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From mouse to humans: detecting preventing vaccination targets associated to breast cancer stem cells. Gene-level analysis

ABSTRACT: The efficacy of cancer treatments have improved constantly in the last decade. However, therapeutic resistance and the lack of curative treatments in metastatic disease, raises the question if conventional anticancer therapies target the right cells. Indeed, these treatments might miss cancer stem cells (CSCs), which might also represent a more chemoresistant and radioresistant subpopulation within cancer. In this view using vaccines in tertiary prevention of cancer, i.e. residual disease treatment, might be particularly effective if vaccine-elicited immune response is directed against CSC oncoantigens (OAs) — proteins required for the neoplastic process — the chance that the tumour will evade the vaccine should be reduced. An important task to devise effective CSC preventive vaccines is therefore the identification of CSC OAs. We used gene-level transcription profiling of TuBo epithelial cell and three mammosphere passages (P1, P2 and P3). This analysis allowed the identification of two new breast cancer CSC OAs: TMPRSS4 and xCT. Both genes are linked to invasion, migration and metastasis. These results were achieved integrating data derived by the analysis of transcription profile of CSCs derived by BALB-neuT mouse breast cancer model with meta-analyses of seven large independent breast tumour data sets.

ORGANISM(S): Mus musculus

PROVIDER: GSE21451 | GEO | 2013/11/30

SECONDARY ACCESSION(S): PRJNA129521

REPOSITORIES: GEO

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Project description:The efficacy of cancer treatments have improved constantly in the last decade. However, therapeutic resistance and the lack of curative treatments in metastatic disease, raises the question if conventional anticancer therapies target the right cells. Indeed, these treatments might miss cancer stem cells (CSCs), which might also represent a more chemoresistant and radioresistant subpopulation within cancer. In this view using vaccines in tertiary prevention of cancer, i.e. residual disease treatment, might be particularly effective if vaccine-elicited immune response is directed against CSC oncoantigens (OAs) — proteins required for the neoplastic process — the chance that the tumour will evade the vaccine should be reduced. An important task to devise effective CSC preventive vaccines is therefore the identification of CSC OAs. We used gene-level transcription profiling of TuBo epithelial cell and three mammosphere passages (P1, P2 and P3). This analysis allowed the identification of two new breast cancer CSC OAs: TMPRSS4 and xCT. Both genes are linked to invasion, migration and metastasis. These results were achieved integrating data derived by the analysis of transcription profile of CSCs derived by BALB-neuT mouse breast cancer model with meta-analyses of seven large independent breast tumour data sets. TuBo cell line (E) was compared to passage 1 (P1), 2 (P2) and 3 (P3) mammospheres (three independent experiments for each experimental condition). Transcription profiling was done using MouseWG-6 v2.0 Illumina beadchips. After normalization and removal of non significant probes (i.e. those not expressed and those not changing) differential expression between epithelial and mammospheres, was assessed using regularized t-test comparing each mammosphere passage with respect to TuBo cells using a FDR ≤ 0.05 together with an |log2(fold-change)|≥1. The union of the three sets of differentially expressed transcripts produced a total of 495 transcripts.

Project description:The efficacy of cancer treatments have improved constantly in the last decade. However, therapeutic resistance and the lack of curative treatments in metastatic disease, raises the question if conventional anticancer therapies target the right cells. Indeed, these treatments might miss cancer stem cells (CSCs), which might also represent a more chemoresistant and radioresistant subpopulation within cancer. In this view using vaccines in tertiary prevention of cancer, i.e. residual disease treatment, might be particularly effective if vaccine-elicited immune response is directed against CSC oncoantigens (OAs) M-bM-^@M-^T proteins required for the neoplastic process M-bM-^@M-^T the chance that the tumour will evade the vaccine should be reduced. An important task to devise effective CSC preventive vaccines is therefore the identification of CSC OAs. In this experiment we used a cell line (TuBo) derived by the mouse breast cancer model BALB-neuT and its CSC subpupolation, enriched by mean of mammosphere formation. Integrating data derived by gene and exon-level transcription profiling of the above experiments with public available normal and tumor datasets we identified two new breast cancer CSC OAs: TMPRSS4 and xCT. Both genes are linked to invasion, migration and metastasis. Furthermore, we observed that alternative splicing events discriminating TuBo cells, grown in adherent medium, with respect of TuBo mammospheres, produced growing in no-adherent medium, are very limited. We detect only one clear splcing event characterizing the beta-isoform of Rabgap1l gene. This SuperSeries is composed of the SubSeries listed below. The adherent TuBo epithelial cells were generated from a mammary carcinoma arising in a BALB/c mouse female transgenic for the activated rat ErbB2 oncogene (BALB-neuT) and were cultured in DMEM supplemented with 20% FCS. Single TuBo cells were plated in ultra low attachment flasks in serum-free DMEM-F12 medium supplemented with bFGF, EGF and insulin. Nonadherent spherical clusters of cells, named mammospheres, were collected by gentle centrifugation after 7 days and dissociated enzymatically and mechanically, using trypsin and pipetting, respectively.

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From mouse to humans: detecting preventing vaccination targets associated to breast cancer stem cells. Gene-level analysis

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