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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.

No MeSH data available.


Related in: MedlinePlus

Derivation of an Extensively Annotated Breast Cancer PDTX-PDTC Biobank Representing Breast Cancer Subtypes(A) Timeline of engraftment for established PDTX models (n = 31; ER+ in red; ER− in blue). Each square represents a time point of engraftment. Average ER+ and ER− re-implantation time is shown on furthermost right panel. Model IDs are color coded according to integrative cluster (IntClust).(B) Bar plots showing the IntClust distribution of PDTX models (n = 40; shadowed) and for comparison primary breast cancers from METABRIC (n = 1,980; dense).(C) Distribution of somatic mutations in tumors from the TCGA cohort (n = 495) and PDTX models (n = 30), stratified by ER status.See also Figure S1.
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fig1: Derivation of an Extensively Annotated Breast Cancer PDTX-PDTC Biobank Representing Breast Cancer Subtypes(A) Timeline of engraftment for established PDTX models (n = 31; ER+ in red; ER− in blue). Each square represents a time point of engraftment. Average ER+ and ER− re-implantation time is shown on furthermost right panel. Model IDs are color coded according to integrative cluster (IntClust).(B) Bar plots showing the IntClust distribution of PDTX models (n = 40; shadowed) and for comparison primary breast cancers from METABRIC (n = 1,980; dense).(C) Distribution of somatic mutations in tumors from the TCGA cohort (n = 495) and PDTX models (n = 30), stratified by ER status.See also Figure S1.

Mentions: We have established a large bank (n = 83) of live human breast cancer explants by implantation of tumor samples in highly immunodeficient mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ or NSGs; see STAR Methods). Comprehensive clinical information on the patients and originating cancer sample implanted to generate PDTXs can be found in Table S1. To date, PDTXs have been successfully established from both primary (n = 46) and metastatic (n = 37) sites, and more than 50% (n = 50) are from ER+ disease (Table S1). The PDTX growth rates upon initial engraftment and after subsequent re-implantation were variable across models, remained mostly stable upon serial engraftment, and tended to be faster in explants originated from ER− tumors (Figure 1A shows data for 31 models). Importantly, all established models tested to date could be flash frozen and subsequently successfully engrafted, ensuring the persistence of the living biobank.


A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds
Derivation of an Extensively Annotated Breast Cancer PDTX-PDTC Biobank Representing Breast Cancer Subtypes(A) Timeline of engraftment for established PDTX models (n = 31; ER+ in red; ER− in blue). Each square represents a time point of engraftment. Average ER+ and ER− re-implantation time is shown on furthermost right panel. Model IDs are color coded according to integrative cluster (IntClust).(B) Bar plots showing the IntClust distribution of PDTX models (n = 40; shadowed) and for comparison primary breast cancers from METABRIC (n = 1,980; dense).(C) Distribution of somatic mutations in tumors from the TCGA cohort (n = 495) and PDTX models (n = 30), stratified by ER status.See also Figure S1.
© Copyright Policy - CC BY
Related In: Results  -  Collection

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

fig1: Derivation of an Extensively Annotated Breast Cancer PDTX-PDTC Biobank Representing Breast Cancer Subtypes(A) Timeline of engraftment for established PDTX models (n = 31; ER+ in red; ER− in blue). Each square represents a time point of engraftment. Average ER+ and ER− re-implantation time is shown on furthermost right panel. Model IDs are color coded according to integrative cluster (IntClust).(B) Bar plots showing the IntClust distribution of PDTX models (n = 40; shadowed) and for comparison primary breast cancers from METABRIC (n = 1,980; dense).(C) Distribution of somatic mutations in tumors from the TCGA cohort (n = 495) and PDTX models (n = 30), stratified by ER status.See also Figure S1.
Mentions: We have established a large bank (n = 83) of live human breast cancer explants by implantation of tumor samples in highly immunodeficient mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ or NSGs; see STAR Methods). Comprehensive clinical information on the patients and originating cancer sample implanted to generate PDTXs can be found in Table S1. To date, PDTXs have been successfully established from both primary (n = 46) and metastatic (n = 37) sites, and more than 50% (n = 50) are from ER+ disease (Table S1). The PDTX growth rates upon initial engraftment and after subsequent re-implantation were variable across models, remained mostly stable upon serial engraftment, and tended to be faster in explants originated from ER− tumors (Figure 1A shows data for 31 models). Importantly, all established models tested to date could be flash frozen and subsequently successfully engrafted, ensuring the persistence of the living biobank.

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