scholarly journals Brain and Breast Cancer Cells with PTEN Loss of Function Demonstrate Enhanced Durotaxis and RHOB Dependent Amoeboid Migration Using 3D Printed Scaffolds and Aligned Microfiber Tracts

2021 ◽  
Author(s):  
Annalena Wieland ◽  
Pamela L. Strissel ◽  
Hannah Schorle ◽  
Ezgi Bakirci ◽  
Dieter Janzen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Morphology ◽  
Live Cell Imaging ◽  
Essential Role ◽  
Cell Imaging ◽  
Loss Of Function ◽  
Pten Loss ◽  
3D Printed ◽  
And Migration

Abstract Background: Glioblastoma multiforme (GBM) and triple-negative breast cancer (TNBC) with PTEN mutations often lead to brain dissemination with very poor patient outcomes. GBM uses axons and vessels as migratory cues to disseminate, however it is not known, if TNBC shares the same behavior. There is a need to understand brain tumor cell spreading and if GBM and TNBC have similar migration properties involving the signaling pathway RHOB-ROCK-PTEN. We tested for durotaxis, adherence and migration of GBM and TNBC using live-cell imaging and performed molecular analyses on three-dimensional (3D) structures.Methods: Aligned 3D printed scaffolds and microfibers were designed to mimic brain axon tracts and vessels for migration. GBM and TNBC cell lines, each with opposing PTEN genotypes, were analysed with RHO, ROCK and PTEN inhibitors and rescuing PTEN function using live-cell imaging. RNA-sequencing and qPCR of tumor cells in 3D with microfibers were performed, while SEM, confocal microscopy and cell tracking addressed cell morphology. Results: GBM and TNBC with homozygote PTEN loss of function and RHOB high expression were amoeboid shaped and demonstrated enhanced durotaxis, adhesion and migration on 3D microfibers, in contrast to PTEN wildtype GBM and TNBC showing elongated cells and low RHOB. RNA-sequencing exhibited that RHOB was significantly the highest expressed gene in GBM PTEN loss of function cells. Pathway inhibitors and PTEN rescue of function verified an essential role of RHOB-ROCK-PTEN signaling for durotaxis, adhesion, migration, cell morphology and plasticity using 3D printed microfibers. Conclusions: This study validates a significant role of a PTEN genotype for cellular properties including durotaxis, adhesion and migration. GBM and TNBC cells with PTEN loss of function have a greater affinity for stiffer brain structures promoting metastasis. We propose the significance of PTEN and RHOB in cellular oncology not only for primary tumors, but also for metastasizing tumors, where RHOB inhibitors could play an essential role for improved therapy.

scholarly journals Brain and Breast Cancer Cells with PTEN Loss of Function Reveal Enhanced Durotaxis and RHOB Dependent Amoeboid Migration Utilizing 3D Scaffolds and Aligned Microfiber Tracts

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5144
Author(s):  
Annalena Wieland ◽  
Pamela L. Strissel ◽  
Hannah Schorle ◽  
Ezgi Bakirci ◽  
Dieter Janzen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Cell Lines ◽  
Essential Role ◽  
Brain Structures ◽  
Loss Of Function ◽  
Pten Loss ◽  
Tumor Cell Migration ◽  
Functional Studies ◽  
Tnbc Cell

Background: Glioblastoma multiforme (GBM) and metastatic triple-negative breast cancer (TNBC) with PTEN mutations often lead to brain dissemination with poor patient outcome, thus new therapeutic targets are needed. To understand signaling, controlling the dynamics and mechanics of brain tumor cell migration, we implemented GBM and TNBC cell lines and designed 3D aligned microfibers and scaffolds mimicking brain structures. Methods: 3D microfibers and scaffolds were printed using melt electrowriting. GBM and TNBC cell lines with opposing PTEN genotypes were analyzed with RHO-ROCK-PTEN inhibitors and PTEN rescue using live-cell imaging. RNA-sequencing and qPCR of tumor cells in 3D with microfibers were performed, while scanning electron microscopy and confocal microscopy addressed cell morphology. Results: In contrast to the PTEN wildtype, GBM and TNBC cells with PTEN loss of function yielded enhanced durotaxis, topotaxis, adhesion, amoeboid migration on 3D microfibers and significant high RHOB expression. Functional studies concerning RHOB-ROCK-PTEN signaling confirmed the essential role for the above cellular processes. Conclusions: This study demonstrates a significant role of the PTEN genotype and RHOB expression for durotaxis, adhesion and migration dependent on 3D. GBM and TNBC cells with PTEN loss of function have an affinity for stiff brain structures promoting metastasis. 3D microfibers represent an important tool to model brain metastasizing tumor cells, where RHO-inhibitors could play an essential role for improved therapy.

