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Establishment and characterization of immortalized human breast cancer cell lines from breast cancer patient-derived xenografts (PDX)

Zhuang, Yongxian, Grainger, Jordan M., Vedell, Peter T., Yu, Jia, Moyer, Ann M., Gao, Huanyao, Fan, Xiao-Yang, Qin, Sisi, Liu, Duan, Kalari, Krishna R., Goetz, Matthew P., Boughey, Judy C., Weinshilboum, Richard M., Wang, Liewei·2021·npj Breast Cancer
DOI 10.1038/s41523-021-00285-xPMC PMC8213738
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Abstract

The application of patient-derived xenografts (PDX) in drug screening and testing is a costly and time-consuming endeavor. While cell lines permit extensive mechanistic studies, many human breast cancer cell lines lack patient characteristics and clinical treatment information. Establishing cell lines that retain patient’s genetic and drug response information would enable greater drug screening and mechanistic studies. Therefore, we utilized breast cancer PDX from the Mayo Breast Cancer Genome Guided Therapy Study (BEAUTY) to establish two immortalized, genomically unique breast cancer cell lines. Through extensive genetic and therapeutic testing, the cell lines were found to retain the same clinical subtype, major somatic alterations, and drug response phenotypes as their corresponding PDX and patient tumor. Our findings demonstrate PDX can be utilized to develop immortalized breast cancer cell lines and provide a valuable tool for understanding the molecular mechanism of drug resistance and exploring novel treatment strategies.

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Fig. 1 Established cell lines are unique breast cancer cell lines. A The images of MC-BR-BTY-0019 and MC-BR-BTY-0006 were presented after they were established as immortalized cell lines. Images were taken at ×20; Scale bar represents 20 μm. B, C 30,000 cells and 85,000 cells were plated onto 24-well plates for the proliferation assay for MC-BR-BTY-0019 and MC-BR-BTY-0006, respectively. The proliferation curves are normalized to day 1. Error bars represent SEM. DNA analysis of D MC-BR-BTY-0019 cell line, E MC-BR-BTY-0006 cell line, F MC-BR-BTY-0019 PDX, and G MC-BR-BTY-0006 PDX was demonstrated by STR profiling. REF refers to allele comparisons to all cell lines available in ATCC, DSMZ, JCRB STR profile databases. “NA” designates no similar allele calls compared to the reference.
Fig. 1 Established cell lines are unique breast cancer cell lines. A The images of MC-BR-BTY-0019 and MC-BR-BTY-0006 were presented after they were established as immortalized cell lines. Images were taken at ×20; Scale bar represents 20 μm. B, C 30,000 cells and 85,000 cells were plated onto 24-well plates for the proliferation assay for MC-BR-BTY-0019 and MC-BR-BTY-0006, respectively. The proliferation curves are normalized to day 1. Error bars represent SEM. DNA analysis of D MC-BR-BTY-0019 cell line, E MC-BR-BTY-0006 cell line, F MC-BR-BTY-0019 PDX, and G MC-BR-BTY-0006 PDX was demonstrated by STR profiling. REF refers to allele comparisons to all cell lines available in ATCC, DSMZ, JCRB STR profile databases. “NA” designates no similar allele calls compared to the reference.CC BY · PubMed Central
Fig. 2 Two newly established breast cancer cells lines presented massive abnormal karyotypes. A, B Cytogenetics G-band staining of chromosomes is presented and chromosome alteration is described for two cells, MC-BR-BTY-0019 and MC-BR-BTY-0006 cell lines, respectively. Each image is a karyotype of one cell. Text below each karyotype refers to International System for the Human Cytogenetic Nomenclature (ISCN) of the karyotype to address the number of chromosomes observed, the sex chromosome, and the abnormalities observed per chromosome. The arrows indicate breakpoints or abnormalities.
