scholarly journals Divergent organ-specific isogenic metastatic cell lines identified using multi-omics exhibit differential drug sensitivity

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0242384
Author(s):  
Paul T. Winnard ◽  
Farhad Vesuna ◽  
Sankar Muthukumar ◽  
Venu Raman
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Metastatic Disease ◽  
Primary Tumor ◽  
Metastatic Cancer ◽  
Tumor Biology ◽  
Treatment Strategies ◽  
Breast Cancer Cell Lines ◽  
Visceral Organs ◽  
Organ Specific

Background Monitoring and treating metastatic progression remains a formidable task due, in part, to an inability to monitor specific differential molecular adaptations that allow the cancer to thrive within different tissue types. Hence, to develop optimal treatment strategies for metastatic disease, an important consideration is the divergence of the metastatic cancer growing in visceral organs from the primary tumor. We had previously reported the establishment of isogenic human metastatic breast cancer cell lines that are representative of the common metastatic sites observed in breast cancer patients. Methods Here we have used proteomic, RNAseq, and metabolomic analyses of these isogenic cell lines to systematically identify differences and commonalities in pathway networks and examine the effect on the sensitivity to breast cancer therapeutic agents. Results Proteomic analyses indicated that dissemination of cells from the primary tumor sites to visceral organs resulted in cell lines that adapted to growth at each new site by, in part, acquiring protein pathways characteristic of the organ of growth. RNAseq and metabolomics analyses further confirmed the divergences, which resulted in differential efficacies to commonly used FDA approved chemotherapeutic drugs. This model system has provided data that indicates that organ-specific growth of malignant lesions is a selective adaptation and growth process. Conclusions The insights provided by these analyses indicate that the rationale of targeted treatment of metastatic disease may benefit from a consideration that the biology of metastases has diverged from the primary tumor biology and using primary tumor traits as the basis for treatment may not be ideal to design treatment strategies.

scholarly journals Stable Isotope-Resolved Metabolomic Differences between Hormone-Responsive and Triple-Negative Breast Cancer Cell Lines

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Jason H. Winnike ◽  
Delisha A. Stewart ◽  
Wimal W. Pathmasiri ◽  
Susan L. McRitchie ◽  
Susan J. Sumner
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Triple Negative ◽  
De Novo ◽  
Tricarboxylic Acid Cycle ◽  
Treatment Strategies ◽  
Energy Utilization ◽  
Breast Cancer Cell Lines ◽  
Luminal A ◽  
Mcf 7

Purpose. To conduct an exploratory study to identify mechanisms that differentiate Luminal A (BT474 and MCF-7) and triple-negative (MDA-MB-231 and MDA-MB-468) breast cancer (BCa) cell lines to potentially provide novel therapeutic targets based on differences in energy utilization. Methods. Cells were cultured in media containing either [U-13C]-glucose or [U-13C]-glutamine for 48 hours. Conditioned media and cellular extracts were analyzed by 1H and 13C NMR spectroscopy. Results. MCF-7 cells consumed the most glucose, producing the most lactate, demonstrating the greatest Warburg effect-associated energy utilization. BT474 cells had the highest tricarboxylic acid cycle (TCA) activity. The majority of energy utilization patterns in MCF-7 cells were more similar to MDA-MB-468 cells, while the patterns for BT474 cells were more similar to MDA-MB-231 cells. Compared to the Luminal A cell lines, TNBC cell lines consumed more glutamine and less glucose. BT474 and MDA-MB-468 cells produced high amounts of 13C-glycine from media [U-13C]-glucose which was integrated into glutathione, indicating de novo synthesis. Conclusions. Stable isotopic resolved metabolomics using 13C substrates provided mechanistic information about energy utilization that was difficult to interpret using 1H data alone. Overall, cell lines that have different hormone receptor status have different energy utilization requirements, even if they are classified by the same clinical BCa subtype; and these differences offer clues about optimizing treatment strategies.

scholarly journals Defining the landscape of metabolic dysregulations in cancer metastasis

2021 ◽  
Author(s):  
Sara Abdul Kader ◽  
Shaima Dib ◽  
Iman W. Achkar ◽  
Gaurav Thareja ◽  
Karsten Suhre ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Metabolism ◽  
Treatment Strategies ◽  
Metastatic Potential ◽  
Breast Cancer Cell Lines ◽  
Growth Media ◽  
High Metastatic Potential ◽  
Tnbc Cell

