Publications by authors named "Francesca M Buffa"

80 Publications

ADGRL4/ELTD1 Expression in Breast Cancer Cells Induces Vascular Normalization and Immune Suppression.

Mol Cancer Res 2021 Aug 4. Epub 2021 Aug 4.

MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford, United Kingdom.

ELTD1/ADGRL4 expression is increased in the vasculature of a number of tumor types and this correlates with a good prognosis. Expression has also been reported in some tumor cells with high expression correlating with a good prognosis in hepatocellular carcinoma (HCC) and a poor prognosis in glioblastoma. Here we show that 35% of primary human breast tumors stain positively for ELTD1, with 9% having high expression that correlates with improved relapse-free survival. Using immunocompetent, syngeneic mouse breast cancer models we found that tumors expressing recombinant murine Eltd1 grew faster than controls, with an enhanced ability to metastasize and promote systemic immune effects. The Eltd1-expressing tumors had larger and better perfused vessels and tumor-endothelial cell interaction led to the release of proangiogenic and immune-modulating factors. M2-like macrophages increased in the stroma along with expression of programmed death-ligand 1 (PD-L1) on tumor and immune cells, to create an immunosuppressive microenvironment that allowed Eltd1-regulated tumor growth in the presence of an NY-ESO-1-specific immune response. Eltd1-positive tumors also responded better to chemotherapy which could explain the relationship to a good prognosis observed in primary human cases. Thus, ELTD1 expression may enhance delivery of therapeutic antibodies to reverse the immunosuppression and increase response to chemotherapy and radiotherapy in this subset of tumors. ELTD1 may be useful as a selection marker for such therapies. IMPLICATIONS: ELTD1 expression in mouse breast tumors creates an immunosuppressive microenvironment and increases vessel size and perfusion. Its expression may enhance the delivery of therapies targeting the immune system.
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http://dx.doi.org/10.1158/1541-7786.MCR-21-0171DOI Listing
August 2021

Replication catastrophe induced by cyclic hypoxia leads to increased APOBEC3B activity.

Nucleic Acids Res 2021 07;49(13):7492-7506

Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford, OX3 7DQ, UK.

Tumor heterogeneity includes variable and fluctuating oxygen concentrations, which result in the accumulation of hypoxic regions in most solid tumors. Tumor hypoxia leads to increased therapy resistance and has been linked to genomic instability. Here, we tested the hypothesis that exposure to levels of hypoxia that cause replication stress could increase APOBEC activity and the accumulation of APOBEC-mediated mutations. APOBEC-dependent mutational signatures have been well-characterized, although the physiological conditions which underpin them have not been described. We demonstrate that fluctuating/cyclic hypoxic conditions which lead to replication catastrophe induce the expression and activity of APOBEC3B. In contrast, stable/chronic hypoxic conditions which induce replication stress in the absence of DNA damage are not sufficient to induce APOBEC3B. Most importantly, the number of APOBEC-mediated mutations in patient tumors correlated with a hypoxia signature. Together, our data support the conclusion that hypoxia-induced replication catastrophe drives genomic instability in tumors, specifically through increasing the activity of APOBEC3B.
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http://dx.doi.org/10.1093/nar/gkab551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287932PMC
July 2021

Hypoxia-induced SETX links replication stress with the unfolded protein response.

Nat Commun 2021 06 17;12(1):3686. Epub 2021 Jun 17.

Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.

Tumour hypoxia is associated with poor patient prognosis and therapy resistance. A unique transcriptional response is initiated by hypoxia which includes the rapid activation of numerous transcription factors in a background of reduced global transcription. Here, we show that the biological response to hypoxia includes the accumulation of R-loops and the induction of the RNA/DNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, and DNA replication rates decrease. Therefore, suggesting that, SETX plays a role in protecting cells from DNA damage induced during transcription in hypoxia. Importantly, we propose that the mechanism of SETX induction in hypoxia is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to hypoxia, which includes both a replication stress-dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways.
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http://dx.doi.org/10.1038/s41467-021-24066-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211819PMC
June 2021

Interferon- and STING-independent induction of type I interferon stimulated genes during fractionated irradiation.

