Co-Mentor: Michel Maira, PhD
Despite our advanced genetic understanding of uveal melanoma (UM), this malignancy remains incurable in more than 50% of cases, and most patients survive fewer than 12 months after diagnosis of metastases. UM arises through an evolutionary process whereby normal melanocytes located in the uveal tract acquire mutations in genes such as GNAQ, GNA11, and BAP1 that erode growth controls, leading to inappropriate cell proliferation, survival, and dissemination.
Our laboratory is interested in understanding the interplay between genetic alterations in UM and how these contribute to tumor progression, alter treatment response, and create vulnerabilities that may be exploited therapeutically. Our orthogonal approach combines genetic, genomic, bioinformatic, and pharmacological tools that enable us to explore various aspects of UM cancer biology in a comprehensive way. For example, we use short hairpin RNA (shRNA) and CRISPR/Cas9 technology to screen for new cancer drivers and dependencies, both in vitro and in vivo. We also take advantage of low molecular weight inhibitors as well as next-generation sequencing technologies to interrogate and characterize the signaling networks underlying UM genetic aberrations. Ultimately, by identifying and characterizing the genes and pathways that are required for tumor maintenance in established cancers, we aim to identify novel therapeutic strategies.
We work in close collaboration with Dr. Michel Maira in NIBR Oncology as well as with different departments within NIBR and external academic collaborators.
A combinatorial strategy for treating KRAS-mutant lung cancer.
Manchado E, Weissmueller S, Morris JP 4th, Chen CC, Wullenkord R, Lujambio A, de Stanchina E, Poirier JT, Gainor JF, Corcoran RB, Engelman JA, Rudin CM, Rosen N, Lowe SW.
Nature. 2016 Jun 30;534(7609):647-51.
Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor β signaling.
Weissmueller S*, Manchado E*, Saborowski M, Morris JP 4th, Wagenblast E, Davis CA, Moon SH, Pfister NT, Tschaharganeh DF, Kitzing T, Aust D, Markert EK, Wu J, Grimmond SM, Pilarsky C, Prives C, Biankin AV, Lowe SW. *co-first authors
Cell. 2014 Apr 10;157(2):382-394.
Targeting mitotic exit leads to tumor regression in vivo: Modulation by Cdk1, Mastl, and the PP2A/B55α,δ phosphatase.
Manchado E, Guillamot M, de Cárcer G, Eguren M, Trickey M, García-Higuera I, Moreno S, Yamano H, Cañamero M, Malumbres M.
Cancer Cell. 2010 Dec 14;18(6):641-54.
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