Lymphangioleiomyomatosis (LAM), a genetic disorder characterized by widespread lesions of smooth muscle-like LAM cells, induces cystic destruction of the lung leading to the loss of pulmonary function for which no therapy exists. LAM is associated with mutational inactivation of the tumor suppressors tuberous sclerosis complex 1 (TSC1) and TSC2;loss of TSC2, in particular, is correlated with disease severity and tumor growth. Our previous studies demonstrate that inactivating mutations in TSC2 constitutively stimulates S6K1 signaling pathway promoting LAM cell growth. Our new preliminary data show that TSC1 and TSC2 may have differential roles in regulating S6K1 signaling via differential activation of the mammalian target of rapamycin (mTOR)/Raptor and mTOR/Rictor pathways. We also found that LAM and TSC2-/- cells escape the anti-proliferative effects of interferon (IFNs) in vitro and in vivo due to the constitutive activation of S6K1 and loss of TSC2 function. In this application, we will test our hypothesis that loss of TSC1 and TSC2 results in LAM cell proliferation due to dysregulation of the two processes: cell growth by the activation of mTOR/Raptor-S6K1 and cell cycle progression by the activation of mTOR/Rictor-Rac1. The constitutive activation of the mTOR-S6K1 signaling pathway due to TSC1/TSC2 loss of function abrogates the anti-proliferative activities of IFNs.
In Aim 1, we will determine whether mTOR/Raptor-S6K1 and mTOR/Rictor- Rac1 are necessary and sufficient, to promote LAM cell growth and proliferation.
In Aim 2, we will define whether the loss of TSC1/TSC2 and the constitutive activation of S6K1 abrogate the anti-proliferative activities of IFNs in LAM, TSC1-/-, and TSC2-/- cells.
In Aim 3, we will examine the, in vivo, role of the constitutively activated S6K1 due to TSC1 or TSC2 loss on tumorigenesis, and establish the translational possibilities for the combined treatment of these tumors with rapamycin and IFNs. These studies will define the key cellular and molecular mechanisms by which the constitutive activation of S6K1 regulates LAM cell growth, and will provide insight into the therapeutic targets that may prevent or abrogate cell growth in LAM.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071106-08
Application #
7778256
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Peavy, Hannah H
Project Start
2002-07-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
8
Fiscal Year
2010
Total Cost
$354,375
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Goncharova, Elena A; James, Melane L; Kudryashova, Tatiana V et al. (2014) Tumor suppressors TSC1 and TSC2 differentially modulate actin cytoskeleton and motility of mouse embryonic fibroblasts. PLoS One 9:e111476
Krymskaya, Vera P (2012) Treatment option(s) for pulmonary lymphangioleiomyomatosis: progress and current challenges. Am J Respir Cell Mol Biol 46:563-5
Goncharova, Elena A; Goncharov, Dmitry A; Fehrenbach, Melane et al. (2012) Prevention of alveolar destruction and airspace enlargement in a mouse model of pulmonary lymphangioleiomyomatosis (LAM). Sci Transl Med 4:154ra134
Goncharova, Elena A; Goncharov, Dmitry A; Li, Hua et al. (2011) mTORC2 is required for proliferation and survival of TSC2-null cells. Mol Cell Biol 31:2484-98
Krymskaya, Vera P; Snow, Jennifer; Cesarone, Gregory et al. (2011) mTOR is required for pulmonary arterial vascular smooth muscle cell proliferation under chronic hypoxia. FASEB J 25:1922-33
Goncharova, Elena A; Lim, Poay N; Chisolm, Amelia et al. (2010) Interferons modulate mitogen-induced protein synthesis in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 299:L25-35
Krymskaya, Vera P; Goncharova, Elena A (2009) PI3K/mTORC1 activation in hamartoma syndromes: therapeutic prospects. Cell Cycle 8:403-13
Goncharova, Elena A; Goncharov, Dmitry A; Damera, Gautam et al. (2009) Signal transducer and activator of transcription 3 is required for abnormal proliferation and survival of TSC2-deficient cells: relevance to pulmonary lymphangioleiomyomatosis. Mol Pharmacol 76:766-77
Goncharova, Elena A; Goncharov, Dmitry A; Chisolm, Amelia et al. (2008) Interferon beta augments tuberous sclerosis complex 2 (TSC2)-dependent inhibition of TSC2-null ELT3 and human lymphangioleiomyomatosis-derived cell proliferation. Mol Pharmacol 73:778-88
Krymskaya, Vera P (2008) Smooth muscle-like cells in pulmonary lymphangioleiomyomatosis. Proc Am Thorac Soc 5:119-26

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