Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Differential in vivo tumorigenicity of distinct subpopulations from a luminal-like breast cancer model (SNP)

ABSTRACT: The cellular heterogeneity of one patient derived orthotopic breast cancer xenograft model PDX was investigated using flow cytometry, combined with assessment of in vivo tumorigenicity and SNP genotyping array for copy number analysis. Epithelial cell adhesion molecule (EpCAM) was revealed as a highly specific cell surface marker of the human tumor cell population in both xenografts. Based on expression patterns observed in primary tumor tissue, SSEA-4 and CD24 were chosen as markers to further subdivide the luminal tumor cells into four subpopulations. FACS sorting was used to isolate four cell subpopulations. Results: In vivo tumorigenicity assay showed that SSEA-4+/CD24+ cells were non-tumorigenic, while the three other subpopulations were tumorigenic. Tumors resulting from the SSEA-4+/CD24- subpopulation of luminal cancer cells, did not express CD24, while tumors arising from the SSEA-4-/CD24-, and SSEA-4-/CD24+ populations both recapitulated the original tumor containing all four subpopulations. Copy number analysis comparing the four subpopulations between eachother, did reveal high similarity. Although there were some minor differencies between the subpopulations, no differences in genome aberrations could explain their difference in tumorigenicity. Discussion: Our results imply that subpopulations from one primary tumor can give rise to dissimilar daughter tumors. These tumors may not necessarily respond to the same targeted treatment, and thereby represent a therapy escape mechanism. This study highlights that to remove the risk of breast cancer recurrence, inhibition of the molecules critical for driving the tumor progression in several tumor cell subpopulations might be essential Four subpopulations were analysed using Infinium HumanOmniExpressExome BeadChip array. Replicates are not included, the HumanOmniExpressExome-8v1-2_A.egt file was used as a reference.

ORGANISM(S): Homo sapiens

SUBMITTER: Nirma Skrbo

PROVIDER: E-GEOD-54595 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Differential in vivo tumorigenicity of distinct subpopulations from a luminal-like breast cancer xenograft.

Skrbo Nirma N Hjortland Geir-Olav GO Kristian Alexandr A Holm Ruth R Nord Silje S Prasmickaite Lina L Engebraaten Olav O Mælandsmo Gunhild M GM Sørlie Therese T Andersen Kristin K

PloS one 20141124 11

Intratumor heterogeneity caused by genetic, phenotypic or functional differences between cancer cell subpopulations is a considerable clinical challenge. Understanding subpopulation dynamics is therefore central for both optimization of existing therapy and for development of new treatment. The aim of this study was to isolate subpopulations from a primary tumor and by comparing molecular characteristics of these subpopulations, find explanations to their differing tumorigenicity. Cell subpopula ...[more]

PMID: 25419568

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Project description:The cellular heterogeneity of one patient derived orthotopic breast cancer xenograft model (PDBCX) was investigated using flow cytometry , combined with assessment of in vivo tumorigenicity and whole genome expression profiling. Epithelial cell adhesion molecule (EpCAM) was revealed as a highly specific cell surface marker of the human tumor cell population in both xenografts. Based on expression patterns observed in primary tumor tissue, SSEA-4 and CD24 were chosen as markers to further subdivide the luminal tumor cells into four subpopulations. FACS sorting was used to isolate four cell subpopulations. Results: In vivo tumorigenicity assay showed that SSEA-4+/CD24+ cells were non-tumorigenic, while the three other subpopulations were tumorigenic. Tumors resulting from the SSEA-4+/CD24- subpopulation of luminal cancer cells, did not express CD24, while tumors arising from the SSEA-4-/CD24-, and SSEA-4-/CD24+ populations both recapitulated the original tumor containing all four subpopulations. Whole genome expression analysis revealed distinct transcriptional profiles, and 44 genes were significantly differentially expressed when comparing the tumorigenic vs non-tumorigenic populations. Several interesting genes putatively suppressing the cancer cells ability to initiate tumors in vivo were upregulated in the non-tumorigenic population. We here show that tumor initiating cells within one primary tumor evidently included more than one phenotype. Furthermore, with respect to cell surface marker expression, one of the subpopulations produced tumors unlike both the originating cells, and the original tumor. Discussion: Our results imply that subpopulations from one primary tumor can give rise to dissimilar daughter tumors. These tumors may not necessarily respond to the same targeted treatment, and thereby represent a therapy escape mechanism. This study highlights that to remove the risk of breast cancer recurrence, inhibition of the molecules critical for driving the tumor progression in several tumor cell subpopulations might be essential Gene expression was measured in four cell subpopulations isolated from Patient derived human luminal-like breast cancer xenograft. Four replicates from three subpopulations and three replicates from one subpopulation.

Dataset Information

Differential in vivo tumorigenicity of distinct subpopulations from a luminal-like breast cancer model (SNP)

Publications

Differential in vivo tumorigenicity of distinct subpopulations from a luminal-like breast cancer xenograft.

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