scholarly journals Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Peter J. Cook ◽  
Rozario Thomas ◽  
Ram Kannan ◽  
Esther Sanchez de Leon ◽  
Alexander Drilon ◽  
...  
Keyword(s):  
High Throughput Sequencing ◽  
Ex Vivo ◽  
Human Cancer ◽  
Chromosomal Rearrangements ◽  
Genomic Rearrangements ◽  
General Strategy ◽  
Widespread Application ◽  
Oncogenic Potential ◽  
Chromosomal Engineering

Abstract The widespread application of high-throughput sequencing methods is resulting in the identification of a rapidly growing number of novel gene fusions caused by tumour-specific chromosomal rearrangements, whose oncogenic potential remains unknown. Here we describe a strategy that builds upon recent advances in genome editing and combines ex vivo and in vivo chromosomal engineering to rapidly and effectively interrogate the oncogenic potential of genomic rearrangements identified in human brain cancers. We show that one such rearrangement, an microdeletion resulting in a fusion between Brevican (BCAN) and Neurotrophic Receptor Tyrosine Kinase 1 (NTRK1), is a potent oncogenic driver of high-grade gliomas and confers sensitivity to the experimental TRK inhibitor entrectinib. This work demonstrates that BCAN-NTRK1 is a bona fide human glioma driver and describes a general strategy to define the oncogenic potential of novel glioma-associated genomic rearrangements and to generate accurate preclinical models of this lethal human cancer.

scholarly journals Combination of Antiretroviral Drugs Zidovudine and Efavirenz Impairs Tumor Growths in a Mouse Model of Cancer

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2396
Author(s):  
Marcel A. Schneider ◽  
Anton A. Buzdin ◽  
Achim Weber ◽  
Pierre-Alain Clavien ◽  
Pieter Borger
Keyword(s):  
Target Gene ◽  
Human Cancer ◽  
Chromosomal Rearrangements ◽  
Antiretroviral Drugs ◽  
Colorectal Tumors ◽  
Oncogenic Potential ◽  
Reading Frame ◽  
Human Cancer Cell Lines

LINE1 retrotransposons, which are thought to be the remnants of ancient integrations of retrovirus-like elements, are aberrantly (re)activated in many cancer cells. Due to LINE1-induced alterations in target gene expression and/or chromosomal rearrangements, they may be important drivers of tumorigenesis. Moreover, LINE1 encoded proteins, Open Reading Frame (ORF)1 and ORF2, may have pro-oncogenic potential through inductors of oncogenic transcription factors or inhibitors of cell cycle suppressors. The current study therefore aimed to investigate in vitro and in vivo anti-tumorigenic effects of two well-known antiretroviral drugs, zidovudine, a nucleoside analogue inhibitor of RT (NRTI), and efavirenz, a non-nucleoside RT inhibitor (NNRTI). Our data demonstrate that both drugs in clinically relevant doses significantly reduced the proliferation of murine and human cancer cell lines, as well as growth of tumors in a murine subcutaneous model. Intriguingly, we found that the combination of both zidovudine and efavirenz almost entirely blocked tumorigenesis in vivo. Because both drugs are FDA-approved agents and the combination was very well tolerated in mice, the combination therapy as presented in our paper might be an opportunity to treat colorectal tumors and metastasis to the liver in an inexpensive way.

IRF6 and TAK1 coordinately promote the activation of HIPK2 to stimulate apoptosis during palate fusion

2019 ◽  
Vol 12 (593) ◽  
pp. eaav7666 ◽  
Author(s):  
Chen-Yeh Ke ◽  
Hua-Hsuan Mei ◽  
Fen-Hwa Wong ◽  
Lun-Jou Lo
Keyword(s):  
Transcription Factor ◽  
Cell Apoptosis ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Ex Vivo ◽  
Human Cancer ◽  
Ectopic Expression ◽  
Interacting Protein ◽  
Human Cancer Cells

