An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer

KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, a deeper understanding of the molecular mechanisms triggered by KRAS oncogene may yield alternative therapeutic strategies. Here we report the identification of a common transcriptional signature across mutant KRAS cancers of distinct tissue origin that includes the transcription factor FOSL1. High FOSL1 expression identifies mutant KRAS lung and pancreatic cancer patients with the worst survival outcome. Furthermore, FOSL1 genetic inhibition is detrimental to both KRAS-driven tumour types. Mechanistically, FOSL1 links the KRAS oncogene to components of the mitotic machinery, a pathway previously postulated to function orthogonally to oncogenic KRAS. FOSL1 targets include AURKA, whose inhibition impairs viability of mutant KRAS cells. Lastly, combination of AURKA and MEK inhibitors induces a deleterious effect on mutant KRAS cells. Our findings unveil KRAS downstream effectors that provide opportunities to treat KRAS-driven cancers

Role of EPCR in breast cancer progression and metastasis

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

Role of EPCR in breast cancer progression and metastasis

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

Matrix-Gla protein promotes osteosarcoma lung metastasis and associates with poor prognosis

Osteosarcoma (OS) is the most prevalent osseous tumour in children and adolescents and, within this, lung metastases remain one of the factors associated with a dismal prognosis. At present, the genetic determinants driving pulmonary metastasis are poorly understood. We adopted a novel strategy using robust filtering analysis of transcriptomic profiling in tumour osteoblastic cell populations derived from human chemo-naive primary tumours displaying extreme phenotypes (indolent versus metastatic) to uncover predictors associated with metastasis and poor survival. We identified MGP, encoding matrix-Gla protein (MGP), a non-collagenous matrix protein previously associated with the inhibition of arterial calcification. Using different orthotopic models, we found that ectopic expression of Mgp in murine and human OS cells led to a marked increase in lung metastasis. This effect was independent of the carboxylation of glutamic acid residues required for its physiological role. Abrogation of Mgp prevented lung metastatic activity, an effect that was rescued by forced expression. Mgp levels dramatically altered endothelial adhesion, trans-endothelial migration in vitro and tumour cell extravasation ability in vivo. Furthermore, Mgp modulated metalloproteinase activities and TGFβ-induced Smad2/3 phosphorylation. In the clinical setting, OS patients who developed lung metastases had high serum levels of MGP at diagnosis. Thus, MGP represents a novel adverse prognostic factor and a potential therapeutic target in OS. Microarray datasets may be found at: http://bioinfow.dep.usal.es/osteosarcoma/This study was supported by the Unión Temporal de Empresas (UTE) Project FIMA Agreement and Redes Temáticas de Investigación Cooperativa en Cáncer (RETICC) from the Instituto de Salud Carlos III (RTICC; Project Nos RD12/0036/0040 and RD12/0036/0068, and Grant No. PI042282 to FL). FL is the recipient of a Research Project Grant in Child Cancer, Asociación Española Contra el Cáncer (AECC) and the Grants in Aid Program (GAP) of the American Society for Bone and Mineral Research (ASBMR). AP was supported by the Spanish Research Sarcoma Group (GEIS; Grant No. FIS PI13/01476) and a Mari Paz Jimenez Casado Foundation Grant. NP was supported by a Formación de Profesorado Univ rsitario (FPU), AP2010-2197 from the Ministerio de Educación, Cultura y Deporte. CO was supported by a Torres Quevedo Programme from the Ministerio de Economía y Competitividad (MINECO) (PTQ-10-04248).Peer Reviewe

"Ich bin ein Sachse, protestiere aber nicht, wenn mich ein bodenständiger Deutscher für einen Rumänen hält." : das (inter-)kulturelle Portrait Paul Schusters

This article is dedicated to the intercultural aspects of Paul Schuster’s stories (1930-2004), a German writer, born in Sibiu, regarded by German literary historians and criticists as one of the most talented prose writers descending from the small German cultural enclave of Transylvania. His work is thematically focused on events of the past century; The German minority he belongs to plays a decisive role, but also its cohabitation with different ethnic groups in Romania as well as the interethnic relations between them. Interculturality in Paul Schuster's stories is revealed on several levels: cultural exchanges between different ethnic groups, aspects of interethnic collaboration, imagology, linguistic interferences and translations from Romanian authors

Additional file 8: Figure S7. of EPCR promotes breast cancer progression by altering SPOCK1/testican 1-mediated 3D growth

Cell growth kinetics of APC-stimulated breast cancer cell lines. A. MTS proliferation assay of cells stimulated with increasing doses of APC. Data were normalized with absorbance values from day 0. Each dot represents mean ± SD of six replicates. B. Percentage of cells in each phase of the cell cycle in control and 50 nM APC-stimulated cells for 24 and 48 h, in serum-free and 4% serum medium. C. Percentage of apoptotic cells in basal and staurosporine-induced conditions, measured by annexin-V binding flow cytometry assay. Cell lines are MDA-MB-231,1833, BT-549, and ANV5, from the left to the right, in all figure sections. (PPTX 325 kb

Additional file 4: Figure S3. of EPCR promotes breast cancer progression by altering SPOCK1/testican 1-mediated 3D growth

Immunohistochemical analysis of several markers in control and EPCR-silenced size-matched mammary tumors resected at different time points. A. Representative images showing H&E staining (×2.5 magnification) and the immunohistochemical staining of Ki67, cleaved caspase-3, CD31, and F4/80 (×20 magnification) in formaldehyde-fixed tumors. Scale bars 80 μm (H&E) and 10 μm (Ki67, caspase-3, CD31, and F4/80). T. mass, tumor mass. T. border, tumor border. B. Quantification of the percentage of immunoreactive cells. Each dot represents one tumor. Data are mean ± SEM. ns means non-statistical significance. (PPTX 2780 kb