AbstractMetastasis is the primary cause of cancer related deaths due to the limited number of efficient druggable targets. Signatures of dysregulated cancer metabolism could serve as a roadmap for the determination of new treatment strategies. However, the metabolic signatures of metastatic cells remain vastly elusive. Our aim was to determine metabolic dysregulations associated with high metastatic potential in breast cancer cell lines. We have selected 5 triple negative breast cancer (TNBC) cell lines including three with high metastatic potential (HMP) (MDA-MB-231, MDA-MB-436, MDA-MB-468) and two with low metastatic potential (LMP) (BT549, HCC1143). The normal epithelial breast cell line (hTERT-HME1) was also investigated. The untargeted metabolic profiling of cells and growth media was conducted and total of 479 metabolites were quantified. First we characterized metabolic features differentiating TNBC cell lines from normal cells as well as identified cell line specific metabolic fingerprints. Next, we determined 92 metabolites in cells and 22 in growth medium that display significant differences between LMP and HMP. The HMP cell lines had elevated level of molecules involved in glycolysis, TCA cycle and lipid metabolism. We identified metabolic advantages of cell lines with HMP beyond enhanced glycolysis by pinpointing the role of branched chain amino acids (BCAA) catabolism as well as molecules supporting coagulation and platelet activation as important contributors to the metastatic cascade. The landscape of metabolic dysregulations, characterized in our study, could serve as a roadmap for the identification of treatment strategies targeting cancer cells with enhanced metastatic potential.

scholarly journals Organ-specific isogenic metastatic breast cancer cell lines exhibit distinct Raman spectral signatures and metabolomes

Oncotarget ◽  
2017 ◽  
Vol 8 (12) ◽  
pp. 20266-20287 ◽  
Author(s):  
Paul T. Winnard ◽  
Chi Zhang ◽  
Farhad Vesuna ◽  
Jeon Woong Kang ◽  
Jonah Garry ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Metastatic Breast ◽  
Breast Cancer Cell Lines ◽  
Spectral Signatures ◽  
Organ Specific ◽  
Raman Spectral

scholarly journals The Dicyano Compound Induces Autophagic or Apoptotic Cell Death Via Twıst/C-Myc Axis Depending on Metastatic Characteristics of Breast Cancer Cells

2021 ◽  
Author(s):  
Ozge ALVUR ◽  
Hakan KUCUKSAYAN ◽  
Yasemin BAYGU ◽  
Nilgun KABAY ◽  
Yasar GOK ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cell Lines ◽  
Epithelial To Mesenchymal Transition ◽  
Apoptotic Cell ◽  
Treatment Strategies ◽  
Breast Cancer Cell Lines ◽  
Mesenchymal Transition ◽  
Cancer Subtypes ◽  
Mcf 7

Abstract Breast cancer is a heterogeneous disease which has distinct subtypes and therefore development of novel targeting treatments to fight aganist breast cancer is needed. Although autophagy and apoptosis considered as the major programmed cell death mechanisms are among the current target mechanisms, there are some difficulties in clinical treatment such as the development of drug resistance and cancer recurrence. Therefore it is important that illumination of distinctive mechanisms between cancer types for development novel treatment strategies. In this study, we examined the anti-proliferative effects of the triazole linked galactose substituted dicyano compound (hereafter referred to as the dicyano compound (the DC)) on two different breast cancer cell lines, MDA-MB-231 and MCF-7. We determined that response of each cell lines to the DC was different, since autophagy was induced in MDA-MB-231 and apoptosis was induced in MCF-7. For this reason, we hypothesized that these different responses may be due to the different characteristics of the cells and evaluated effects of aggresiveness degrees of both cell lines on response to the DC. As a result of our analysis, we determined that c-Myc regulation in both cell lines was different upon the DC treatment depending on expression of Twist, an epithelial-to-mesenchymal transition (EMT) mediator. Therefore, we suggest that Twist/c-Myc axis may have a role in different response to the DC-induced cell death pathways in breast cancer subtypes.

scholarly journals Raman spectroscopy reveals phenotype switches in breast cancer metastasis

2021 ◽  
Author(s):  
Santosh Kumar Paidi ◽  
Joel Rodriguez Troncoso ◽  
Mason G. Harper ◽  
Zhenhui Liu ◽  
Khue G. Nguyen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Machine Learning ◽  
Raman Spectroscopy ◽  
Random Forest ◽  
Cell Lines ◽  
Primary Tumor ◽  
Cancer Metastasis ◽  
Breast Cancer Cell Lines ◽  
Metastatic Phenotype ◽  
Phenotypic Switch

AbstractThe accurate analytical characterization of metastatic phenotype at primary tumor diagnosis and its evolution with time are critical for controlling metastatic progression of cancer. Here, we report a label-free optical strategy using Raman spectroscopy and machine learning to identify distinct metastatic phenotypes observed in tumors formed by isogenic murine breast cancer cell lines of progressively increasing metastatic propensities. Our Raman spectra-based random forest analysis provided evidence that machine learning models built on spectral data can allow the accurate identification of metastatic phenotype of independent test tumors. By silencing genes critical for metastasis in highly metastatic cell lines, we showed that the random forest classifiers provided predictions consistent with the observed phenotypic switch of the resultant tumors towards lower metastatic potential. Furthermore, the spectral assessment of lipid and collagen content of these tumors was consistent with the observed phenotypic switch. Overall, our findings indicate that Raman spectroscopy may offer a novel strategy to evaluate metastatic risk during primary tumor biopsies in clinical patients.

