Perurena, N. (Naiara)

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2012 - 20152

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    Receptor of Activated Protein C Promotes Metastasis and Correlates with Clinical Outcome in Lung Adenocarcinoma
    (American Thoracic Society, 2012) Pajares, M.J. (María José); Ormazábal, C. (Cristina); Agorreta, J. (Jackeline); Hermida, J. (José); Martinez-Canarias, S. (Susana); Luis-Ravelo, D. (Diego); Perurena, N. (Naiara); Rivas, J. (Javier) de las; Montuenga-Badia, L.M. (Luis M.); Molina, E. (Eva); Valencia, K. (Karmele); Wistuba, I.I. (Ignacio I.); Anton, I. (Iker); Lecanda, F. (Fernando); Segura, V. (Víctor); Zandueta, C. (Carolina)
    RATIONALE: Efficient metastasis requires survival and adaptation of tumor cells to stringent conditions imposed by the extracellular milieu. Identification of critical survival signaling pathways in tumor cells might unveil novel targets relevant in disease progression. OBJECTIVES: To investigate the contribution of activated protein C (APC) and its receptor (EPCR) in animal models of lung cancer metastasis and in patients with lung adenocarcinoma. METHODS: Signaling pathway triggered by APC/EPCR and its relevance in apoptosis was studied in vitro. Functional significance was assessed by silencing and blocking antibodies in several in vivo models of lung cancer metastasis. We examined EPCR levels using a microarray dataset of 107 patients. Immunohistochemical analysis was performed in an independent cohort of 295 patients with lung adenocarcinoma. MEASUREMENTS AND MAIN RESULTS: The effects of APC binding to EPCR rapidly triggered Akt and ERK signaling pathways, leading to attenuated in vitro apoptosis. In vivo, silencing of EPCR expression or blocking APC/EPCR interaction reduced homing resulting in impaired prometastatic activity. Moreover, overexpression of EPCR induced an increase metastatic activity to target organs. Analysis of clinical samples showed a robust association between high EPCR levels and poor prognosis particularly in stage I patients. CONCLUSIONS: EPCR and its ligand APC promote cell survival that contributes to tumor cell endurance to stress favoring prometastatic activity of lung adenocarcinoma (ADC). EPCR/APC is a novel target of relevance in the clinical outcome of early-stage lung cancer.
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    Role of EPCR in breast cancer progression and metastasis
    (2015-08-27) Perurena, N. (Naiara); Lecanda, F. (Fernando)
    Endothelial protein C receptor (EPCR) is a transmembrane receptor widely expressed in endothelial cells where it exerts cytoprotective and anticoagulant activities. It is also expressed in lung tumor cells where EPCR promotes tumor cell survival and increases metastatic activity. However, to date the contribution of EPCR to tumorigenesis and metastasis in breast cancer remains ill defined. Global expression analysis in a cohort of 286 breast cancer patients revealed that patients with high EPCR expression levels have significantly shorter relapse-free survival times. In vitro, stimulation with activated protein C (APC) or shRNA-mediated EPCR silencing did not alter growth kinetics of bone metastatic human breast cancer cells in basal or pro-apoptotic conditions. However, subcutaneous and orthotopic inoculation of control and EPCR-silenced (shEPCR) bone metastatic cells showed a marked reduction in tumor growth, while markers of cell growth, apoptosis and angiogenesis were unaffected. EPCR effects on tumorigenesis were independent of heterotypic tumor-stroma interactions, including fibroblasts and immune cells. Interestingly, EPCR silencing led to a substantial reduction in skeletal metastatic burden and osteolytic lesions in an intracardiac inoculation model, compared to control cells. Moreover, EPCR silencing reduced tumor bone colonization in a model of intratibial injection. Furthermore, lung metastasis was blocked in another in vivo model of metastasis when EPCR was silenced in murine breast tumor cells, despite their similar growth kinetics in vitro. Transcriptomic analysis of tumors identified SPOCK1 as the most robustly downregulated gene in EPCR-silenced tumors. Furthermore, SPOCK1 expression levels were associated with high EPCR expression levels in breast cancer patients and correlated with shorter relapse-free survival times in a subset of breast cancer patients. These data indicate that EPCR is a clinically relevant factor in breast cancer, which promotes primary tumor growth and metastatic activity in target organs, including the skeleton and lungs. Taken together, these data suggest that EPCR represents a potential therapeutic target in breast cancer metastasis.