Cleft palate is a common craniofacial defect caused by a failure in palate fusion. The palatal shelves migrate toward one another and meet at the embryonic midline, creating a seam. Transforming growth factor–β3 (TGF-β3)–induced apoptosis of the medial edge epithelium (MEE), the cells located along the seam, is required for completion of palate fusion. The transcription factor interferon regulatory factor 6 (IRF6) promotes TGF-β3–induced MEE cell apoptosis by stimulating the degradation of the transcription factor ΔNp63 and promoting the expression of the gene encoding the cyclin-dependent kinase inhibitor p21. Because homeodomain-interacting protein kinase 2 (HIPK2) functions downstream of IRF6 in human cancer cells and is required for ΔNp63 protein degradation in keratinocytes, we investigated whether HIPK2 played a role in IRF6-induced ΔNp63 degradation in palate fusion. HIPK2 was present in the MEE cells of mouse palatal shelves during seam formation in vivo, and ectopic expression of IRF6 in palatal shelves cultured ex vivo stimulated the expression of Hipk2 and the accumulation of phosphorylated HIPK2. Knockdown and ectopic expression experiments in organ culture demonstrated that p21 was required for HIPK2- and IRF6-dependent activation of caspase 3, MEE apoptosis, and palate fusion. Contact between palatal shelves enhanced the phosphorylation of TGF-β–activated kinase 1 (TAK1), which promoted the phosphorylation of HIPK2 and palate fusion. Our findings demonstrate that HIPK2 promotes seam cell apoptosis and palate fusion downstream of IRF6 and that IRF6 and TAK1 appear to coordinately enhance the abundance and activation of HIPK2 during palate fusion.

scholarly journals Bioengineered 3D models of human pancreatic cancer recapitulate in vivo tumour biology

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
David Osuna de la Peña ◽  
Sara Maria David Trabulo ◽  
Estelle Collin ◽  
Ying Liu ◽  
Shreya Sharma ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Human Cancer ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Patient Specific ◽  
In Vivo Models ◽  
Mesenchymal Transition ◽  
Matrix Deposition ◽  
Tumour Biology

AbstractPatient-derived in vivo models of human cancer have become a reality, yet their turnaround time is inadequate for clinical applications. Therefore, tailored ex vivo models that faithfully recapitulate in vivo tumour biology are urgently needed. These may especially benefit the management of pancreatic ductal adenocarcinoma (PDAC), where therapy failure has been ascribed to its high cancer stem cell (CSC) content and high density of stromal cells and extracellular matrix (ECM). To date, these features are only partially reproduced ex vivo using organoid and sphere cultures. We have now developed a more comprehensive and highly tuneable ex vivo model of PDAC based on the 3D co-assembly of peptide amphiphiles (PAs) with custom ECM components (PA-ECM). These cultures maintain patient-specific transcriptional profiles and exhibit CSC functionality, including strong in vivo tumourigenicity. User-defined modification of the system enables control over niche-dependent phenotypes such as epithelial-to-mesenchymal transition and matrix deposition. Indeed, proteomic analysis of these cultures reveals improved matrisome recapitulation compared to organoids. Most importantly, patient-specific in vivo drug responses are better reproduced in self-assembled cultures than in other models. These findings support the use of tuneable self-assembling platforms in cancer research and pave the way for future precision medicine approaches.

scholarly journals Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer

Science ◽  
2020 ◽  
Vol 370 (6522) ◽  
pp. 1328-1334
Author(s):  
Sri Krishna ◽  
Frank J. Lowery ◽  
Amy R. Copeland ◽  
Erol Bahadiroglu ◽  
Ratnadeep Mukherjee ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Human Cancer ◽  
Clinical Success ◽  
Tumor Infiltrating Lymphocytes ◽  
Adoptive T Cell Therapy ◽  
Complete Regression ◽  
Autologous Tumor ◽  
T Cell Therapy ◽  
The Impact

Adoptive T cell therapy (ACT) using ex vivo–expanded autologous tumor-infiltrating lymphocytes (TILs) can mediate complete regression of certain human cancers. The impact of TIL phenotypes on clinical success of TIL-ACT is currently unclear. Using high-dimensional analysis of human ACT products, we identified a memory-progenitor CD39-negative stem-like phenotype (CD39−CD69−) associated with complete cancer regression and TIL persistence and a terminally differentiated CD39-positive state (CD39+CD69+) associated with poor TIL persistence. Most antitumor neoantigen-reactive TILs were found in the differentiated CD39+ state. However, ACT responders retained a pool of CD39− stem-like neoantigen-specific TILs that was lacking in ACT nonresponders. Tumor-reactive stem-like TILs were capable of self-renewal, expansion, persistence, and superior antitumor response in vivo. These data suggest that TIL subsets mediating ACT response are distinct from TIL subsets enriched for antitumor reactivity.

