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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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Related in: MedlinePlus

Related to Figure 3 and STAR Methods(A) Box plots of MATH scores for each model analyzed (n = 238 samples from 39 models). Each box plot represents the distribution of scores for matched tumor (red T), PDTXs and PDTCs.(B) Plots of average change in clonal cluster prevalence. PyClone was used to infer clonal architecture for the set of samples from each PDTX model. For all PDTX models with more than two samples, the absolute change in clonal cluster prevalence was averaged over all clusters. Left plot: average change in clonal cluster prevalence with short-term culture of PDTX cells (n = 5 comparisons from 3 models). Middle plot: average change in clonal cluster prevalence with serial passaging (n = 38 passages from 12 models). Right plot: average change in clonal cluster prevalence with implantation (originating sample versus earliest PDTX passage; n = 24 pairs from 16 models). Dot size is proportional to number of samples analyzed.(C) PyClone individual cluster plots showing clonal mean cellular prevalences for 22 models. Width lines are proportional to the number of variants in each clonal cluster. The legend indicates the name of the cluster and the number of variants in it. Asterisks remark clusters whose cellular frequencies are significantly different between samples. Only clusters with at least one variant are shown in the plot.
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figs3: Related to Figure 3 and STAR Methods(A) Box plots of MATH scores for each model analyzed (n = 238 samples from 39 models). Each box plot represents the distribution of scores for matched tumor (red T), PDTXs and PDTCs.(B) Plots of average change in clonal cluster prevalence. PyClone was used to infer clonal architecture for the set of samples from each PDTX model. For all PDTX models with more than two samples, the absolute change in clonal cluster prevalence was averaged over all clusters. Left plot: average change in clonal cluster prevalence with short-term culture of PDTX cells (n = 5 comparisons from 3 models). Middle plot: average change in clonal cluster prevalence with serial passaging (n = 38 passages from 12 models). Right plot: average change in clonal cluster prevalence with implantation (originating sample versus earliest PDTX passage; n = 24 pairs from 16 models). Dot size is proportional to number of samples analyzed.(C) PyClone individual cluster plots showing clonal mean cellular prevalences for 22 models. Width lines are proportional to the number of variants in each clonal cluster. The legend indicates the name of the cluster and the number of variants in it. Asterisks remark clusters whose cellular frequencies are significantly different between samples. Only clusters with at least one variant are shown in the plot.

Mentions: Quantification of intra-tumor heterogeneity using the mutant-allele tumor heterogeneity (MATH) method (Mroz and Rocco, 2013) revealed that the originating patient tumor samples had a range of scores (from low to high), as expected given their diverse IntClust subtype. The heterogeneity scores in multiple passages of matched PDTXs were similar, demonstrating explants preserve intra-tumor heterogeneity (Figure S3A).


A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds
Related to Figure 3 and STAR Methods(A) Box plots of MATH scores for each model analyzed (n = 238 samples from 39 models). Each box plot represents the distribution of scores for matched tumor (red T), PDTXs and PDTCs.(B) Plots of average change in clonal cluster prevalence. PyClone was used to infer clonal architecture for the set of samples from each PDTX model. For all PDTX models with more than two samples, the absolute change in clonal cluster prevalence was averaged over all clusters. Left plot: average change in clonal cluster prevalence with short-term culture of PDTX cells (n = 5 comparisons from 3 models). Middle plot: average change in clonal cluster prevalence with serial passaging (n = 38 passages from 12 models). Right plot: average change in clonal cluster prevalence with implantation (originating sample versus earliest PDTX passage; n = 24 pairs from 16 models). Dot size is proportional to number of samples analyzed.(C) PyClone individual cluster plots showing clonal mean cellular prevalences for 22 models. Width lines are proportional to the number of variants in each clonal cluster. The legend indicates the name of the cluster and the number of variants in it. Asterisks remark clusters whose cellular frequencies are significantly different between samples. Only clusters with at least one variant are shown in the plot.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037319&req=5

figs3: Related to Figure 3 and STAR Methods(A) Box plots of MATH scores for each model analyzed (n = 238 samples from 39 models). Each box plot represents the distribution of scores for matched tumor (red T), PDTXs and PDTCs.(B) Plots of average change in clonal cluster prevalence. PyClone was used to infer clonal architecture for the set of samples from each PDTX model. For all PDTX models with more than two samples, the absolute change in clonal cluster prevalence was averaged over all clusters. Left plot: average change in clonal cluster prevalence with short-term culture of PDTX cells (n = 5 comparisons from 3 models). Middle plot: average change in clonal cluster prevalence with serial passaging (n = 38 passages from 12 models). Right plot: average change in clonal cluster prevalence with implantation (originating sample versus earliest PDTX passage; n = 24 pairs from 16 models). Dot size is proportional to number of samples analyzed.(C) PyClone individual cluster plots showing clonal mean cellular prevalences for 22 models. Width lines are proportional to the number of variants in each clonal cluster. The legend indicates the name of the cluster and the number of variants in it. Asterisks remark clusters whose cellular frequencies are significantly different between samples. Only clusters with at least one variant are shown in the plot.
Mentions: Quantification of intra-tumor heterogeneity using the mutant-allele tumor heterogeneity (MATH) method (Mroz and Rocco, 2013) revealed that the originating patient tumor samples had a range of scores (from low to high), as expected given their diverse IntClust subtype. The heterogeneity scores in multiple passages of matched PDTXs were similar, demonstrating explants preserve intra-tumor heterogeneity (Figure S3A).

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