Molecular Portrait of Breast-Cancer-Derived Cell Lines Reveals Poor Similarity with Tumors

Cifani, Paolo; Kirik, Ufuk; Waldemarson, Sofia; James, Peter

doi:10.1021/acs.jproteome.5b00375

Cited by 9 publications

(9 citation statements)

References 30 publications

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“…However, the heterogeneity of all the cell types found in patient tumors cannot be replicated using cell lines. A higher level of amplification and a differential protein expression pattern compared to primary tumor cells has also been observed in breast cancer cell lines, one explanation might be the source of the cells which is mainly from pleural effusions or triple negative primary cancer [ 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

Testing chemotherapy efficacy in HER2 negative breast cancer using patient-derived spheroids

Halfter¹,

Hoffmann²,

Ditsch

et al. 2016

J Transl Med

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BackgroundTargeted anti-HER2 therapy has greatly improved the prognosis for many breast cancer patients. However, treatment for HER2 negative disease is currently still selected from a multitude of untargeted chemotherapeutic treatment options. A predictive test was developed using patient-derived spheroids to identify the most effective therapy for patients with HER2 negative breast cancer of all stages, for clinically relevant subgroups, as well as individual patients.MethodsTumor samples from 120 HER2 negative patients obtained through biopsy or surgical excision were tested in the breast cancer spheroid model using scaffold-free cell culture. Similarly, spheroids were also generated from established HER2 negative breast cancer cell lines T-47D, MCF7, HCC1143, and HCC1937 to compare treatment efficacy of heterogeneous cell populations from patient tumor tissue with homogeneous cell lines. Spheroids were treated in vitro with guideline-recommended compounds. Treatment mediated impact on cell survival was subsequently quantified using an ATP assay.ResultsDifferences were observed in the metabolic activity of the untreated spheroids, whereby cell lines consistently achieved higher values compared to tissue spheroids (p < 0.001). A higher number of cells per spheroid correlated with a higher basal metabolic activity in tissue-derived spheroids (p < 0.01), while the opposite was observed for cell line spheroids (p < 0.01). Recurrent tumors showed a higher mean vitality (p < 0.01) compared to primary tumors. Except for taxanes, treatment efficacy for most tested compounds differed significantly between breast cancer tissue spheroids and breast cancer cell lines. Overall a high variability in treatment response in vitro was seen in the tissue spheroids regardless of the tested substances. A greater response to anthracycline/docetaxel was observed for hormone receptor negative samples (p < 0.01). A higher response to 5-FU (p < 0.01) and anthracycline (p < 0.05) was seen in high grade tumors. Smaller tumor size and negative lymph node status were both associated with a higher treatment efficacy to anthracycline treatment combined with 5-FU (cT1/2 vs cT3/4, p = 0.035, cN+ vs cN−, p < 0.05).ConclusionsThe tissue spheroid model reflects current guideline treatment recommendations for HER2 negative breast cancer, whereas tested cell lines did not. This model represents a unique diagnostic method to select the most effective therapy out of several equivalent treatment options.

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Section: Introductionmentioning

confidence: 99%

Testing chemotherapy efficacy in HER2 negative breast cancer using patient-derived spheroids

Halfter¹,

Hoffmann²,

Ditsch

et al. 2016

J Transl Med

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show abstract

“…Although immortalized cellular models provide invaluable knowledge regarding cancer biology and drug effects on cellular systems, they are limited in their inability to re-create essential features of tumors. More speci cally, these models cannot accurately re ect the tumor architecture, three-dimensional structure and alignment of tumor cells, matrix, and surrounding stroma, and cannot reproduce the cellular heterogeneity that is present in the original patient tumor [36][37][38][39] . Conversely, orthotopic xenograft models recapitulate the complexity of tumors, but the inability to scale these models limits their use in large drug screens.…”

