BRafV600E cooperates with Pten silencing to elicit metastatic melanoma

By D. Dankort, D. Curley, Robert A. Cartlidge, Betsy M. Nelson, A. Karnezis, William Damsky, M. J. You, R. DePinho, M. McMahon, M. Bosenberg. Nature Genetics, 2009

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Mutational activation of BRAF is the earliest and most common genetic alteration in human melanoma. To build a model of human melanoma, we generated mice with conditional melanocyte-specific expression of BRafV600E. Upon induction of BRafV600E expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15–20 months. By contrast, expression of BRafV600E combined with Pten tumor suppressor gene silencing elicited development of melanoma with 100% penetrance, short latency and with metastases observed in lymph nodes and lungs. Melanoma was prevented by inhibitors of mTorc1 (rapamycin) or MEK1/2 (PD325901) but, upon cessation of drug administration, mice developed melanoma, indicating the presence of long-lived melanoma-initiating cells in this system. Notably, combined treatment with rapamycin and PD325901 led to shrinkage of established melanomas. These mice, engineered with a common genetic profile to human melanoma, provide a system to study melanoma's cardinal feature of metastasis and for preclinical evaluation of agents designed to prevent or treat metastatic disease.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/5ed1c46edad1ca612b939b1c95e2111c023f0ed3

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Citations in the corpus

STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors (2014, methodology): “Therefore, a genetic melanoma model was employed, driven by conditional active B-Raf expression and PTEN deletion in the melanocyte lineage using tyrosinase-CreER (Dankort et al., 2009).”
Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy (2017, neutral): “…MacMahon), loxP-Pten (provided by Tak Mak), loxP-CAT-STA (provided by Fotini Gounari), loxP-rosa-SIY and loxP-rosa-YFP (Jackson Laboratories, strain 006148) (Bosenberg et al., 2006; Dankort et al., 2009; DuPage et al., 2012; Gounari et al., 2002; Sirma Ekmekci et al., 2012; Spranger et al., 2015) .”
PTEN loss in the continuum of common cancers, rare syndromes and mouse models (2011, positive): “Simultaneous activation of BRAF and deletion of Pten in melanocytes leads toearly onset spontaneous melanomas, with metastasis to the lymph nodes and lun”
Systemic Immunity is Required for Effective Cancer Immunotherapy (2017, neutral): “Similar results were found in a genetically engineered inducible mouse model of melanoma driven byBrafV600E and loss of Pten (referred to as BP melanoma mice) on day 8 after treatment with effective therapy (Figure S3A) (Dankort et al., 2009).”
Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging (2011, result): “In contrast, another group of researchers generated mice that conditionally-expressed melanocyte-specific B-Raf that were only able to induce benign melanocytic hyperplasias and were unable to progress any further over a 15-20 month period [128].”
Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF (2013, positive): “In mice, activation of BRAF in combination with deletion of the tumor suppressor genes PTEN or INK4A leads to melanoma with complete penetrance (Dankort et al., 2009; Dhomen et al., 2009).”
The essence of senescence. (2010, background): “In contrast, in combination with a mutant Braf knock-in allele, loss of Pten produced aggressive tumorsmuch resembling human metastatic melanoma (Dankort et al. 2009).”
In vivo identification of tumor suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma (2011, positive): “In mice, complete or partial PTEN loss dramatically accelerates BRAFV600E-induced melanoma (Dankort et al., 2009), thus highlighting the oncogenic potential of combined hyperactivation of PI3K/AKT and MAPK signaling.”
Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF (2010, background): “It has been shown that V600EBRAF is 500-fold activated, can stimulates constitutive MEK–ERK signaling in cells (Gray-Schopfer et al., 2007) and induce melanoma in mice (Dankort et al., 2009; Dhomen et al., 2009), showing that it can be a founder mutation in melanoma.”
Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses (2015, methodology): “…and hence, effector functions in TILs, we first compared the concentration of glucose in the interstitial fluid of the spleen, blood, and tumors from melanoma-bearing Tyr-creERT2/BrafV600E/Ptenlox (Braf/Pten) mice (Dankort et al., 2009) (Figure 1A) and B16 melanoma-bearing mice (data not shown).”