J Exp Clin Cancer Res 2021 May 8;40(1):161. Epub 2021 May 8.

Department of Radiation Oncology, Cancer Center Amsterdam, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands.

Background: Improvement of radiotherapy efficacy requires better insight in the dynamic responses that occur during irradiation. Here, we aimed to identify the molecular responses that are triggered during clinically applied fractionated irradiation.

Methods: Gene expression analysis was performed by RNAseq or microarray analysis of cancer cells or xenograft tumors, respectively, subjected to 3-5 weeks of 5 × 2 Gy/week. Validation of altered gene expression was performed by qPCR and/or ELISA in multiple cancer cell lines as well as in pre- and on-treatment biopsies from esophageal cancer patients ( NCT02072720 ). Targeted protein inhibition and CRISPR/Cas-induced gene knockout was used to analyze the role of type I interferons and cGAS/STING signaling pathway in the molecular and cellular response to fractionated irradiation.

Results: Gene expression analysis identified type I interferon signaling as the most significantly enriched biological process induced during fractionated irradiation. The commonality of this response was confirmed in all irradiated cell lines, the xenograft tumors and in biopsies from esophageal cancer patients. Time-course analyses demonstrated a peak in interferon-stimulated gene (ISG) expression within 2-3 weeks of treatment. The response was accompanied by a variable induction of predominantly interferon-beta and/or -lambda, but blocking these interferons did not affect ISG expression induction. The same was true for targeted inhibition of the upstream regulatory STING protein while knockout of STING expression only delayed the ISG expression induction.

Conclusions: Collectively, the presented data show that clinically applied fractionated low-dose irradiation can induce a delayed type I interferon response that occurs independently of interferon expression or STING signaling. These findings have implications for current efforts that aim to target the type I interferon response for cancer treatment.
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http://dx.doi.org/10.1186/s13046-021-01962-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106844PMC
May 2021

Mitochondrial Inhibitor Atovaquone Increases Tumor Oxygenation and Inhibits Hypoxic Gene Expression in Patients with Non-Small Cell Lung Cancer.

Clin Cancer Res 2021 May 17;27(9):2459-2469. Epub 2021 Feb 17.

Department of Oncology, University of Oxford, Oxford, England, United Kingdom.

Purpose: Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial drug atovaquone, a known mitochondrial inhibitor, reduces hypoxia in non-small cell lung cancer (NSCLC).

Patients And Methods: Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: cohort 1 received oral atovaquone at the standard clinical dose of 750 mg twice daily, while cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Intercohort comparison of hypoxia gene expression signatures using RNA sequencing from resected tumors was performed.

Results: Thirty patients were evaluable for hypoxia PET-CT analysis, 15 per cohort. Median treatment duration was 12 days. Eleven (73.3%) atovaquone-treated patients had meaningful HV reduction, with median change -28% [95% confidence interval (CI), -58.2 to -4.4]. In contrast, median change in untreated patients was +15.5% (95% CI, -6.5 to 35.5). Linear regression estimated the expected mean HV was 55% (95% CI, 24%-74%) lower in cohort 1 compared with cohort 2 ( = 0.004), adjusting for cohort, tumor volume, and baseline HV. A key pharmacodynamics endpoint was reduction in hypoxia-regulated genes, which were significantly downregulated in atovaquone-treated tumors. Data from multiple additional measures of tumor hypoxia and perfusion are presented. No atovaquone-related adverse events were reported.

Conclusions: This is the first clinical evidence that targeting tumor mitochondrial metabolism can reduce hypoxia and produce relevant antitumor effects at the mRNA level. Repurposing atovaquone for this purpose may improve treatment outcomes for NSCLC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611473PMC
May 2021

Correction to: Disruption of hypoxia-inducible fatty acid binding protein 7 induces beige fat-like differentiation and thermogenesis in breast cancer cells.

