scholarly journals A CTC-Cluster-Specific Signature Derived from OMICS Analysis of Patient-Derived Xenograft Tumors Predicts Outcomes in Basal-Like Breast Cancer

2019 ◽  
Vol 8 (11) ◽  
pp. 1772 ◽  
Author(s):  
Hariprasad Thangavel ◽  
Carmine De Angelis ◽  
Suhas Vasaikar ◽  
Raksha Bhat ◽  
Mohit Kumar Jolly ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epithelial Mesenchymal Transition ◽  
B Cell Lymphoma ◽  
Gene Signature ◽  
Enrichment Score ◽  
Specific Gene ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Patient Derived Xenograft ◽  
Pdx Models

Circulating tumor cell clusters (CTCcl) have a higher metastatic potential compared to single CTCs and predict long-term outcomes in breast cancer (BC) patients. Because of the rarity of CTCcls, molecular characterization of primary tumors that give rise to CTCcl hold significant promise for better diagnosis and target discovery to combat metastatic BC. In our study, we utilized the reverse-phase protein array (RPPA) and transcriptomic (RNA-Seq) data of 10 triple-negative BC patient-derived xenograft (TNBC PDX) transplantable models with CTCs and evaluated expression of upregulated candidate protein Bcl2 (B-cell lymphoma 2) by immunohistochemistry (IHC). The sample-set consisted of six CTCcl-negative (CTCcl−) and four CTCcl-positive (CTCcl+) models. We analyzed the RPPA and transcriptomic profiles of CTCcl− and CTCcl+ TNBC PDX models. In addition, we derived a CTCcl-specific gene signature for testing if it predicted outcomes using a publicly available dataset from 360 patients with basal-like BC. The RPPA analysis of CTCcl+ vs. CTCcl− TNBC PDX tumors revealed elevated expression of Bcl2 (false discovery rate (FDR) < 0.0001, fold change (FC) = 3.5) and reduced acetyl coenzyme A carboxylase-1 (ACC1) (FDR = 0.0005, FC = 0.3) in CTCcl+ compared to CTCcl− tumors. Genome-wide transcriptomic analysis of CTCcl+ vs. CTCcl− tumors revealed 549 differentially expressed genes associated with the presence of CTCcls. Apoptosis was one of the significantly downregulated pathways (normalized enrichment score (NES) = −1.69; FDR < 0.05) in TNBC PDX tumors associated with CTCcl positivity. Two out of four CTCcl+ TNBC PDX primary tumors had high Bcl2 expression by IHC (H-score > 34); whereas, only one of six CTCcl− TNBC PDX primary tumors met this criterion. Evaluation of epithelial-mesenchymal transition (EMT)-specific signature did not show significant differences between CTCcl+ and CTCcl− tumors. However, a gene signature associated with the presence of CTCcls in TNBC PDX models was associated with worse relapse-free survival in the publicly available dataset from 360 patients with basal-like BC. In summary, we identified the multigene signature of primary PDX tumors associated with the presence of CTCcls. Evaluation of additional TNBC PDX models and patients can further illuminate cellular and molecular pathways facilitating CTCcl formation.

scholarly journals A Six-Epithelial–Mesenchymal Transition Gene Signature May Predict Metastasis of Triple-Negative Breast Cancer

2020 ◽  
Vol Volume 13 ◽  
pp. 6497-6509
Author(s):  
Li Yuan Wei ◽  
Xiao Jun Zhang ◽  
Li Wang ◽  
Li Na Hu ◽  
Xu Dong Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Gene Signature ◽  
Mesenchymal Transition

Abrrant expression of a subset of epithelial–mesenchymal transition genes in triple-negative breast cancer before and after EC-T neoadjuvant chemotherapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12617-e12617
Author(s):  
Liyuan Wei ◽  
Li Wang ◽  
Xiaojun Zhang ◽  
Xu Dong Zhang ◽  
Jinnan Gao
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Residual Disease ◽  
Gene Signature ◽  
Mesenchymal Transition ◽  
Early Metastasis ◽  
Early Stages

