title: A targetable GATA2-IGF2 axis confers aggressiveness in lethal prostate cancer.
abstract: Elucidating the determinants of aggressiveness in lethal prostate cancer may stimulate therapeutic strategies that improve clinical outcomes. We used experimental models and clinical databases to identify GATA2 as a regulator of chemotherapy resistance and tumorigenicity in this context. Mechanistically, direct upregulation of the growth hormone IGF2 emerged as a mediator of the aggressive properties regulated by GATA2. IGF2 in turn activated IGF1R and INSR as well as a downstream polykinase program. The characterization of this axis prompted a combination strategy whereby dual IGF1R/INSR inhibition restored the efficacy of chemotherapy and improved survival in preclinical models. These studies reveal a GATA2-IGF2 aggressiveness axis in lethal prostate cancer and identify a therapeutic opportunity in this challenging disease.
authors: College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Samuel J
authors: SJ
authors: Vidal
authors: Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Veronica
authors: V
authors: Rodriguez-Bravo
authors: Department of Pathology and Cell Biology, Columbia University, New York, NY, USA 10032, USA.
authors: S Aidan
authors: SA
authors: Quinn
authors: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Ruth
authors: R
authors: Rodriguez-Barrueco
authors: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Amaia
authors: A
authors: Lujambio
authors: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Estrelania
authors: E
authors: Williams
authors: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Xiaochen
authors: X
authors: Sun
authors: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Janis
authors: J
authors: de la Iglesia-Vicente
authors: Department of Biomedical Informatics, Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10031, USA.
authors: Albert
authors: A
authors: Lee
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Ben
authors: B
authors: Readhead
authors: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Xintong
authors: X
authors: Chen
authors: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Matthew
authors: M
authors: Galsky
authors: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Berta
authors: B
authors: Esteve
authors: Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT 06510, USA.
authors: Daniel P
authors: DP
authors: Petrylak
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Joel T
authors: JT
authors: Dudley
authors: Department of Biomedical Informatics, Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10031, USA.
authors: Raul
authors: R
authors: Rabadan
authors: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Jose M
authors: JM
authors: Silva
authors: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Yujin
authors: Y
authors: Hoshida
authors: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Scott W
authors: SW
authors: Lowe
authors: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: carlos.cordon-cardo@mssm.edu.
authors: Carlos
authors: C
authors: Cordon-Cardo
authors: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: josep.domingo-domenech@mssm.edu.
authors: Josep
authors: J
authors: Domingo-Domenech
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D050989:GATA2 Transcription Factor / Q000235:genetics*; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008297:Male; D051379:Mice; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D011972:Receptor, Insulin / Q000235:genetics; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D015703:Antigens, CD; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C035170:IGF2 protein, human; D007335:Insulin-Like Growth Factor II; C435941:INSR protein, human; D011972:Receptor, Insulin