Section: Discussionmentioning

confidence: 99%

Evaluating Drug Response in 3D Triple Negative Breast Cancer Tumoroids with High Content Imaging and Analysis

Sirenko

Brock

Lim

et al. 2022

Preprint

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There is a critical need to develop methods for efficient testing of drug efficacy in patient-derived tumor samples to discover new therapeutics. Two-dimensional (2D) cell culture remains the primary method of drug screening, despite being considered less physiologically relevant than three-dimensional (3D) culture. Increased complexity and technical challenges of 3D systems have limited its widespread adoption as a primary screening method. In this study, we demonstrate methods for increased throughput, imaging and automation in 3D assays that are suitable for compound screening using patient-derived samples. In addition, we show analysis approaches and descriptors that allow gain more information about disease phenotypes and compound effects. We measured responses to drug treatment in 3D tumoroids for cytotoxicity and altered morphology. Tumoroids were formed from primary cells isolated from a patient-derived tumor explant, TU-BcX-4IC, that represents metaplastic breast cancer with a triple-negative subtype and treated with 165 compounds, of approved cancer drugs, at multiple concentrations. We characterize multiple quantitative descriptors for tumor phenotypes and compound effects. Cell Painting method was used for 3D tumoroids for evaluation of phenotypic effects. Eight compounds were detected that demonstrated effects at low concentrations (10nM), including romidepsin, trametinib, bortezomib, carfilzomib, panobinostat, which will be further investigated as potential drug candidates.

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“…models acquire irreversible genetic and behavioral changes upon serial passaging (6,7). Such pre-clinical models also lack stromal elements that are unable to mirror the architecture and heterogeneity of human tumors (7)(8)(9). Guo et al (10) have reported poor cancer type specificity in cancer cell lines, suggesting that they deviate both histologically, pathologically and molecularly from patient tumors.…”

Section: Development and Characterization Of A Patient-derived Orthot...mentioning

confidence: 99%

Development and characterization of a patient‑derived orthotopic xenograft of therapy‑resistant breast cancer

et al. 2023

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Numerous years of cell line-based studies have enhanced the current understanding of cancer and its treatment. However, limited success has been achieved in treating hormone receptor-positive, HER2-negative metastatic breast cancers that are refractory to treatment. The majority of cancer cell lines are unsuitable for use as pre-clinical models that mimic this critical and often fatal clinical type, since they are derived from treatment-naive or non-metastatic breast cancer cases. The aim of the present study was to develop and characterize patient-derived orthotopic xenografts (PDOXs) from patients with endocrine hormone receptor-positive, HER2-negative metastatic breast cancer who had relapsed on therapy. A patient who progressed on endocrine hormone therapy provided her tumor via a biobank. This tumor was implanted in mice. It was then serially passaged by implanting PDOX tumor fragments into another set of mice to develop further generations of PDOXs. These tissues were characterized using various histological and biochemical techniques. Histological, immunofluorescence and western blot analyses indicated that the PDOX tumors retained a similar morphology, histology and subtype-specific molecular features to that of the patient's tumor. The present study successfully established PDOXs of hormone-resistant breast cancer and characterized them in comparison with those derived from the original breast cancer tissue of the patient. The data highlight the reliability and usefulness of PDOX models for studies of biomarker discovery and preclinical drug screening. The present study was registered with the clinical trial registry of India (CTRI; registration no. CTRI/2017/11/010553; registered on 17/11/2017).

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Molecular Portrait of Breast-Cancer-Derived Cell Lines Reveals Poor Similarity with Tumors

Cited by 9 publications

References 30 publications

Testing chemotherapy efficacy in HER2 negative breast cancer using patient-derived spheroids

Testing chemotherapy efficacy in HER2 negative breast cancer using patient-derived spheroids

Evaluating Drug Response in 3D Triple Negative Breast Cancer Tumoroids with High Content Imaging and Analysis

Development and characterization of a patient‑derived orthotopic xenograft of therapy‑resistant breast cancer

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