e12617 Background: Pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) is associated with favorable outcomes of patients with triple-negative breast cancer (TNBC). However, the heterogeneous nature of the disease often results in diverse responses to the same NACT protocol. In particular, a proportion of patients with residual disease (RD) develop metastasis at early stages after treatment. Further stratification of TNBC patients without pCR to NACT is needed for the development of novel strategies in the management of these patients. Methods: A retrospective series of ten TNBC patients with locally residual disease after NACT with the EC-T regimen at Shanxi Bethune Hospital between 2014 and 2018 were included. Total RNA from FFPE pre-NACT core biopsies and paired surgical specimens was subjected to the Affymetrix Human Transcriptome Array. Gene Set Enrichment Analysis (GSEA) was used to identify signal pathways and gene signatures associated with early metastasis after NACT followed by surgery. The Cox proportional hazard model and Kaplan-Meier survival curves on DMFS (distant metastasis-free survival) were employed to assess the prognostic value of the identified signature in TNBC patients from GEO datasets. Results: The epithelial-mesenchymal transition (EMT) pathway was markedly more enriched in pre- (NES = 1.92; p.adjust = 0.019) and post-NACT samples (NES = 2.02; p.adjust = 0.010) from patients who developed metastasis at relatively early stages ( < 18 months) after surgery compared with those who had been disease-free. Noticeably, the EC-T NACT differentially affected the expression of EMT genes resulting in global promotion or inhibition of the pathway in a case-dependent manner. Nevertheless, a subset of 6 EMT genes including LUM, SFRP4, DCN, MMP2, CXCL12, and HTRA1 was expressed constantly at higher levels in samples from patients who progressed to metastasis. The potential of this 6-EMT gene signature to predict TNBC metastasis was validated in the MDACC neoadjuvant series (GSE25066) that contained 113 TNBC patients with RD (55 with metastasis; p = 0.0008; HR = 0.36; 95% CI: 0.200-0.685) and the ICO–UMGC dataset (GSE103091) including 107 TNBC patients (31 with metastasis; p = 0.032, HR = 0.46, 95% CI:0.225-0.937). Conclusions: The expression of the 6-EMT gene signature at diagnosis may be a predictive value of metastasis of TNBC. Moreover, the persistently high expression of the signature may signal early metastasis in TNBC patients with residual disease after EC-T NACT.

scholarly journals FSIP1 binds HER2 directly to regulate breast cancer growth and invasiveness

2017 ◽  
Vol 114 (29) ◽  
pp. 7683-7688 ◽  
Author(s):  
Tong Liu ◽  
Hao Zhang ◽  
Li Sun ◽  
Danyu Zhao ◽  
Peng Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Matrix Protein ◽  
Epithelial Mesenchymal Transition ◽  
Gene Signature ◽  
Extracellular Matrix Protein ◽  
Breast Cancers ◽  
Fibrous Sheath ◽  
Mesenchymal Transition

Fibrous sheath interacting protein 1 (FSIP1), a spermatogenesis-related testicular antigen, is expressed in abundance in breast cancers, particularly in those overexpressing human epidermal growth factor receptor 2 (HER2); however, little is known about its role in regulating the growth and metastasis of breast cancer cells. We and others have shown previously that FSIP1 expression in breast cancer correlates positively with HER2-positivity, recurrence, and metastases and negatively with survival. Here, using coimmunoprecipitation and microscale thermophoresis, we find that FSIP1 binds to the intracellular domain of HER2 directly. We further show that shRNA-inducedFSIP1knockdown in SKBR3 and MCF-7 breast cancer cells inhibits proliferation, stimulates apoptosis, attenuates epithelial–mesenchymal transition, and impairs migration and invasiveness. Consistent with reduced proliferation and enhanced apoptosis, xenotransplantation of SKBR3 cells stably transfected with sh-FSIP1intonu/numice results in reduced tumor volumes compared with sh-NC transplants. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) mapping using sh-FSIP1gene signature yielded associations with extracellular matrix protein pathways, and a reduction in SNAI2 protein expression was confirmed on Western blot analysis. Complementarily, interrogation of the Connectivity Map using the same gene signature yielded, as top hits, chemicals known to inhibit epithelial–mesenchymal transition, including rapamycin, 17-N-allylamino-17-demethoxygeldanamycin, and LY294002. These compounds phenocopy the effects of sh-FSIP1on SKBR3 cell viability. Thus, FSIP1 suppression limits oncogenesis and invasiveness in breast cancer cells and, considering its absence in most other tissues, including normal breast, may become a potential target for breast cancer therapy.

scholarly journals Evaluation of Androgen Receptor in Relation to Estrogen Receptor (AR/ER) and Progesterone Receptor (AR/PgR): A New Must in Breast Cancer?

