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Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness.

PloS one (2015-07-15)
Gorka Ruiz de Garibay, Carmen Herranz, Alicia Llorente, Jacopo Boni, Jordi Serra-Musach, Francesca Mateo, Helena Aguilar, Laia Gómez-Baldó, Anna Petit, August Vidal, Fina Climent, Javier Hernández-Losa, Álex Cordero, Eva González-Suárez, José Vicente Sánchez-Mut, Manel Esteller, Roger Llatjós, Mar Varela, José Ignacio López, Nadia García, Ana I Extremera, Anna Gumà, Raúl Ortega, María Jesús Plà, Adela Fernández, Sònia Pernas, Catalina Falo, Idoia Morilla, Miriam Campos, Miguel Gil, Antonio Román, María Molina-Molina, Piedad Ussetti, Rosalía Laporta, Claudia Valenzuela, Julio Ancochea, Antoni Xaubet, Álvaro Casanova, Miguel Angel Pujana
ABSTRACT

Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.

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