Monitoring the dynamics of clonal tumour evolution in vivo using secreted luciferases

Charles, Joël P.; Fuchs, Jeannette; Hefter, Mirjam; Vischedyk, Jonas B.; Kleint, Maximilian; Vogiatzi, Fotini; Schäfer, Jonas; Nist, Andrea; Timofeev, Oleg; Wanzel, Michael; Stiewe, Thorsten

doi:10.1038/ncomms4981

Cited by 20 publications

(32 citation statements)

References 34 publications

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“…Indeed, Lee et al. found a relation of early tumor recurrence and chromosomal instability with drug resistance . Misale et al.…”

Section: Discussionmentioning

confidence: 99%

“…Due to the heterogeneity and chromosome instability of cancer cells, targeted therapy may be compromised [24,25]. Indeed, Lee et al found a relation of early tumor recurrence and chromosomal instability with drug resistance [26][27][28]. Misale et al performed genotyping on cfDNA exacted from plasma of 24 patients with colorectal cancer, and showed that clinical resistance arose through the acquisition of mutations detected by cfDNA [22,29].…”

Section: Discussionmentioning

confidence: 99%

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Post surgery circulating free tumor DNA is a predictive biomarker for relapse of lung cancer

Yang

Zhang

et al. 2017

Cancer Medicine

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Cancer cells release DNA fragments into plasma as circulating free DNA (cfDNA). However, quantitative measurement of tumor‐derived DNA in cfDNA remains challenge. The purpose of this study was to quantitatively assess tumor‐derived DNA in lung cancer patients. By optimizing competitive allele‐specific TaqMan PCR (CAST‐PCR), we assessed the copy number of mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) and epidermal growth factor receptor (EGFR) alleles in the pre/post surgery plasma of 168 lung cancer patients. An absolute quantitative PCR method was developed to assess the number of total cfDNA. All mutations detected in tumors were also found in the plasma after surgery. At the time of 30 days after surgery, EGFR mutation of circulating cell‐free DNA was detected only in two patients who recurred in 4 months after surgery. Compared to that of normal control at 30 days after surgery, five patients who recurred in 4 months had significantly higher circulating cell‐free DNA (P < 0.001), whereas six patients who recurred after 4 months (P = 0.207) and five patients without recurrence (P = 0.901) demonstrated significantly lower circulating cell‐free DNA. Our findings suggest that cfDNA analysis in plasma is an alternative and supplement to tissue analysis and hold promise for clinical application. Stratification of patients according to cfDNA levels at 30 days after surgery might be helpful in selecting lung cancer patients for adjuvant therapy after surgery.

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“…Indeed, Lee et al. found a relation of early tumor recurrence and chromosomal instability with drug resistance . Misale et al.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Post surgery circulating free tumor DNA is a predictive biomarker for relapse of lung cancer

Yang

Zhang

et al. 2017

Cancer Medicine

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“…Lung colonization after i.v. tail vein injection of tumor cells was performed as previously described (39). In brief,…”

Section: Methodsmentioning

confidence: 99%

“…To quantitatively track the proliferation of knock-down cells in vivo, we coupled shRNA expression to secreted luciferases that accumulate in the blood of tumor-bearing mice and can be used as an artificial tumor marker for longitudinal monitoring of tumor burden (39). To directly compare knockdown and control cells within the same animal, we used a dual luciferase labeling approach (39). First, MDA-MB-231 cells were labeled with Gaussia luciferase (GLuc) in conjunction with shRNAs targeting mutp53, ENTPD5 or a nontargeting (nsh) control (Fig.…”