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Giuseppe Bronte ◽  
Andrea Rocca ◽  
Sara Ravaioli ◽  
Emanuela Scarpi ◽  
Massimiliano Bonafè ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Survival Data ◽  
Epithelial Mesenchymal Transition ◽  
Case Series ◽  
Transition Process ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Early Primary ◽  
Patient Prognosis

Steroid nuclear receptors are known to be involved in the regulation of epithelial-mesenchymal transition process with important roles in invasion and metastasis initiation. Androgen receptor (AR) has been extensively studied, but its role in relation to breast cancer patient prognosis remains to be clarified. AR/ER ratio has been reported to be an unfavorable prognostic marker in early primary breast cancer, but its role in the patients with advanced disease has to be cleared. We retrospectively analyzed ER, PgR, and AR expression on a case series of 159 specimens of primary BC samples by using immunohistochemistry and 89 patients of these had luminal tumors for which AR and ER expression and survival data were available. For twenty-four patients both primary and metastatic tumors were available. A significantly shorter overall survival was observed in primary tumors with AR/PgR ratio ≥ 1.54 (HR = 2.27; 95% CI 1.30-3.97; p = 0.004). Similarly OS was significantly shorter when ER/PgR ratio ≥2 in primary tumors (HR = 1.89; 95% CI 1.10-3.24; p = 0.021). The analysis of the 24 patients who had biomarker determinations both in primary tumors and metastasis showed a better OS when AR/ER ratio in the metastasis was ≥ 0.90 (p = 0.022). Patients with a high AR/ER ratio in primary tumor that remained high in the metastasis had better prognosis in terms of OS (p = 0.011). Despite we suggested that the ratios AR/ER and AR/PgR could be used to identify patients with different prognosis, their real value needs to be better clarified in different BC settings through prospective studies.

scholarly journals Palladium nanoplates scotch breast cancer lung metastasis by constraining epithelial-mesenchymal transition

2020 ◽  
Author(s):  
Shunhao Wang ◽  
Jingchao Li ◽  
Mei Chen ◽  
Liting Ren ◽  
Wenya Feng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Metastasis ◽  
Transforming Growth Factor Beta ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Synergistic Effects ◽  
Cancer Therapeutics ◽  
Primary Tumors ◽  
Mesenchymal Transition

ABSTRACT Metastasis accounts for the majority of cancer deaths in many tumor types including breast cancer. Epithelial-mesenchymal transition (EMT) is the driving force for the occurrence and progression of metastasis, however, no targeted strategies to block the EMT program are currently available to combat metastasis. Diverse engineered nanomaterials (ENMs) have been reported to exert promising anti-cancer effects, however, no ENMs have been designed to target EMT. Palladium (Pd) nanomaterials, a type of ENM, have received substantial attention in nanomedicine due to their favorable photothermal performance for cancer therapeutics. Herein, Pd nanoplates (PdPL) were found to be preferentially biodistributed to both primary tumors and metastatic tumors. Importantly, PdPL showed a significant inhibition of lung metastasis with and without near-infrared (NIR) irradiation. Mechanistic investigations revealed that EMT was significantly compromised in breast cancer cells upon the PdPL treatment, which was partially due to the inhibition of the transforming growth factor-beta (TGF-β) signaling. Strikingly, the PdPL was found to directly interact with TGF-β proteins to diminish TGF-β functions in activating its downstream signaling, as evidenced by the reduced phosphorylation of Smad2. Notably, TGF-β-independent pathways were also involved in undermining EMT and other important biological processes that are necessary for metastasis. Additionally, NIR irradiation elicited synergistic effects on PdPL-induced inhibition of primary tumors and metastasis. In summary, these results revealed that the PdPL remarkably curbed metastasis by inhibiting EMT signaling, thereby indicating the promising potential of PdPL as a therapeutic agent for treating breast cancer metastasis.

scholarly journals Phenotypic Heterogeneity of Triple-Negative Breast Cancer Mediated by Epithelial–Mesenchymal Plasticity

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2188
Author(s):  
Barbora Kvokačková ◽  
Ján Remšík ◽  
Mohit Kumar Jolly ◽  
Karel Souček
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Intratumoral Heterogeneity ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Metastatic Colonization ◽  
Evolutionarily Conserved

Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma known for its unusually aggressive behavior and poor clinical outcome. Besides the lack of molecular targets for therapy and profound intratumoral heterogeneity, the relatively quick overt metastatic spread remains a major obstacle in effective clinical management. The metastatic colonization of distant sites by primary tumor cells is affected by the microenvironment, epigenetic state of particular subclones, and numerous other factors. One of the most prominent processes contributing to the intratumoral heterogeneity is an epithelial–mesenchymal transition (EMT), an evolutionarily conserved developmental program frequently hijacked by tumor cells, strengthening their motile and invasive features. In response to various intrinsic and extrinsic stimuli, malignant cells can revert the EMT state through the mesenchymal–epithelial transition (MET), a process that is believed to be critical for the establishment of macrometastasis at secondary sites. Notably, cancer cells rarely undergo complete EMT and rather exist in a continuum of E/M intermediate states, preserving high levels of plasticity, as demonstrated in primary tumors and, ultimately, in circulating tumor cells, representing a simplified element of the metastatic cascade. In this review, we focus on cellular drivers underlying EMT/MET phenotypic plasticity and its detrimental consequences in the context of TNBC cancer.