Fig. 2 Two newly established breast cancer cells lines presented massive abnormal karyotypes. A, B Cytogenetics G-band staining of chromosomes is presented and chromosome alteration is described for two cells, MC-BR-BTY-0019 and MC-BR-BTY-0006 cell lines, respectively. Each image is a karyotype of one cell. Text below each karyotype refers to International System for the Human Cytogenetic Nomenclature (ISCN) of the karyotype to address the number of chromosomes observed, the sex chromosome, and the abnormalities observed per chromosome. The arrows indicate breakpoints or abnormalities.CC BY · PubMed Central
Fig. 3 Cell lines, MC-BR-BTY-0019 and MC-BR-BTY-0006 maintain the subtype characterization and drug response consistent with PDX-derived organoid and PDX tumor. A Western blot and quantification of the levels of HER2, EGFR, and beta-actin in breast cancer cell lines, newly established cell lines, their corresponding PDX-derived organoids and PDX tumors. Expression of HER2 and EGFR for MC-BR-BTY-0019 cell line, organoid, and PDX was normalized to beta-actin and then SKBR3. Expression of HER2 and EGFR for MC-BR-BTY-0006 cell line, organoid, and PDX was normalized to beta-actin and then MDA-MB-231. All blots are derived from the same experiment and were processed in parallel. B MC-BR-BTY-0019 and MC-BR-BTY-0006 cell lines were stained with HER2 and DAPI and images were taken at ×100. Scale bar represents 10 μm. C MC-BR-BTY-0019 and MC-BR-BTY-0006 cell lines were stained with EGFR and DAPI and images were taken at ×100. Scale bar represents 10 μm. D 10,000 cells/well of MC-BR-BTY-0019 cell line were seeded in 96-well plates in triplicates, treated with indicated concentrations of lapatinib for 48 h, and cell viability was measured by MTS assay and normalized to DMSO. IC50 = 438.531 nM. E 10,000 cells/well of MC-BR-BTY-0006 cell line were seeded in 96-well plates in triplicates, treated with paclitaxel at indicated concentrations for 48 h, and cell viability was measured by MTS assay and normalized to DMSO. IC50 = Indeterminate. F, G PDX tumors were collected when the tumor achieved 10–20 mm in diameter, and primary breast cancer cells were isolated after dissociation of tumor tissue from mouse cells, as previously described7. MC-BR-BTY-0019 PDX-derived organoids were generated by seeding 10,000 cells of the primary breast cancer single-cell suspension per well in Nanoculture plates in triplicates and treated with indicated concentrations of lapatinib for 5 days (IC50 = 979.49 nM). MC-BR-BTY-0006 PDX-derived organoids were treated with indicated concentrations of paclitaxel for 5 days (IC50 = Indeterminate). Organoid viability was measured using 3D Cell TiterGlo viability assay, normalized to DMSO, and plotted using GraphPad PRISM software. Error bars represent SEM.