DNA-mediated transfection as a model for oncogenesis

1988 ◽  
Vol 66 (6) ◽  
pp. 594-616 ◽  
Author(s):  
Mary Pat Moyer ◽  
John W. Egan ◽  
J. Bradley Aust ◽  
Rex C. Moyer
Keyword(s):  
Animal Models ◽  
Human Cancer ◽  
Neoplastic Transformation ◽  
Dna Transfer ◽  
Dna Transfection ◽  
Tumor Induction ◽  
Oncogenic Potential ◽  
Cancer Initiation

DNA transfer technology has greatly contributed to progress in understanding molecular biology and genetics. In recent years, great efforts have been expended to determine the oncogenic potential of single, defined genes or complex gene mixtures as a prelude to defining the role those genes may play in neoplastic transformation in vitro and tumor induction in vivo. This paper reviews the currently available DNA transfection techniques and their application toward understanding cancer initiation and progression, and how the in vitro and animal models may apply to human cancer.

scholarly journals Cytolytic Activity of the Human Papillomavirus Type 16 E711-20Epitope-Specific Cytotoxic T Lymphocyte Is Enhanced by Heat Shock Protein 110 inHLA-A*0201Transgenic Mice

2013 ◽  
Vol 20 (7) ◽  
pp. 1027-1033 ◽  
Author(s):  
Zhenzhen Ding ◽  
Rongying Ou ◽  
Bing Ni ◽  
Jun Tang ◽  
Yunsheng Xu
Keyword(s):  
Immune Response ◽  
Human Papillomavirus ◽  
Heat Shock ◽  
Mouse Model ◽  
Cytotoxic T Lymphocyte ◽  
Ex Vivo ◽  
Human Cancer ◽  
Cytolytic Activity ◽  
Protein Antigens

ABSTRACTHeat shock proteins (HSPs) have been successfully applied to a broad range of vaccines as biological adjuvants to enhance the immune response. The recently defined HSP110, in particular, exhibits strong protein binding affinity and is capable of enhancing the immunogenicity of protein antigens remarkably more than other HSP family members. In our previous study, we verified that murine HSP110 (mHSP110) significantly enhanced the immune response of a C57BL/6 mouse model to the H-2d-restricted human papillomavirus (HPV) E749-57epitope (short peptide spanning the 49th to 57th amino acid residues in the E7 protein). To determine whether HSP110 similarly enhances the immunogenicity of human epitope peptides, we used theHLA-A2transgenic mouse model to investigate the efficacy of the mHSP110 chaperone molecule as an immunoadjuvant of the human HLA-A2-restricted HPV16 E711-20epitope vaccine. Results showed that mHSP110 efficiently formed a noncovalently bound complex with the E711-20epitope. The mHSP110-E711-20complex induced epitope-specific splenocyte proliferation and E711-20-specific gamma interferon (IFN-γ) secretion. Importantly, cytotoxic T lymphocytes primed by the mHSP110-E711-20complex exerted strong cytolytic effects on target T2cells pulsed with the E711-20peptide or TC-1 cells transfected with theHLA-A2gene. In addition, the mHSP110-E711-20complex elicited strongerex vivoandin vivoantitumor responses than either emulsified complete Freund's adjuvant or HSP70-chaperoned E711-20peptide. These collective data suggest that HSP110 is a promising immunomodulator candidate for peptide-based human cancer vaccines, such as for the HLA-A2-restricted E711-20epitope.

scholarly journals Calcium Imaging of Living Astrocytes in the Mouse Spinal Cord following Sensory Stimulation

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Giovanni Cirillo ◽  
Daniele De Luca ◽  
Michele Papa
Keyword(s):  
Spinal Cord ◽  
Cultured Cells ◽  
Ex Vivo ◽  
Sensory Stimulation ◽  
Widespread Application ◽  
Two Photon Microscopy ◽  
Two Photon ◽  
Heart Beating ◽  
Sensory Activity

Astrocytic Ca2+dynamics have been extensively studied inex vivomodels; however, the recent development of two-photon microscopy and astrocyte-specific labeling has allowed the study of Ca2+signaling in living central nervous system. Ca2+waves in astrocytes have been described in cultured cells and slice preparations, but evidence for astrocytic activation during sensory activity is lacking. There are currently few methods to image living spinal cord: breathing and heart-beating artifacts have impeded the widespread application of this technique. We here imaged the living spinal cord by two-photon microscopy in C57BL6/J mice. Through pressurized injection, we specifically loaded spinal astrocytes using the red fluorescent dye sulforhodamine 101 (SR101) and imaged astrocytic Ca2+levels with Oregon-Green BAPTA-1 (OGB). Then, we studied astrocytic Ca2+levels at rest and after right electrical hind paw stimulation. Sensory stimulation significantly increased astrocytic Ca2+levels within the superficial dorsal horn of the spinal cord compared to rest. In conclusion,in vivomorphofunctional imaging of living astrocytes in spinal cord revealed that astrocytes actively participate to sensory stimulation.