scholarly journals TMOD-34. PATIENT-DERIVED XENOGRAFT AND CELL LINE MODELS FACILITATE NOVEL TREATMENT DISCOVERY IN CENTRAL NERVOUS SYSTEM LYMPHOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii235-ii235
Author(s):  
David Meredith ◽  
Kin Hoe Chow ◽  
Pei-Lun Kao ◽  
Yu Zeng ◽  
Rileen Sinha ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cell Line ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Primary Tumors ◽  
Patient Derived Xenograft ◽  
Novel Treatment ◽  
Pdx Models

Abstract Lymphomas of the central nervous system (CNSL) are rare tumors with few treatment options; however, recent genomic studies have uncovered several druggable targets. To facilitate novel treatment discovery, we sought to establish patient-derived xenograft (PDX) models and cell lines from patients with newly diagnosed or recurrent CNSL. PDX models were attempted from fresh tumor samples from 18 consented patients for whom rich clinical annotation was available. Orthotopic intracranial injections were performed via stereotactic injection. Cell line generation was attempted from both primary tumors (PDCL) and PDX samples (PDXCL). Characterization included histopathology, targeted exome sequencing, low-pass whole-genome sequencing for copy number evaluation, and expression profiling of matched patient tumors and PDXs. Drug response testing was performed using CellTiterGlo. From 18 samples attempted, 8 PDX models were successfully generated: 2 primary CNS diffuse large B-cell lymphoma (DLBCL), 5 secondary CNS DLBCL, and 1 secondary cutaneous T-cell lymphoma (CTCL). Mean time to moribund was 66 days. All 8 PDXs grew successfully as orthotopic models, and 4 also grew in subrenal capsule. Additionally, 6 PDCL and 2 PDXCL were established (&gt; P3). Models faithfully represented primaries, showing nearly identical histopathology, immunoprofiles, and genomic signatures. To support expanded and rapid preclinical use of these models in drug testing we documented that PDX could be explanted to create short-term cell preparations or long-term cell lines with a 100% and 40% success rate, respectively. Proof of principle testing showed that explanted DLBCL PDX cells and cell lines showed sensitivity to copanlisib and venetoclax, which were not efficacious in the CTCL PDX. These findings showcase a diverse collection of CNSL models demonstrating high fidelity to primary tumors at the genomic and phenotypic levels, emphasizing their utility for preclinical studies and as patient avatars to rapidly determine sensitivities to existing and novel regimens prior to initiation of therapy.

scholarly journals Interplay between desmoglein2 and hypoxia controls metastasis in breast cancer

2021 ◽  
Vol 118 (3) ◽  
pp. e2014408118
Author(s):  
Po-Hao Chang ◽  
Min-Che Chen ◽  
Ya-Ping Tsai ◽  
Grace Y. T. Tan ◽  
Pang-Hung Hsu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Poor Prognosis ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Cancer ◽  
Circulatory System ◽  
Recurrence Risk ◽  
Breast Cancer Patients ◽  
Dynamic Regulation ◽  
Primary Tumors ◽  
Mesenchymal Transition

Metastasis is the major cause of cancer death. An increased level of circulating tumor cells (CTCs), metastatic cancer cells that have intravasated into the circulatory system, is particularly associated with colonization of distant organs and poor prognosis. However, the key factors required for tumor cell dissemination and colonization remain elusive. We found that high expression of desmoglein2 (DSG2), a component of desmosome-mediated intercellular adhesion complexes, promoted tumor growth, increased the prevalence of CTC clusters, and facilitated distant organ colonization. The dynamic regulation of DSG2 by hypoxia was key to this process, as down-regulation of DSG2 in hypoxic regions of primary tumors led to elevated epithelial−mesenchymal transition (EMT) gene expression, allowing cells to detach from the primary tumor and undergo intravasation. Subsequent derepression of DSG2 after intravasation and release of hypoxic stress was associated with an increased ability to colonize distant organs. This dynamic regulation of DSG2 was mediated by Hypoxia-Induced Factor1α (HIF1α). In contrast to its more widely observed function to promote expression of hypoxia-inducible genes, HIF1α repressed DSG2 by recruitment of the polycomb repressive complex 2 components, EZH2 and SUZ12, to the DSG2 promoter in hypoxic cells. Consistent with our experimental data, DSG2 expression level correlated with poor prognosis and recurrence risk in breast cancer patients. Together, these results demonstrated the importance of DSG2 expression in metastasis and revealed a mechanism by which hypoxia drives metastasis.

Sign in / Sign up

Export Citation Format

Share Document