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Lam, Hilaire

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Lam

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Hilaire

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Lam, Hilaire

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2014 - 20173

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Author's Publications: search.filters.isAuthorOfPublication.f38d3004-8ae8-4c5c-abc6-abef5787aef2

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    Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex
    (The Rockefeller University Press, 2014) Liang, Ning; Zhang, Chi; Dill, Patricia; Panasyuk, Ganna; Pion, Delphine; Koka, Vonda; Gallazzini, Morgan; Olson, Eric N.; Lam, Hilaire; Henske, Elizabeth; Dong, Zheng; Apte, Udayan; Pallet, Nicolas; Johnson, Randy L.; Terzi, Fabiola; Kwiatkowski, David; Scoazec, Jean-Yves; Martignoni, Guido; Pende, Mario
    Genetic studies have shown that the tuberous sclerosis complex (TSC) 1–TSC2–mammalian target of Rapamycin (mTOR) and the Hippo–Yes-associated protein 1 (YAP) pathways are master regulators of organ size, which are often involved in tumorigenesis. The crosstalk between these signal transduction pathways in coordinating environmental cues, such as nutritional status and mechanical constraints, is crucial for tissue growth. Whether and how mTOR regulates YAP remains elusive. Here we describe a novel mouse model of TSC which develops renal mesenchymal lesions recapitulating human perivascular epithelioid cell tumors (PEComas) from patients with TSC. We identify that YAP is up-regulated by mTOR in mouse and human PEComas. YAP inhibition blunts abnormal proliferation and induces apoptosis of TSC1–TSC2-deficient cells, both in culture and in mosaic Tsc1 mutant mice. We further delineate that YAP accumulation in TSC1/TSC2-deficient cells is due to impaired degradation of the protein by the autophagosome/lysosome system. Thus, the regulation of YAP by mTOR and autophagy is a novel mechanism of growth control, matching YAP activity with nutrient availability under growth-permissive conditions. YAP may serve as a potential therapeutic target for TSC and other diseases with dysregulated mTOR activity.
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    mTORC1 Couples Nucleotide Synthesis to Nucleotide Demand Resulting in a Targetable Metabolic Vulnerability
    (Elsevier BV, 2017-11-13) Valvezan, Alexander J.; Turner, Marc; Belaid, Amine; Lam, Hilaire; Miller, Spencer K.; Mcnamara, Molly; Baglini, Christian; Housden, Benjamin; Perrimon, Norbert; Kwiatkowski, David; Asara, John; Henske, Elizabeth; Manning, Brendan
    The mechanistic target of rapamycin complex 1 (mTORC1) supports proliferation through parallel induction of key anabolic processes, including protein, lipid, and nucleotide synthesis. We hypothesized that these processes are coupled to maintain anabolic balance in cells with mTORC1 activation, a common event in human cancers. Loss of the tuberous sclerosis complex (TSC) tumor suppressors results in activation of mTORC1 and development of the tumor syndrome TSC. We find that pharmacological inhibitors of guanylate nucleotide synthesis have selective deleterious effects on TSC-deficient cells, including in mouse tumor models. This effect stems from replication stress and DNA damage caused by mTORC1-driven ribosomal RNA synthesis, which renders nucleotide pools limiting. These findings reveal a metabolic vulnerability downstream of mTORC1 triggered by anabolic imbalance.
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    Rapamycin-induced miR-21 promotes mitochondrial homeostasis and adaptation in mTORC1 activated cells
    (Impact Journals LLC, 2017) Lam, Hilaire; Liu, Heng-Jia; Baglini, Christian V.; Filippakis, Harilaos; Alesi, Nicola; Nijmeh, Julie; Du, Heng; Lope, Alicia Llorente; Cottrill, Katherine A.; Handen, Adam; Asara, John; Kwiatkowski, David; Ben-Sahra, Issam; Oldham, William; Chan, Stephen Y.; Henske, Elizabeth
    mTORC1 hyperactivation drives the multi-organ hamartomatous disease tuberous sclerosis complex (TSC). Rapamycin inhibits mTORC1, inducing partial tumor responses; however, the tumors regrow following treatment cessation. We discovered that the oncogenic miRNA, miR-21, is increased in Tsc2-deficient cells and, surprisingly, further increased by rapamycin. To determine the impact of miR-21 in TSC, we inhibited miR-21 in vitro. miR-21 inhibition significantly repressed the tumorigenic potential of Tsc2-deficient cells and increased apoptosis sensitivity. Tsc2-deficient cells’ clonogenic and anchorage independent growth were reduced by ∼50% (p<0.01) and ∼75% (p<0.0001), respectively, and combined rapamycin treatment decreased soft agar growth by ∼90% (p<0.0001). miR-21 inhibition also increased sensitivity to apoptosis. Through a network biology-driven integration of RNAseq data, we discovered that miR-21 promotes mitochondrial adaptation and homeostasis in Tsc2-deficient cells. miR-21 inhibition reduced mitochondrial polarization and function in Tsc2-deficient cells, with and without co-treatment with rapamycin. Importantly, miR-21 inhibition limited Tsc2-deficient tumor growth in vivo, reducing tumor size by approximately 3-fold (p<0.0001). When combined with rapamcyin, miR-21 inhibition showed even more striking efficacy, both during treatment and after treatment cessation, with a 4-fold increase in median survival following rapamycin cessation (p=0.0008). We conclude that miR-21 promotes mTORC1-driven tumorigenesis via a mechanism that involves the mitochondria, and that miR-21 is a potential therapeutic target for TSC-associated hamartomas and other mTORC1-driven tumors, with the potential for synergistic efficacy when combined with rapalogs.