scholarly journals Protein Tyrosine Kinase 7 Regulates EGFR/Akt Signaling Pathway and Correlates With Malignant Progression in Triple-Negative Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Nai-Peng Cui ◽  
Shu Qiao ◽  
Shan Jiang ◽  
Jin-Lin Hu ◽  
Ting-Ting Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Protein Tyrosine Kinase ◽  
Akt Signaling ◽  
Loss Of Function ◽  
Tnbc Cell ◽  
And Migration ◽  
Protein Tyrosine Kinase 7

PurposeTriple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is associated with high invasiveness, high metastatic occurrence and poor prognosis. Protein tyrosine kinase 7 (PTK7) plays an important role in multiple cancers. However, the role of PTK7 in TNBC has not been well addressed. This study was performed to evaluate the role of PTK7 in the progression of TNBC.MethodsCorrelation of PTK7 expression with clinicopathological parameters was assessed using tissue microarray immunohistochemistry (IHC) staining in 280 patients with breast cancer. PTK7 expression in TNBC (MDA-MB-468, MDA-MB-436 and MDA-MB-231) and non-TNBC (MCF7 and SK-BR-3) breast cancer cell lines were examined using immunoblotting assay. PTK7 correlated genes in invasive breast carcinoma were analyzed using cBioPortal breast cancer datasets including 1,904 patients. PTK7 overexpressed or knockdown TNBC cell lines (MDA-MB-468 and MDA-MB-436) were used to analyze the potential roles of PTK7 in TNBC metastasis and tumor progression. A TNBC tumor bearing mouse model was established to further analyze the role of PTK7 in TNBC tumorigenicity in vivo.ResultsPTK7 is highly expressed in breast cancer and correlates with worse prognosis and associates with tumor metastasis and progression in TNBC. Co-expression analysis and gain- or loss-of-function of PTK7 in TNBC cell lines revealed that PTK7 participates in EGFR/Akt signaling regulation and associated with extracellular matrix organization and migration genes in breast cancer, including COL1A1, FN1, WNT5B, MMP11, MMP14 and SDC1. Gain- or loss-of-function experiments of PTK7 suggested that PTK7 promotes proliferation and migration in TNBC cell lines. PTK7 knockdown MDA-MB-468 cell bearing mouse model further demonstrated that PTK7-deficiency inhibits TNBC tumor progression in vivo.ConclusionThis study identified PTK7 as a potential marker of worse prognosis in TNBC and revealed PTK7 promotes TNBC metastasis and progression via EGFR/Akt signaling pathway.

Challenges in the correct assessment of a case of aggressive thyroid carcinoma with synchronous breast cancer, case report and review of the literature: essential role of radiopharmaceuticals

2020 ◽  
Vol 13 ◽  
Author(s):  
Andra Piciu ◽  
Alexandru Mester ◽  
George Rusu ◽  
Doina Piciu
Keyword(s):  
Breast Cancer ◽  
Papillary Thyroid Carcinoma ◽  
Breast Carcinoma ◽  
Thyroid Carcinoma ◽  
Bone Metastases ◽  
Essential Role ◽  
Papillary Thyroid ◽  
Invasive Ductal Breast Carcinoma ◽  
Ductal Breast Carcinoma

Background: Thyroid carcinoma represents a complex pathology that can still be considered a medical challenge, despite having a better prognosis and life expectancy than most other neoplasms, also the scenario of multiple malignancies involving thyroid cancer is nowadays a common reality. Materials and methods: We reviewed the literature regarding the aggressive presentation of synchronous thyroid and breast cancer. In the current paper we are reporting the case of a 59 years-old woman, diagnosed with invasive ductal breast carcinoma and papillary thyroid carcinoma, presenting a natural history of both aggressive synchronous tumors. At the moment of hospitalization, the diagnostic was breast carcinoma with multiple secondary lesions, suggestive for lung and bone metastases, and nodular goiter. Results: Searching the literature PUBMED with the terms “thyroid carcinoma and synchronous breast carcinoma we found 86 studies; introducing the term “aggressive” the result included 4 studies, among them none being relevant for aggressive and synchronous. A similar search was done in SCOPUS finding 92 documents and after introducing the term aggressive, the number of papers was 8, none being for the synchronous aggressive metastatic thyroid and breast carcinoma. The majority of imaging diagnostic tools were used in this particular medical case, in order to ensure the best potential outcome. The final diagnostic was papillary thyroid carcinoma with lung and unusual multiple bone metastases and synchronous invasive ductal breast carcinoma with subcutaneous metastases. Conclusion: The case illustrates the challenges in correct assessment of oncologic patients, despite the advances in medical imaging and technologies and underlines the essential role of nuclear medicine procedures in the diagnostic and therapy protocols.

