human tumour cells
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Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1049
Author(s):  
Valentina Poltavets ◽  
Jessica W. Faulkner ◽  
Deepak Dhatrak ◽  
Robert J. Whitfield ◽  
Shaun R. McColl ◽  
...  

Metastatic breast cancer has one of the highest mortality rates among women in western society. Chemokine receptors CXCR4 and CCR7 have been shown to be linked to the metastatic spread of breast cancer, however, their precise function and underlying molecular pathways leading to the acquisition of the pro-metastatic properties remain poorly understood. We demonstrate here that the CXCR4 and CCR7 receptor ligands, CXCL12 and CCL19, cooperatively bind and selectively elicit synergistic signalling responses in invasive breast cancer cell lines as well as primary mammary human tumour cells. Furthermore, for the first time, we have documented the presence of CXCR4-CCR7 heterodimers in advanced primary mammary mouse and human tumours where number of CXCR4-CCR7 complexes directly correlate with the severity of the disease. The functional significance of the CXCR4-CCR7 association was also demonstrated when their forced heterodimerization led to the acquisition of invasive phenotype in non-metastatic breast cancer cells. Taken together, our data establish the CXCR4-CCR7 receptor complex as a new functional unit, which is responsible for the acquisition of breast cancer cell metastatic phenotype and which may serve as a novel biomarker for invasive mammary tumours.


2020 ◽  
Author(s):  
Simon Ng ◽  
Shuhui Lim ◽  
Adrian Chong Nyi Sim ◽  
Ruban Mangadu ◽  
Ally Lau ◽  
...  

Immune checkpoint blockade (ICB) leads to durable and complete tumour regression in some patients but in others gives temporary, partial or no response. Accordingly, significant efforts are underway to identify tumour-intrinsic mechanisms underlying ICB resistance. Results from a published mouse model CRISPR screen suggested that targeting an E3 ligase (STUB1) involved with protein homeostasis, may overcome ICB resistance but the molecular basis behind this observation is unclear. Using the ICB-resistant and poorly immunogenic B16-F10 murine melanoma model, we reveal an under-appreciated role of STUB1 to dampen the interferon gamma (IFNγ) response. Deletion of Stub1 in tumour cells increased IFNGR1 abundance on cellular surface, thus lowering the stimulating threshold of IFNγ. These outcomes translated to IFNγ-enhanced antigen presentation and upregulation of the immunoproteasome complexes. Through proteomics and gene expression profiling, we confirmed STUB1 as a negative regulator of the IFNγ signaling pathway. To block the function of STUB1 in tumour cells, we stably expressed a rationally designed inhibitory biologic, which recapitulated the Stub1-null phenotypes in both murine and human tumour cells. Overall, our findings elucidate STUB1 as a barrier for IFNγ sensing and offer a roadmap to pursue STUB1 inhibitors, which may improve tumour response to checkpoint inhibitory therapy.


2020 ◽  
Vol 40 (9) ◽  
pp. 5001-5013
Author(s):  
MARIJA PETROVIC ◽  
SUZANA POPOVIC ◽  
DEJAN BASKIC ◽  
MILOS TODOROVIC ◽  
PREDRAG DJURDJEVIC ◽  
...  

Author(s):  
Andrés Méndez-Lucas ◽  
Wei Lin ◽  
Paul C. Driscoll ◽  
Nathalie Legrave ◽  
Laura Novellasdemunt Vilaseca ◽  
...  

SummaryPlasticity of cancer metabolism can be a major obstacle for efficient targeting of tumour-specific metabolic vulnerabilities. Here, we identify and quantify the compensatory mechanisms following the inhibition of major pathways of central carbon metabolism in c-MYC-induced liver tumours. We find that glutaminase isoform Gls2, expressed in normal liver, compensates for the deletion of Gls1 isoform expressed in tumours. Inhibiting both glutaminases significantly delays tumourigenesis but does not completely block glutamine catabolism through the Krebs cycle. We reveal that glutamine catabolism is then driven by amidotransferases. Consistently, the synergistic effect of glutaminase and amidotransferase inhibitors on proliferation of mouse and human tumour cells is observed in vitro and in vivo. Furthermore, when Gls1 is deleted the Krebs cycle activity and tumour formation can also be significantly affected if glycolysis is co-inhibited (Gls1KO/Hk2KO). Finally, the inhibition of either serine (Psat1KO) or fatty acid (FasnKO) biosynthesis can be compensated by uptake of circulating nutrients. Thus, removing these nutrients from the diet produces synergistic effects on suppression of tumourigenesis. These results highlight the high flexibility of tumour metabolism and demonstrate how targeting compensatory mechanisms can improve a therapeutic outcome.


