Welcome to
the Gilbert-Ross Lab.
Understanding how cancer cells work
The Gilbert-Ross lab uses a multi-model approach to solve complex problems in cancer biology.
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a) A defining characteristic of cancer is a loss of cell polarity and cell adhesion. Investigations as to whether loss of cell polarity is causative, or a consequence of deregulated cell growth and proliferation has been a major outstanding question in cancer biology. We designed a mosaic screen in the Drosophila eye that mimics a multi-hit model of mammalian tumorigenesis, and identified and characterized myopic (mop), the Drosophila ortholog of mammalian His-domain protein tyrosine phosphatase (HD-PTP). HD-PTP is a substrate adaptor protein of the ESCRT complex which controls endocytic sorting of cell adhesion and growth receptrors. Our work identified the in vivo oncogenic target of Mop/HD-PTP as Yorkie (mammalian Yap1), which is the co-transcriptional activator of the Hippo/Mst2 tumor suppressor pathway.
Check out the original manuscript in Developmental Cell https://www.cell.com/developmental-cell/fulltext/S1534-5807(11)00163-8
b) Our more recent work extends to human HD-PTP where we found that loss-of-function alterations in the gene that encodes HD-PTP (PTPN23) occur in up to 14% of lung cancers in the ORIEN Avatar lung cancer cohort, and significantly associate with adenosquamous histology. Knockdown of HD-PTP in RAS-transformed lung cancer cells is sufficient to promote FAK-dependent invasion in vitro, and studies in Drosophila show that Mop synergizes to promote RAS-dependent neoplastic progression in vivo. Our findings support HD-PTP as a bone fide lung tumor suppressor.
Check out our findings in the preprint in bioRxiv
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The acquisition of invasive properties is a prerequisite for tumor progression and metastasis. Molecular subtypes of KRAS-driven lung cancer exhibit distinct modes of invasion that contribute to unique growth properties and therapeutic susceptibilities. We screened for targetable signaling pathways linked to early invasion phenotypes in the two most prominent molecular subtypes, TP53 and LKB1, of KRAS-driven lung adenocarcinoma (LUAD). By combining live-cell imaging of human bronchial epithelial cells in a 3D invasion matrix with RNA transcriptome profiling, we identified the LKB1-specific upregulation of bone morphogenetic protein 6 (BMP6). Examination of early-stage lung cancer patients confirmed upregulation of BMP6 in LKB1-mutant lung tumors. At the molecular level, we found that the canonical iron regulatory hormone Hepcidin is induced via BMP6 signaling upon LKB1 loss, where intact LKB1 kinase activity is necessary to maintain signaling homeostasis. Furthermore, pre-clinical studies in a novel Kras/Lkb1-mutant syngeneic mouse model show that potent growth suppression was achieved by inhibiting the ALK2/BMP6 signaling axis with single agents that are currently in clinical trials.
Check out the original manuscript in Cancer Research
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Close-up study
The Gilbert-Ross Lab studies the molecular and cell biologic mechanisms that drive lung cancer tumor progression and metastasis. Mutations in the tumor suppressor LKB1 are present in up to 30% of patients, and collaborate with mutations in KRAS to produce aggressive lung tumors that are refractory to both standard and targeted therapies.
With flourescent markers
In order to study how KRAS LKB1-mutant cells gain a metastatic advantage in the tumor microenvironment, Dr. Gilbert-Ross applies their expertise in tissue-specific mosaic analysis to fluorescently mark KrasG12D Lkb1fl/fl mutant cells in vivo in a mouse model of non-small cell lung cancer (NSCLC).
High resolution
High resolution tumor invasion imaging lets us see how cancer cells react and respond to treatment in real time.
Of live tumor invasion in fruit flies
The Gilbert-Ross Lab studies Drosophila (commonly known as a fruit fly) cells and watches how they respond to live tumor invasion imaging.