scholarly journals Synthesis and characterization of novel protein nanodots as drug delivery carriers with an enhanced biological efficacy of melatonin in breast cancer cells

RSC Advances ◽  
2021 ◽  
Vol 11 (16) ◽  
pp. 9076-9085
Author(s):  
Kanchan Yadav ◽  
Megha Das ◽  
Nurul Hassan ◽  
Archana Mishra ◽  
Jayeeta Lahiri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Delivery ◽  
Cancer Cells ◽  
Live Cell Imaging ◽  
Biomedical Applications ◽  
Breast Cancer Cells ◽  
Cell Imaging ◽  
Synthesis And Characterization ◽  
Novel Protein

A novel nanodot-using protein has been synthesized for the live cell imaging and drug delivery of melatonin in breast cancer cells. Its unique properties hold potential for various biomedical applications in the field of bioimaging and drug delivery.

Essential Role of Src Suppressed C Kinase Substrates in Schwann Cells Adhesion, Spreading and Migration

2008 ◽  
Vol 34 (5) ◽  
pp. 1002-1010 ◽  
Author(s):  
Meijuan Yan ◽  
Chun Cheng ◽  
Jing Jiang ◽  
Yonghua Liu ◽  
Ying Gao ◽  
...  
Keyword(s):  
Schwann Cells ◽  
Essential Role ◽  
And Migration ◽  
Kinase Substrates

scholarly journals Cell adaptive response to extracellular matrix density is controlled by ICAP-1–dependent β1-integrin affinity

2008 ◽  
Vol 180 (2) ◽  
pp. 427-441 ◽  
Author(s):  
Angélique Millon-Frémillon ◽  
Daniel Bouvard ◽  
Alexei Grichine ◽  
Sandra Manet-Dupé ◽  
Marc R. Block ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Β1 Integrin ◽  
Embryonic Fibroblasts ◽  
Matrix Surface ◽  
Extracellular Microenvironment ◽  
And Migration ◽  
Integrated Response ◽  
Insight Into

Cell migration is an integrated process requiring the continuous coordinated assembly and disassembly of adhesion structures. How cells orchestrate adhesion turnover is only partially understood. We provide evidence for a novel mechanistic insight into focal adhesion (FA) dynamics by demonstrating that integrin cytoplasmic domain–associated protein 1 (ICAP-1) slows down FA assembly. Live cell imaging, which was performed in both Icap-1–deficient mouse embryonic fibroblasts and cells expressing active β1 integrin, shows that the integrin high affinity state favored by talin is antagonistically controlled by ICAP-1. This affinity switch results in modulation in the speed of FA assembly and, consequently, of cell spreading and migration. Unexpectedly, the ICAP-1–dependent decrease in integrin affinity allows cell sensing of matrix surface density, suggesting that integrin conformational changes are important in mechanotransduction. Our results clarify the function of ICAP-1 in cell adhesion and highlight the central role it plays in the cell's integrated response to the extracellular microenvironment.

scholarly journals PDGFBB promotes proliferation and migration via regulating miR-1181/STAT3 axis in human pulmonary arterial smooth muscle cells

2018 ◽  
Vol 315 (6) ◽  
pp. L965-L976 ◽  
Author(s):  
Zhengjiang Qian ◽  
Yanjiao Li ◽  
Haiyang Yang ◽  
Jidong Chen ◽  
Xiang Li ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Causative Factor ◽  
Loss Of Function ◽  
Migration Flow ◽  
Pulmonary Arterial ◽  
And Migration ◽  
Proliferation And Migration

