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A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds

View Article: PubMed Central - PubMed

ABSTRACT

The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance.

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PDTXs Closely Match Originating Patient Cancer Samples(A) Heatmap of Pearson correlation scores across molecular data types (different sample sizes described in the main text).(B) Panels with individual examples for five types of molecular data. (Left panel: top) CNA plots for AB551 (originating sample [T], PDTX, and PDTC) are shown; (bottom) scatterplot of methylated CpGs (from RRBS data) in AB521M is shown. (Right panel: top) Scatterplots of pathway activity scores in AB521M are shown. (Middle) Scatterplots of variant allelic fractions in STG139 are shown. (Bottom) Mutational profiles in AB551 are shown.
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fig2: PDTXs Closely Match Originating Patient Cancer Samples(A) Heatmap of Pearson correlation scores across molecular data types (different sample sizes described in the main text).(B) Panels with individual examples for five types of molecular data. (Left panel: top) CNA plots for AB551 (originating sample [T], PDTX, and PDTC) are shown; (bottom) scatterplot of methylated CpGs (from RRBS data) in AB521M is shown. (Right panel: top) Scatterplots of pathway activity scores in AB521M are shown. (Middle) Scatterplots of variant allelic fractions in STG139 are shown. (Bottom) Mutational profiles in AB551 are shown.

Mentions: We used these data to determine how implantation, serial passaging, and replicate engraftment affected gene expression, cancer pathway activation scores, allelic fractions of somatic mutations, CNAs, and DNA methylation. This analysis, done also for comparison in reference sets (different tumor samples and technical and biological replicates), revealed a high degree of correlation in matched sample pairs for all data types (FigureĀ 2A).


A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds
PDTXs Closely Match Originating Patient Cancer Samples(A) Heatmap of Pearson correlation scores across molecular data types (different sample sizes described in the main text).(B) Panels with individual examples for five types of molecular data. (Left panel: top) CNA plots for AB551 (originating sample [T], PDTX, and PDTC) are shown; (bottom) scatterplot of methylated CpGs (from RRBS data) in AB521M is shown. (Right panel: top) Scatterplots of pathway activity scores in AB521M are shown. (Middle) Scatterplots of variant allelic fractions in STG139 are shown. (Bottom) Mutational profiles in AB551 are shown.
© Copyright Policy - CC BY
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5037319&req=5

fig2: PDTXs Closely Match Originating Patient Cancer Samples(A) Heatmap of Pearson correlation scores across molecular data types (different sample sizes described in the main text).(B) Panels with individual examples for five types of molecular data. (Left panel: top) CNA plots for AB551 (originating sample [T], PDTX, and PDTC) are shown; (bottom) scatterplot of methylated CpGs (from RRBS data) in AB521M is shown. (Right panel: top) Scatterplots of pathway activity scores in AB521M are shown. (Middle) Scatterplots of variant allelic fractions in STG139 are shown. (Bottom) Mutational profiles in AB551 are shown.
Mentions: We used these data to determine how implantation, serial passaging, and replicate engraftment affected gene expression, cancer pathway activation scores, allelic fractions of somatic mutations, CNAs, and DNA methylation. This analysis, done also for comparison in reference sets (different tumor samples and technical and biological replicates), revealed a high degree of correlation in matched sample pairs for all data types (FigureĀ 2A).

View Article: PubMed Central - PubMed

ABSTRACT

The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance.

No MeSH data available.


Related in: MedlinePlus