Fig. 3 Cell lines, MC-BR-BTY-0019 and MC-BR-BTY-0006 maintain the subtype characterization and drug response consistent with PDX-derived organoid and PDX tumor. A Western blot and quantification of the levels of HER2, EGFR, and beta-actin in breast cancer cell lines, newly established cell lines, their corresponding PDX-derived organoids and PDX tumors. Expression of HER2 and EGFR for MC-BR-BTY-0019 cell line, organoid, and PDX was normalized to beta-actin and then SKBR3. Expression of HER2 and EGFR for MC-BR-BTY-0006 cell line, organoid, and PDX was normalized to beta-actin and then MDA-MB-231. All blots are derived from the same experiment and were processed in parallel. B MC-BR-BTY-0019 and MC-BR-BTY-0006 cell lines were stained with HER2 and DAPI and images were taken at ×100. Scale bar represents 10 μm. C MC-BR-BTY-0019 and MC-BR-BTY-0006 cell lines were stained with EGFR and DAPI and images were taken at ×100. Scale bar represents 10 μm. D 10,000 cells/well of MC-BR-BTY-0019 cell line were seeded in 96-well plates in triplicates, treated with indicated concentrations of lapatinib for 48 h, and cell viability was measured by MTS assay and normalized to DMSO. IC50 = 438.531 nM. E 10,000 cells/well of MC-BR-BTY-0006 cell line were seeded in 96-well plates in triplicates, treated with paclitaxel at indicated concentrations for 48 h, and cell viability was measured by MTS assay and normalized to DMSO. IC50 = Indeterminate. F, G PDX tumors were collected when the tumor achieved 10–20 mm in diameter, and primary breast cancer cells were isolated after dissociation of tumor tissue from mouse cells, as previously described7. MC-BR-BTY-0019 PDX-derived organoids were generated by seeding 10,000 cells of the primary breast cancer single-cell suspension per well in Nanoculture plates in triplicates and treated with indicated concentrations of lapatinib for 5 days (IC50 = 979.49 nM). MC-BR-BTY-0006 PDX-derived organoids were treated with indicated concentrations of paclitaxel for 5 days (IC50 = Indeterminate). Organoid viability was measured using 3D Cell TiterGlo viability assay, normalized to DMSO, and plotted using GraphPad PRISM software. Error bars represent SEM.CC BY · PubMed Central
Fig. 4 The two established breast cancer cell lines form CDX tumors in vivo, maintain similar pathology features as their corresponding PDX tumors and show similar drug response in vivo. A, B Pathology staining of HE, Ki67, ER, PR, EGFR, and HER2 was performed in both PDX tumor tissue and CDX tumor formed from MC-BR-BTY-0019 cell line (A) and MC-BR-BTY-0006 (B). Images taken at ×200; Scale bar represents 200 μm. C Detailed description of the pathology staining features of tumor tissue of the PDX and CDX is summarized for MC-BR-BTY-0019 and MC-BR-BTY-0006. D MC-BR-BTY-0019 CDX in vivo tumors were formed by injecting 2 million cells of MC-BR-BTY-0019 cell line into 10 NSG mice, which were randomized when tumor achieved 50–100 mm3 in volume, and treated with either control (n = 5, vehicle, 5 days/week) or lapatinib (n = 5, 50 mg/kg, 5 days/week) for 3 weeks. Tumor volume was measured at indicated time points and plotted using GraphPad PRISM software. Error bars represent SEM. **p < 0.01, 2 tailed Student’s t-test comparing vehicle to drug treatment. E MC-BR-BTY-0019 PDX tumor was formed by injecting earlier passage of PDX tumor into flank of 15 NSG mice, 13 mice with similar size of tumors were randomized when tumor achieved 50–100 mm3 in volume and treated with either control (n = 6, vehicle, 5 days/week) or lapatinib (n = 7, 50 mg/kg, 5 days/week) for 3 weeks. Tumor volume was measured at indicated time points and plotted using GraphPad PRISM software. Error bars represent SEM. **p < 0.01, 2 tailed Student’s t-test comparing vehicle to drug treatment. F MC-BR-BTY-0006 CDX in vivo tumors were formed by injecting 5 million cells of MC-BR-BTY-0006 cell line into 10 NSG mice, which were randomized when the tumor reached 50–100 mm3 in volume, and treated with either control (n = 5, vehicle, 2 times/week) or paclitaxel (n = 5, 12.5 mg/kg, 2 times/week) for 3 weeks. Tumor volume was measured at indicated time points and plotted using GraphPad PRISM software. Error bars represent SEM. p-value = ns, 2 tailed Student’s t-test comparing vehicle to drug treatment. G MC-BR-BTY-0006 PDX tumor was formed by injecting earlier passage of PDX tumor into flank of 15 NSG mice, 12 mice with similar size of tumor were randomized when tumor reached 50–100 mm3 in volume, and treated with either control (n = 6, vehicle, 2 times/week) or paclitaxel (n = 6, 12.5 mg/kg, 2 times/week) for 3 weeks. Tumor volume was measured at indicated time points and plotted using GraphPad PRISM software. Error bars represent SEM. p-value = ns, 2 tailed Student’s t-test comparing vehicle to drug treatment.