Proteomes ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 45 ◽  
Author(s):  
Orla Coleman ◽  
Michael Henry ◽  
Fiona O'Neill ◽  
Sandra Roche ◽  
Niall Swan ◽  
...  

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide; it develops in a relatively symptom-free manner, leading to rapid disease progression and metastasis, leading to a 5-year survival rate of less than 5%. A lack of dependable diagnostic markers and rapid development of resistance to conventional therapies are among the problems associated with management of the disease. A better understanding of pancreatic tumour biology and discovery of new potential therapeutic targets are important goals in pancreatic cancer research. This study describes the comparative quantitative LC-MS/MS proteomic analysis of the membrane-enriched proteome of 10 human pancreatic ductal adenocarcinomas, 9 matched adjacent-normal pancreas and patient-derived xenografts (PDXs) in mice (10 at F1 generation and 10 F2). Quantitative label-free LC-MS/MS data analysis identified 129 proteins upregulated, and 109 downregulated, in PDAC, compared to adjacent-normal tissue. In this study, analysing peptide MS/MS data from the xenografts, great care was taken to distinguish species-specific peptides definitively derived from human sequences, or from mice, which could not be distinguished. The human-only peptides from the PDXs are of particular value, since only human tumour cells survive, and stromal cells are replaced during engraftment in the mouse; this list is, therefore, enriched in tumour-associated proteins, some of which might be potential therapeutic or diagnostic targets. Using human-specific sequences, 32 proteins were found to be upregulated, and 113 downregulated in PDX F1 tumours, compared to primary PDAC. Differential expression of CD55 between PDAC and normal pancreas, and expression across PDX generations, was confirmed by Western blotting. These data indicate the value of using PDX models in PDAC research. This study is the first comparative proteomic analysis of PDAC which employs PDX models to identify patient tumour cell-associated proteins, in an effort to find robust targets for therapeutic treatment of PDAC.


2018 ◽  
Vol 2 (12) ◽  
pp. 915-929 ◽  
Author(s):  
Ryan A. Carpenter ◽  
Jun-Goo Kwak ◽  
Shelly R. Peyton ◽  
Jungwoo Lee

2018 ◽  
Vol 42 (16) ◽  
pp. 13784-13789 ◽  
Author(s):  
Guillermo Valdomir ◽  
María de los Ángeles Fernández ◽  
Irene Lagunes ◽  
Juan I. Padrón ◽  
Víctor S. Martín ◽  
...  

Inspired by marine bioactive compounds, the principle of molecular hybridization was applied combining diverse heterocyclic systems by a triazole ring, to produce new and more active compounds.


2018 ◽  
Vol 9 (4) ◽  
pp. 2290-2299 ◽  
Author(s):  
María Agustina Castro ◽  
Boris Rodenak-Kladniew ◽  
Adriana Massone ◽  
Mónica Polo ◽  
Margarita García de Bravo ◽  
...  

Mandarin peel oil exerts an antiproliferative effect on in vitro and in vivo human tumour cells without toxicity effects.


2017 ◽  
Vol 2 (4) ◽  
pp. 101-107
Author(s):  
Adel Sharaf Al-Zubairi

Objective: Several natural products are being increasingly used in the treatment of cancer to minimize the adverse side effects of cancer chemotherapy. Zerumbone (ZER), the sesquiterpene derived from Zingiber zerumbet Smith, has been reported to have an in vitro anticancer effects against various human tumour cells as well as in vivo against a number of induced malignancies in mice. Previously we have reported the genotoxic effects of ZER in vitro against CHO cell lines. Material and Method: The aim of this study was to investigate the genotoxic effects of the combination of ZER along with cisplatin in CHO cells. Two cytogenetic endpoints were used, namely Chromosomal Aberrations assay (CA) and Micronucleus test (MN). Both cytogenetic endpoints were performed without any metabolic activation. Result: ZER treated cultures showed the significant increase in the frequency of the chromosome aberrations and MN induction. In CA assay, marked changes have been observed after co-treatment of CHO cell lines with different concentration of ZER along with 5 µM Cisplatin when compared to ZER treatment alone, suggesting a possible synergistic genetoxic effects. Whereas, treatment of CHO cell lines with different concentrations of ZER along with 2.5 µM Cisplatin was found to reduce chromosomal aberrations, suggesting an antagonistic genotoxic effect. On the other hand, in MN induction test, co-treatment of CHO cell lines with both 2.5 µM and 5 µM Cisplatin and different concentration of ZER found to reduce the genotoxic effects compared to the 2.5 µM and 5 µM Cisplatin alone suggesting an antagonistic genotoxic effect.Conclusion: The genotoxic effects of combined low concentrations of Cisplatin with different concentrations of ZER could have an antagonist genotoxic potential in vitro in CHO cell lines.


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