Platelet-derived growth factor (PDGF) can induce hyperproliferation of pulmonary artery smooth muscle cells (PASMCs), which is a key causative factor to the occurrence and progression of pulmonary arterial hypertension (PAH). We previously identified that miR-1181 is significantly downregulated by PDGFBB in human PASMCs. In this work, we further explore the function of miR-1181 and underlying regulatory mechanisms in PDGF-induced PASMCs. First, the expression pattern of miR-1181 was characterized under PDGFBB treatment, and PDGF receptor/PKCβ signaling was found to repress miR-1181 expression. Then, gain- and loss-of-function experiments were respectively conducted and revealed the prominent role of miR-1181 in inhibiting PASMC proliferation and migration. Flow cytometry analysis suggested that miR-1181 regulated the PASMC proliferation through influencing the cell cycle transition from G0/G1 to S phase. Moreover, we exhibited that miR-1181 targeting STAT3 formed a regulatory axis to modulate PASMC proliferation. Finally, serum miR-1181 expression was also observed to be reduced in adult and newborn patients with PAH. Overall, this study provides novel findings that the miR-1181/STAT3 axis mediated PDGFBB-induced dysfunction in human PASMCs, implying a potential use of miR-1181 as a therapeutic and diagnostic candidate for the vascular remodeling diseases.

scholarly journals LRRK2 mediates tubulation and vesicle sorting from membrane damaged lysosomes

2020 ◽  
Author(s):  
Luis Bonet-Ponce ◽  
Alexandra Beilina ◽  
Chad D. Williamson ◽  
Eric Lindberg ◽  
Jillian H. Kluss ◽  
...  
Keyword(s):  
Live Cell Imaging ◽  
Cell Imaging ◽  
Super Resolution ◽  
Adaptor Protein ◽  
Dependent Manner ◽  
Leucine Rich Repeat ◽  
Biological Functions ◽  
New Process ◽  
Sporadic Parkinson’S Disease

ABSTRACTMutations in the leucine rich repeat kinase 2 (LRRK2) gene are a cause of familial and sporadic Parkinson’s disease (PD). Nonetheless, the biological functions of LRRK2 remain incompletely understood. Here, we observed that LRRK2 is recruited to lysosomes that have a ruptured membrane. Using unbiased proteomics, we observed that LRRK2 is able to recruit the motor adaptor protein JIP4 to permeabilized lysosomes in a kinase-dependent manner through the phosphorylation of RAB35 and RAB10. Super-resolution live cell imaging microscopy and FIB-SEM revealed that once at the lysosomal membrane, JIP4 promotes the formation of LAMP1-negative lysosomal tubules that release membranous content from ruptured lysosomes. Released vesicular structures are able to interact with other lysosomes. Thus, we described a new process that uses lysosomal tubulation to release vesicular structures from permeabilized lysosomes. LRRK2 orchestrates this process that we name LYTL (LYsosomal Tubulation/sorting driven by LRRK2) that, given the central role of the lysosome in PD, is likely to be disease relevant.

scholarly journals The Potential Prognostic Role of Oligosaccharide-Binding Fold-Containing Protein 2A (OBFC2A) in Triple-Negative Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Qianxue Wu ◽  
Xin Tang ◽  
Wenming Zhu ◽  
Qing Li ◽  
Xiang Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Candidate Genes ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
G1 Phase ◽  
And Migration

BackgroundPatients with triple-negative breast cancer (TNBC) have poor overall survival. The present study aimed to investigate the potential prognostics of TNBC by analyzing breast cancer proteomic and transcriptomic datasets.MethodsCandidate proteins selected from CPTAC (the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium) were validated using datasets from METABRIC (Molecular Taxonomy of Breast Cancer International Consortium). Kaplan-Meier analysis and ROC (receiver operating characteristic) curve analysis were performed to explore the prognosis of candidate genes. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis were performed on the suspected candidate genes. Single-cell RNA-seq (scRNA-seq) data from GSE118389 were used to analyze the cell clusters in which OBFC2A (Oligosaccharide-Binding Fold-Containing Protein 2A) was mainly distributed. TIMER (Tumor Immune Estimation Resource) was used to verify the correlation between OBFC2A expression and immune infiltration. Clone formation assays and wound healing assays were used to detect the role of OBFC2A expression on the proliferation, invasion, and migration of breast cancer cells. Flow cytometry was used to analyze the effects of silencing OBFC2A on breast cancer cell cycle and apoptosis.ResultsSix candidate proteins were found to be differentially expressed in non-TNBC and TNBC groups from CPTAC. However, only OBFC2A was identified as an independently poor prognostic gene marker in METABRIC (HR=3.658, 1.881-7.114). And OBFC2A was associated with immune functions in breast cancer. Biological functional experiments showed that OBFC2A might promote the proliferation and migration of breast cancer cells. The inhibition of OBFC2A expression blocked the cell cycle in G1 phase and inhibited the transformation from G1 phase to S phase. Finally, downregulation of OBFC2A also increased the total apoptosis rate of cells.ConclusionOn this basis, OBFC2A may be a potential prognostic biomarker for TNBC.

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