Fig. 4 The two established breast cancer cell lines form CDX tumors in vivo, maintain similar pathology features as their corresponding PDX tumors and show similar drug response in vivo. A, B Pathology staining of HE, Ki67, ER, PR, EGFR, and HER2 was performed in both PDX tumor tissue and CDX tumor formed from MC-BR-BTY-0019 cell line (A) and MC-BR-BTY-0006 (B). Images taken at ×200; Scale bar represents 200 μm. C Detailed description of the pathology staining features of tumor tissue of the PDX and CDX is summarized for MC-BR-BTY-0019 and MC-BR-BTY-0006. D MC-BR-BTY-0019 CDX in vivo tumors were formed by injecting 2 million cells of MC-BR-BTY-0019 cell line into 10 NSG mice, which were randomized when tumor achieved 50–100 mm3 in volume, and treated with either control (n = 5, vehicle, 5 days/week) or lapatinib (n = 5, 50 mg/kg, 5 days/week) for 3 weeks. Tumor volume was measured at indicated time points and plotted using GraphPad PRISM software. Error bars represent SEM. **p < 0.01, 2 tailed Student’s t-test comparing vehicle to drug treatment. E MC-BR-BTY-0019 PDX tumor was formed by injecting earlier passage of PDX tumor into flank of 15 NSG mice, 13 mice with similar size of tumors were randomized when tumor achieved 50–100 mm3 in volume and treated with either control (n = 6, vehicle, 5 days/week) or lapatinib (n = 7, 50 mg/kg, 5 days/week) for 3 weeks. Tumor volume was measured at indicated time points and plotted using GraphPad PRISM software. Error bars represent SEM. **p < 0.01, 2 tailed Student’s t-test comparing vehicle to drug treatment. F MC-BR-BTY-0006 CDX in vivo tumors were formed by injecting 5 million cells of MC-BR-BTY-0006 cell line into 10 NSG mice, which were randomized when the tumor reached 50–100 mm3 in volume, and treated with either control (n = 5, vehicle, 2 times/week) or paclitaxel (n = 5, 12.5 mg/kg, 2 times/week) for 3 weeks. Tumor volume was measured at indicated time points and plotted using GraphPad PRISM software. Error bars represent SEM. p-value = ns, 2 tailed Student’s t-test comparing vehicle to drug treatment. G MC-BR-BTY-0006 PDX tumor was formed by injecting earlier passage of PDX tumor into flank of 15 NSG mice, 12 mice with similar size of tumor were randomized when tumor reached 50–100 mm3 in volume, and treated with either control (n = 6, vehicle, 2 times/week) or paclitaxel (n = 6, 12.5 mg/kg, 2 times/week) for 3 weeks. Tumor volume was measured at indicated time points and plotted using GraphPad PRISM software. Error bars represent SEM. p-value = ns, 2 tailed Student’s t-test comparing vehicle to drug treatment.CC BY · PubMed Central
Fig. 5 Exome sequencing reveals several patient-specific cancer driver mutations and an evolutionary trajectory that features their preservation in the presence of somatic changes suggestive of genome instability. A Oncogenic mutations in five cancer genes were detected in all three MC-BR-BTY-0006 tumor samples. Pathogenic loss-of-function somatic SNVs were detected in one allele of each of the genes TP53, PTEN, and BRCA2 as well as the other allele (loss of heterozygosity, or LOH). Thus, loss of function of both copies of tumor-suppressor genes TP53, PTEN, and BRCA2 could be inferred. RB1 loss of heterozygosity (LOH) and amplification of MYC were other oncogenic events observed. B Oncogenic mutations in eight cancer genes were detected in all three MC-BR-BTY-0019 tumor samples. A different pathogenic loss-of-function mutation in TP53 for cell line, but was again observed alongside LOH. So, loss of function of both copies can be inferred for TP53 as well as for three other tumor suppressor genes, CDKN2A, the