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Transcription profiling of human highly metastatic cell lines derived from Non-Small Cell Lung Carcinoma (NSCLC) with specific bone tropism reveals a novel lung cancer gene signature mediates metastatic bone colonization by a dual mechanism

ABSTRACT: Bone is a frequent target of lung cancer metastasis, which is associated with significant morbidity and a dismal prognosis. To identify and functionally characterize genes involved in the mechanisms of osseous metastasis we developed a murine lung cancer model. Comparative transcriptomic analysis identified genes encoding signaling molecules (such as TCF4 and PRKD3), and cell anchorage related proteins (MCAM, and SUSD5), some of which were basally modulated by TGFbeta in tumor cells and in conditions mimicking tumor-stroma interactions. Triple gene combinations induced not only high osteoclastogenic activity but also a marked enhancement of global metalloproteolytic activities in vitro. These effects were strongly associated with robust bone colonization in vivo, whereas this gene subset was ineffective in promoting local tumor growth and cell homing activity to bone. Interestingly, global inhibition of metalloproteolytic activities and simultaneous TGFbeta blockade in vivo led to increased survival and a remarkable attenuation of bone tumor burden and osteolytic metastasis. Thus, this metastatic gene signature mediates bone-matrix degradation by a dual mechanism of induction of TGFbeta-dependent osteoclastogenic bone resorption and enhancement of stroma-dependent metalloproteolytic activities. Our findings suggest the cooperative contribution of host-derived and cell-autonomous effects directed by a small subset of genes in mediating aggressive osseous colonization. Experiment Overall Design: Human highly metastatic cell lines derived from Non-Small Cell Lung Carcinoma (NSCLC) with specific bone tropism. Cell lines were selected by induction of prominent bone metastases lesions. The metastatic lines were systematically and accurately discriminate using 3 complementary parameters: survival curves of newly injected mice; computerized image analysis of bone metastatic areas; conspicuous SCCs derived from each animal (10 mice/group). Experiment Overall Design: Genome-wide expression analysis was done using 13 microarrays, corresponding to 4 samples of control non-metastatic cell lines and 9 samples of 3 different highly metastatic cell lines (M1, M4, M5) each with 3 biological replicates. Moreover, in each microarray pools of 3 groups of the corresponding cells were used.

ORGANISM(S): Homo sapiens

SUBMITTER: Rivas Javier De Las

PROVIDER: S-ECPF-GEOD-10096 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Bone is a frequent target of lung cancer metastasis, which is associated with significant morbidity and a dismal prognosis. To identify and functionally characterize genes involved in the mechanisms of osseous metastasis we developed a murine lung cancer model. Comparative transcriptomic analysis identified genes encoding signaling molecules (such as TCF4 and PRKD3), and cell anchorage related proteins (MCAM, and SUSD5), some of which were basally modulated by TGFbeta in tumor cells and in conditions mimicking tumor-stroma interactions. Triple gene combinations induced not only high osteoclastogenic activity but also a marked enhancement of global metalloproteolytic activities in vitro. These effects were strongly associated with robust bone colonization in vivo, whereas this gene subset was ineffective in promoting local tumor growth and cell homing activity to bone. Interestingly, global inhibition of metalloproteolytic activities and simultaneous TGFbeta blockade in vivo led to increased survival and a remarkable attenuation of bone tumor burden and osteolytic metastasis. Thus, this metastatic gene signature mediates bone-matrix degradation by a dual mechanism of induction of TGFbeta-dependent osteoclastogenic bone resorption and enhancement of stroma-dependent metalloproteolytic activities. Our findings suggest the cooperative contribution of host-derived and cell-autonomous effects directed by a small subset of genes in mediating aggressive osseous colonization. Experiment Overall Design: Human highly metastatic cell lines derived from Non-Small Cell Lung Carcinoma (NSCLC) with specific bone tropism. Cell lines were selected by induction of prominent bone metastases lesions. The metastatic lines were systematically and accurately discriminate using 3 complementary parameters: survival curves of newly injected mice; computerized image analysis of bone metastatic areas; conspicuous SCCs derived from each animal (10 mice/group). Experiment Overall Design: Genome-wide expression analysis was done using 13 microarrays, corresponding to 4 samples of control non-metastatic cell lines and 9 samples of 3 different highly metastatic cell lines (M1, M4, M5) each with 3 biological replicates. Moreover, in each microarray pools of 3 groups of the corresponding cells were used.

Project description:The majority of the deaths from breast cancer is due to metastasis. Bone is the most common organ to which breast cancer cells metastasize. The mechanism regulating the bone-metastatic preference remains unclear; there is a lack of a gene signature to distinguish bone-metastatic breast cancer cells. Herein, florescence-labeled MDA-MB-231 cells were transplanted into the fat pads of of the mammary gland in nude mice to generate breast tumors. Tumor cells invaded into the circulation were tracked by in vivo flow cytometry system. Metastatic tumor cells in the bone were isolated using fluorescent-activated cell sorting technique, followed by assays of cell colony formation, migration and invasion, mammosphere formation in vitro, mammary gland tumorigenesis in vivo, and Next-Generation Sequencing analysis as well. Through tumor regeneration and cell sorting, two bone-metastatic cell sublines were derived from MDA-MB-231 cells; which showed higher abilities to proliferate, migrate, invade and epithelial-to-mesenchymal transit in vitro, and stronger ability to regenerate tumors and metastasize to the bone in vivo. Both cell sublines exhibited cancer stem cell-like characteristics including higher expression levels of stem cell markers and stronger ability for mommaspheres formation. Furthermore, a Normal Distribution-like pattern of the bone-metastatic cells invading into circulation was firstly identified. Deep-sequencing analysis indicated upregulation of multiple signaling pathways in regulating EMT, cell membrane budding and morphologic change, lipid metabolism, and protein translation, which are required to provide adequate metabolic enzymes, structural proteins, and energy for the cells undergoing metastasis. In conclusion, we established two bone-metastatic breast cancer cell sublines, carrying higher degree of stemness and malignancy. The gene signature distinguishing the bone-metastatic breast cancer cells holds therapeutic potentials in prevention of breast cancer metastasis to the bone.

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Transcription profiling of human highly metastatic cell lines derived from Non-Small Cell Lung Carcinoma (NSCLC) with specific bone tropism reveals a novel lung cancer gene signature mediates metastatic bone colonization by a dual mechanism

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