scholarly journals Single-Cell Cloning of Breast Cancer Cells Secreting Specific Subsets of Extracellular Vesicles

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4397
Author(s):  
Mohsen Fathi ◽  
Robiya Joseph ◽  
Jay R. T. Adolacion ◽  
Melisa Martinez-Paniagua ◽  
Xingyue An ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Cell ◽  
Cancer Cells ◽  
Cell Lines ◽  
Extracellular Vesicles ◽  
Metastatic Cancer ◽  
Metastatic Breast ◽  
Tumor Formation ◽  
Breast Cancer Cell Lines ◽  
Metastatic Cells

Extracellular vesicles (EVs) mediate communication in health and disease. Conventional assays are limited in profiling EVs secreted from large populations of cells and cannot map EV secretion onto individual cells and their functional profiles. We developed a high-throughput single-cell technique that enabled the mapping of dynamics of EV secretion. By utilizing breast cancer cell lines, we established that EV secretion is heterogeneous at the single-cell level and that non-metastatic cancer cells can secrete specific subsets of EVs. Single-cell RNA sequencing confirmed that pathways related to EV secretion were enriched in the non-metastatic cells compared with metastatic cells. We established isogenic clonal cell lines from non-metastatic cells with differing propensities for CD81+CD63+EV secretion and showed for the first time that specificity in EV secretion is an inheritable property preserved during cell division. Combined in vitro and animal studies with these cell lines suggested that CD81+CD63+EV secretion can impede tumor formation. In human non-metastatic breast tumors, tumors enriched in signatures of CD81+CD63+EV have a better prognosis, higher immune cytolytic activity, and enrichment of pro-inflammatory macrophages compared with tumors with low CD81+CD63+EVs signatures. Our single-cell methodology enables the direct integration of EV secretion with multiple cellular functions and enables new insights into cell/disease biology.

scholarly journals Evaluating cell lines as models for metastatic breast cancer through integrative analysis of genomic data

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Ke Liu ◽  
Patrick A. Newbury ◽  
Benjamin S. Glicksberg ◽  
William Z. D. Zeng ◽  
Shreya Paithankar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Patient ◽  
Breast Cancer Patient ◽  
Cell Lines ◽  
Metastatic Cancer ◽  
Metastatic Breast ◽  
Genomic Data ◽  
Metastatic Breast Cancer Patient ◽  
Breast Cancer Cell Lines

AbstractCell lines are widely-used models to study metastatic cancer although the extent to which they recapitulate the disease in patients remains unknown. The recent accumulation of genomic data provides an unprecedented opportunity to evaluate the utility of them for metastatic cancer research. Here, we reveal substantial genomic differences between breast cancer cell lines and metastatic breast cancer patient samples. We also identify cell lines that more closely resemble the different subtypes of metastatic breast cancer seen in the clinic and show that surprisingly, MDA-MB-231 cells bear little genomic similarities to basal-like metastatic breast cancer patient samples. Further comparison suggests that organoids more closely resemble the transcriptome of metastatic breast cancer samples compared to cell lines. Our work provides a guide for cell line selection in the context of breast cancer metastasis and highlights the potential of organoids in these studies.

scholarly journals Molecular Cytogenomic Characterization of the Murine Breast Cancer Cell Lines C-127I, EMT6/P and TA3 Hauschka

2020 ◽  
Vol 21 (13) ◽  
pp. 4716 ◽  
Author(s):  
Shaymaa Azawi ◽  
Thomas Liehr ◽  
Martina Rincic ◽  
Mattia Manferrari
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Treatment Strategies ◽  
Breast Cancer Cell Lines ◽  
Future Research ◽  
Comparative Genomic ◽  
Murine Cell ◽  
Advanced Tumor ◽  
Tumor Stages

Background: To test and introduce effective and less toxic breast cancer (BC) treatment strategies, animal models, including murine BC cell lines, are considered as perfect platforms. Strikingly, the knowledge on the genetic background of applied BC cell lines is often sparse though urgently necessary for their targeted and really justified application. Methods: In this study, we performed the first molecular cytogenetic characterization for three murine BC cell lines C-127I, EMT6/P and TA3 Hauschka. Besides fluorescence in situ hybridization-banding, array comparative genomic hybridization was also applied. Thus, overall, an in silico translation for the detected imbalances and chromosomal break events in the murine cell lines to the corresponding homologous imbalances in humans could be provided. The latter enabled a comparison of the murine cell line with human BC cytogenomics. Results: All three BC cell lines showed a rearranged karyotype at different stages of complexity, which can be interpreted carefully as reflectance of more or less advanced tumor stages. Conclusions: Accordingly, the C-127I cell line would represent the late stage BC while the cell lines EMT6/P and TA3 Hauschka would be models for the premalignant or early BC stage and an early or benign BC, respectively. With this cytogenomic information provided, these cell lines now can be applied really adequately in future research studies.

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