adjacent CDKN2B, and MAP2K4, due to homozygous deletion (HomDel). Mutations were also observed in PIK3R1 and ARID1A. The mutations affect sites in regions frequently altered in cancer. Amplifications of TERT and ERBB2, or HER2, were also detected, with particularly high amplification for ERBB2. C Of the somatic SNV/INDELs detected in the patient tumor tissue samples, proportions detected in PDXs and cell lines were high (≥72%) for both patients. Of those mutations detected in PDXs, proportions detected in cell lines were also high (79%, 67%). D Changes in ploidy by sample type pair. For each patient, the absolute differences were nearly 1 copy from tissue to PDX with a Tissue→PDX increase observed for MC-BR-BTY-0006 and a Tissue→PDX decrease observed for MC-BR-BTY-0019. Despite these changes, the profiles of within-sample relative copy numbers for Tissue and PDX still showed similarity as the correlation of copy number was still 0.70 or greater. Slight decreases in ploidy were observed from PDX to cell line for both patients.
Fig. 5 Exome sequencing reveals several patient-specific cancer driver mutations and an evolutionary trajectory that features their preservation in the presence of somatic changes suggestive of genome instability. A Oncogenic mutations in five cancer genes were detected in all three MC-BR-BTY-0006 tumor samples. Pathogenic loss-of-function somatic SNVs were detected in one allele of each of the genes TP53, PTEN, and BRCA2 as well as the other allele (loss of heterozygosity, or LOH). Thus, loss of function of both copies of tumor-suppressor genes TP53, PTEN, and BRCA2 could be inferred. RB1 loss of heterozygosity (LOH) and amplification of MYC were other oncogenic events observed. B Oncogenic mutations in eight cancer genes were detected in all three MC-BR-BTY-0019 tumor samples. A different pathogenic loss-of-function mutation in TP53 for cell line, but was again observed alongside LOH. So, loss of function of both copies can be inferred for TP53 as well as for three other tumor suppressor genes, CDKN2A, the adjacent CDKN2B, and MAP2K4, due to homozygous deletion (HomDel). Mutations were also observed in PIK3R1 and ARID1A. The mutations affect sites in regions frequently altered in cancer. Amplifications of TERT and ERBB2, or HER2, were also detected, with particularly high amplification for ERBB2. C Of the somatic SNV/INDELs detected in the patient tumor tissue samples, proportions detected in PDXs and cell lines were high (≥72%) for both patients. Of those mutations detected in PDXs, proportions detected in cell lines were also high (79%, 67%). D Changes in ploidy by sample type pair. For each patient, the absolute differences were nearly 1 copy from tissue to PDX with a Tissue→PDX increase observed for MC-BR-BTY-0006 and a Tissue→PDX decrease observed for MC-BR-BTY-0019. Despite these changes, the profiles of within-sample relative copy numbers for Tissue and PDX still showed similarity as the correlation of copy number was still 0.70 or greater. Slight decreases in ploidy were observed from PDX to cell line for both patients.CC BY · PubMed Central

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Metadata

Authors
Zhuang, Y., Grainger, J. M., Vedell, P. T., Yu, J., Moyer, A. M., Gao, H., Fan, X.-Y., Qin, S., Liu, D., Kalari, K. R., Goetz, M. P., Boughey, J. C., Weinshilboum, R. M., & Wang, L.
ORCID
Venue
npj Breast Cancer
Publisher
Springer Science and Business Media LLC
Published
2021-06-18
Volume
7
Issue
1
ISSN
2374-4677
DOI
10.1038/s41523-021-00285-x
PMC
PMC8213738
Cited by
11
References
2
Language
en
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