Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Gene expression profiling of metastatic lung cancer cell lines

ABSTRACT: During malignant disease progression, the extracellular matrix (ECM) of epithelial tumors accumulates inter-molecular cross-links between collagen strands; these cross-links enhance ECM stiffness and trigger tumor cell invasion and dissemination, but the mechanisms that regulate intra-tumoral collagen maturation have not been fully defined. Using a new mouse model of metastatic lung adenocarcinoma driven by mutant K-ras expression and Cdkn1a inactivation, we showed that tumor cell invasion and metastasis are driven by high expression of lysyl hydroxylase 2 (LH2), an enzyme that hydroxylates telomeric lysine (Lys) residues on collagen. We interbred KrasLA1 mice, which develop non-metastatic lung adenocarcinomas at 8-10 months of age because of the expression of a somatically activated K-rasG12D allele, with Cdkn1a-/- mice, which develop sarcomas and B cell lymphomas because of depletion of p21. Cohorts were generated that had neither, either, or both mutant alleles. KrasLA1 mice that were p21-deficient (KC mice) had a shorter mean time to death than did p21-replete ones. We established cell lines from the tumors, and compared cell lines from highly metastatic tumors with those from poorly metastatic tumors.

ORGANISM(S): Mus musculus

SUBMITTER: Chad Creighton

PROVIDER: E-GEOD-49315 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma.

Chen Yulong Y Terajima Masahiko M Yang Yanan Y Sun Li L Ahn Young-Ho YH Pankova Daniela D Puperi Daniel S DS Watanabe Takeshi T Kim Min P MP Blackmon Shanda H SH Rodriguez Jaime J Liu Hui H Behrens Carmen C Wistuba Ignacio I II Minelli Rosalba R Scott Kenneth L KL Sanchez-Adams Johannah J Guilak Farshid F Pati Debananda D Thilaganathan Nishan N Burns Alan R AR Creighton Chad J CJ Martinez Elisabeth D ED Zal Tomasz T Grande-Allen K Jane KJ Yamauchi Mitsuo M Kurie Jonathan M JM

The Journal of clinical investigation 20150209 3

Epithelial tumor metastasis is preceded by an accumulation of collagen cross-links that heighten stromal stiffness and stimulate the invasive properties of tumor cells. However, the biochemical nature of collagen cross-links in cancer is still unclear. Here, we postulated that epithelial tumorigenesis is accompanied by changes in the biochemical type of collagen cross-links. Utilizing resected human lung cancer tissues and a p21CIP1/WAF1-deficient, K-rasG12D-expressing murine metastatic lung can ...[more]

PMID: 25664850

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Project description:Metastatic disease is a primary cause of cancer-related death, and factors governing tumor cell metastasis have not been fully elucidated. Here we addressed this question by using tumor cell lines derived from mice that develop metastatic lung adenocarcinoma owing to expression of mutant K-ras and p53. A feature of metastasis-prone tumor cells that distinguished them from metastasis-incompetent tumor cells was plasticity in response to changes in their microenvironment. They transited reversibly between epithelial and mesenchymal states, forming highly polarized epithelial spheres in 3-dimensional culture that underwent epithelial-mesenchymal transition (EMT) following treatment with transforming growth factor-beta or injection into syngeneic mice. This plasticity was entirely dependent upon the microRNA-200 family, which decreased during EMT. Forced expression of miR-200 abrogated the capacity of these tumor cells to undergo EMT, invade, and metastasize and conferred transcriptional features of metastasis-incompetent tumor cells. We conclude that microenvironmental cues direct tumor metastasis by regulating miR-200 expression. Experiment Overall Design: Cell lines from p53R172Hâ??g/+ K-rasLA1/+ mice were derived from tumor tissues removed at autopsy from two different mice (#344 and #393). The tissues were minced, placed in culture, and passed serially in RPMI 1640 supplemented with 10% fetal bovine serum (FBS), which yielded mass populations of tumor cells derived from primary lung tumors (344P and 393P), mediastinal lymph nodes (344LN and 393LN), and a subcutaneous site (344SQ). Stable 344SQ cell lines expressing the miR-200b-200a-429 cluster or control vector were generated by transduction with lentivirus vectors. GFP positive transfectant pools were selected by growth in RPMI 1640 with 10% FBS and puromycin. RNA samples of miR-200b-200a-429 knockup versus control (from triplicate cultures of each) were processed and analyzed on Affymetrix Mouse Expression Array 430A 2.0 chips.

Dataset Information

Gene expression profiling of metastatic lung cancer cell lines

Publications

Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma.

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