scholarly journals Viral Causality of Human Cancer and Potential Roles of Human Endogenous Retroviruses in the Multi-Omics Era: An Evolutionary Epidemiology Review

2021 ◽  
Vol 11 ◽  
Author(s):  
Konstantina Kitsou ◽  
Maria Iliopoulou ◽  
Vana Spoulou ◽  
Pagona Lagiou ◽  
Gkikas Magiorkinis
Keyword(s):  
Cell Biology ◽  
High Throughput Sequencing ◽  
Clinical Epidemiology ◽  
Human Cancer ◽  
Endogenous Retroviruses ◽  
International Agency ◽  
Human Virus ◽  
Sequencing Technologies

Being responsible for almost 12% of cancers worldwide, viruses are among the oldest known and most prevalent oncogenic agents. The quality of the evidence for the in vivo tumorigenic potential of microorganisms varies, thus accordingly, viruses were classified in 4 evidence-based categories by the International Agency for Research on Cancer in 2009. Since then, our understanding of the role of viruses in cancer has significantly improved, firstly due to the emergence of high throughput sequencing technologies that allowed the “brute-force” recovery of unknown viral genomes. At the same time, multi-omics approaches unravelled novel virus-host interactions in stem-cell biology. We now know that viral elements, either exogenous or endogenous, have multiple sometimes conflicting roles in human pathophysiology and the development of cancer. Here we integrate emerging evidence on viral causality in human cancer from basic mechanisms to clinical studies. We analyze viral tumorigenesis under the scope of deep-in-time human-virus evolutionary relationships and critically comment on the evidence through the eyes of clinical epidemiology, firstly by reviewing recognized oncoviruses and their mechanisms of inducing tumorigenesis, and then by examining the potential role of integrated viruses in our genome in the process of carcinogenesis.

Higher Atazanavir Plasma Exposure in Rats is Associated with Gut Microbiota Changes Induced by Cotrimoxazole

2019 ◽  
Vol 20 (11) ◽  
pp. 898-906
Author(s):  
Joe Miantezila Basilua ◽  
Olivier Sawoo ◽  
Irène Mangin ◽  
Flore Dossou-Yovo ◽  
Aline Boussard ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
High Throughput Sequencing ◽  
Opportunistic Infections ◽  
Ex Vivo ◽  
Gastrointestinal Transit ◽  
Concomitant Administration ◽  
Primary Prophylaxis ◽  
Control Group ◽  
Gastrointestinal Transit Time

Background: Cotrimoxazole (TMP-SMX) is concomitantly used as a primary prophylaxis of opportunistic infections with antiretroviral agents, such as Atazanavir (ATV). Results from an ex vivo study showed changes in intestinal absorption of ATV when rats were pretreated with TMP-SMX. The objective of this in vivo study is to determine the effect of TMP-SMX on the pharmacokinetics of ATV in rats. We also studied changes in gut microbiota induced by TMP-SMX. Methods: We used the non-compartment analysis to compare the pharmacokinetics of ATV in a parallel group of rats treated with a low or therapeutic dose of TMP-SMX for nine days to untreated control rats. Gut microbiota was characterized using qPCR and High Throughput Sequencing of 16S rDNA. Results: Rats treated with TMP-SMX showed a much broader exposure to ATV compared to the control group (AUC0-8h (ng.mL-1.h), 25975.9±4048.7 versus 2587.6±546.9, p=0.001). The main observation regarding the gut microbiota was a lower proportion of enterobacteria related to the administration of TMP-SMX. Moreover, the Total Gastrointestinal Transit Time (TGTT) was longer in the TMP-SMX treated group. Conclusion: Concomitant administration of TMP-SMX and ATV significantly increased ATV exposure in rats. This increase could be the result of a prolonged TGTT leading to an increase in the intestinal residence time of ATV favoring its absorption. Gut microbiota changes induced by TMP-SMX could be at the origin of this prolonged TGTT. If demonstrated in humans, this potential interaction could be accompanied by an increase in the adverse effects of ATV.

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