[10
]}

Arruabarrena-Aristorena, Amaia ^{[1
]}

Velasco, Guillermo ^{[10
,11
]}

Gomez-Munoz, Antonio ^{[4
]}

Suarez-Cabrera, Cristian ^{[12
,13
]}

Lodewijk, Iris ^{[12
,13
]}

Flores, Juana M. ^{[14
]}

Sutherland, James D. ^{[1
]}

Barrio, Rosa ^{[1
]}

de Bono, Johann S. ^{[7
,15
]}

Paramio, Jesus M. ^{[2
,12
,13
]}

Trka, Jan ^{[16
,17
,18
]}

Graupera, Mariona ^{[2
,9
]}

Gomis, Roger R. ^{[2
,3
,19
]}

Carracedo, Arkaitz ^{[1
,2
,4
,20
]}

机构：

[1] BRTA, Ctr Cooperat Res Biosci, Derio, Spain

[2] CIBERONC Ctr Invest Biomed Red Canc, Madrid, Spain

[3] Barcelona Inst Sci & Technol, Inst Res Biomed, Canc Sci Program, Barcelona, Spain

[4] Univ Basque Country, Biochem & Mol Biol Dept, Bilbao, Spain

[5] Univ Autonoma Barcelona, Inst Neurociencies, Prot Kinases & Signal Transduct Lab, Barcelona, Spain

[6] Univ Autonoma Barcelona, Dept Bioquim & Biol Mol, Barcelona, Spain

[7] Inst Canc Res, London, England

[8] Univ Basque Country, Cruces Univ Hosp, Biocruces Inst, Dept Pathol, Baracaldo, Spain

[9] Inst Invest Biomed Bellvitge, Vasc Signalling Lab, Program Canc Therapeut Resistance ProCURE, Barcelona, Spain

[10] Univ Complutense Madrid, Sch Biol, Dept Biochem & Mol Biol, Madrid, Spain

[11] Inst Invest Sanitarias San Carlos, Madrid, Spain

[12] Hosp Univ 12 Octubre, Grp Oncol Celular & Mol, Madrid, Spain

[13] Ctr Invest Energet Medioambientales & Tecnol, Unidad Oncol Mol, Madrid, Spain

[14] Univ Complutense Madrid, Sch Vet Med, Dept Anim Med & Surg, Madrid, Spain

[15] Royal Marsden Natl Hlth Serv Fdn Trust, London, England

[16] Childhood Leukaemia Invest, Prague, Czech Republic

[17] Charles Univ Prague, Fac Med 2, Dept Paediat Haematol Oncol, Prague, Czech Republic

[18] Univ Hosp Motol, Prague, Czech Republic

[19] Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain

[20] Basque Fdn Sci, Ikerbasque, Bilbao, Spain

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2020年 / 217卷 / 06期

基金：

欧盟地平线“2020”; 欧洲研究理事会;

关键词：

CONSENSUS REPORT; MOUSE MODELS; PTEN LEADS; NEOPLASIA; CLASSIFICATION; EXPRESSION; HALLMARKS; PATHOLOGY; MUTATION; MARKERS;

D O I：

10.1084/jem.20191787

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 Lkbl 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, LKB1(K781), 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.

引用

页数：19

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