Section: Entpd5mentioning

confidence: 99%

Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5

Vogiatzi

Brandt

Schneikert

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in cancer and are often associated with progression from benign to invasive stages with metastatic potential. Mutations inactivate tumor suppression by p53, and some endow the protein with novel gain of function (GOF) properties that actively promote tumor progression and metastasis. By comparative gene expression profiling of p53-mutated and p53-depleted cancer cells, we identified ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a mutant p53 target gene, which functions as a uridine 5′-diphosphatase (UDPase) in the endoplasmic reticulum (ER) to promote the folding of N-glycosylated membrane proteins. A comprehensive pan-cancer analysis revealed a highly significant correlation between p53 GOF mutations and ENTPD5 expression. Mechanistically, mutp53 is recruited by Sp1 to the ENTPD5 core promoter to induce its expression. We show ENTPD5 to be a mediator of mutant p53 GOF activity in clonogenic growth, architectural tissue remodeling, migration, invasion, and lung colonization in an experimental metastasis mouse model. Our study reveals folding of N-glycosylated membrane proteins in the ER as a mechanism underlying the metastatic progression of tumors with mutp53 that could provide new possibilities for cancer treatment.M utations in the TP53 tumor suppressor gene are the most frequent genetic alterations in human cancer and commonly compromise the gene's tumor suppressor activity. p53-knockout mice succumb to tumors very early in life, arguing that the loss of function associated with p53 mutations is sufficient on its own to explain the high mutation frequency observed in patients with cancer (1). However, in striking contrast to mutations in other tumor suppressor genes, the vast majority of TP53 gene alterations in patients with cancer neither ablate p53 expression nor produce unstable or truncated proteins. Instead, p53 mutations are mostly missense mutations resulting in expression of mutant p53 (mutp53) proteins with only single-amino acid substitutions that accumulate to steady-state levels greatly exceeding those of wild-type p53 (wtp53) in normal tissues. Immunohistochemical positivity for p53 is therefore considered a diagnostic marker for the presence of a TP53 mutation (2). The high prevalence of missense mutations suggests a selective advantage during cancer progression, so it was hypothesized early on in p53 research that p53 mutations are neomorphic and endow the mutp53 protein with novel oncogenic functions that actively promote cancer progression and therapy resistance (2). These oncogenic properties are generally referred to as the mutp53 gain of function (GOF).Over the years, substantial experimental evidence for mutp53 GOF has accumulated (3-5). For example, mice expressing cancer-associated p53 hot spot mutations from the endogenous Trp53 gene locus are remarkably different from p53-deficient mice: tumorigenesis is accelerated, and the spectrum of tumors is shifted toward carcinomas and more meta...

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“…After concentration, residue was purified by column chromatography (silica gel, hexane, ethyl acetate, then acetone) to yield 0.59 g (88%) of product 4 . 3 1 H NMR (400 MHz, CD 3 COCD 3 , ppm) δ 2.65 (t, J = 2.4 Hz, 1 H), 3.97 (d, J = 5.6 Hz, 2 H), 4.05 (dd, J = 5.6, 2.5 Hz, 2 H), 6.30 (s, 1 H), 7.17 (m, 1 H), 7.19 (s, 1 H), 7.79 (s, 1 H), 7.96 (d, J = 8.6 Hz, 1 H). Mass calculated for C 13 H 11 N 4 OS + (M + H + ) 271.065, found 271.064.…”

Section: Methodsmentioning

confidence: 99%

Biotinylated Bioluminescent Probe for Long Lasting Targeted in Vivo Imaging of Xenografted Brain Tumors in Mice

Jiang

Zhu

Moore

et al. 2017

ACS Chem. Neurosci.

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Bioluminescence is a useful tool for imaging of cancer in in vivo animal models that endogenously express luciferase, an enzyme that requires a substrate for visual readout. Current bioluminescence imaging, using commonly available luciferin substrates, only lasts a short time (15–20 min). To avoid repeated administration of luciferase substrate during cancer detection and surgery, a long lasting bioluminescence imaging substrate or system is needed. A novel water-soluble biotinylated luciferase probe, B-YL (1), was synthesized. A receptor-targeted complex of B-YL with streptavidin (SA) together with a biotinylated epidermal growth factor short peptide (B-EGF) (SA/B-YL/B-EGF = 1:3:1, molar ratio) was then prepared to demonstrate selective targeting. The complex was incubated with brain cancer cell lines overexpressing the EGF receptor (EGFR) and transfected with the luciferase gene. Results show that the complex specifically detects cancer cells by bioluminescence. The complex was further used to image xenograft brain tumors transfected with a luciferase gene in mice. The complex detects the tumor immediately, and bioluminescence lasts for 5 days. Thus, the complex generates a long lasting bioluminescence for cancer detection in mice. The complex with selective targeting may be used in noninvasive cancer diagnosis and accurate surgery in cancer treatment in clinics in the future.

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Monitoring the dynamics of clonal tumour evolution in vivo using secreted luciferases

Cited by 20 publications

References 34 publications

Post surgery circulating free tumor DNA is a predictive biomarker for relapse of lung cancer

Post surgery circulating free tumor DNA is a predictive biomarker for relapse of lung cancer

Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5

Biotinylated Bioluminescent Probe for Long Lasting Targeted in Vivo Imaging of Xenografted Brain Tumors in Mice

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