Cancer Metab 2020 10;8:18. Epub 2020 Aug 10.

Department of Oncology, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS UK.

[This corrects the article DOI: 10.1186/s40170-020-00219-4.].
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http://dx.doi.org/10.1186/s40170-020-00224-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418190PMC
August 2020

Disruption of hypoxia-inducible fatty acid binding protein 7 induces beige fat-like differentiation and thermogenesis in breast cancer cells.

Cancer Metab 2020 6;8:13. Epub 2020 Jul 6.

Department of Oncology, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS UK.

Background: Humans produce heat through non-shivering thermogenesis, a metabolic process that occurs in inducible beige adipocytes expressing uncoupling protein 1 (UCP1). UCP1 dissipates the proton gradient of the mitochondrial inner membrane and converts that energy into heat. It is unclear whether cancer cells can exhibit autonomous thermogenesis. Previously, we found that the knockdown of hypoxia-inducible fatty acid binding protein 7 (FABP7) increased reactive oxygen species (ROS) in breast cancer cells. ROS are known to induce beige adipocyte differentiation.

Methods: We investigated the association of tumor hypoxia, FABP7, and UCP1 across breast cancer patients using METABRIC and TCGA data sets. Furthermore, using a breast cancer cell line, HCC1806, we tested the effect of FABP7 knockdown on cellular physiology including thermogenesis.

Results: We found a strong mutual exclusivity of FABP7 and UCP1 expression both in METABRIC and in TCGA, indicating major metabolic phenotypic differences. FABP7 was preferentially distributed in poorly differentiated-, estrogen receptor (ER) negative tumors. In contrast, UCP1 was highly expressed in normal ducts and well-differentiated-, ER positive-, less hypoxic tumors. In the cell line-based experiments, UCP1 and its transcriptional regulators were upregulated upon FABP7 knockdown. UCP1 was induced in about 20% of cancer cells, and the effect was increased further in hypoxia. UCP1 depolarized mitochondrial membranes at the site of expression. UCP1 induction was associated with the increase in proton leak, glycolysis, and maximal respiration, mimicking the typical energy profile of beige adipocytes. Most importantly, UCP1 induction elevated cancer cell temperature associated with increased vulnerability to hypoxia and γ-irradiation.

Conclusions: We demonstrated that breast cancer cells can undergo thermogenesis through UCP1 induction. Disrupting FABP7-mediated fatty acid metabolism can unlock UCP1-mediated thermogenesis, potentially making it possible to develop therapies to target thermogenesis. Further study would be warranted to investigate the effect of rise in temperature of cancer cells on patients' outcomes and the relationship to other metabolic pathways.
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http://dx.doi.org/10.1186/s40170-020-00219-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336487PMC
July 2020

Heritable genetic variants in key cancer genes link cancer risk with anthropometric traits.

J Med Genet 2021 06 26;58(6):392-399. Epub 2020 Jun 26.

Ludwig Cancer Institute, Medical Sciences Division, University of Oxford, Oxford, UK

Background: Height and other anthropometric measures are consistently found to associate with differential cancer risk. However, both genetic and mechanistic insights into these epidemiological associations are notably lacking. Conversely, inherited genetic variants in tumour suppressors and oncogenes increase cancer risk, but little is known about their influence on anthropometric traits.

Methods: By integrating inherited and somatic cancer genetic data from the Genome-Wide Association Study Catalog, expression Quantitative Trait Loci databases and the Cancer Gene Census, we identify SNPs that associate with different cancer types and differential gene expression in at least one tissue type, and explore the potential pleiotropic associations of these SNPs with anthropometric traits through SNP-wise association in a cohort of 500,000 individuals.

Results: We identify three regulatory SNPs for three important cancer genes, FANCA, MAP3K1 and TP53 that associate with both anthropometric traits and cancer risk. Of particular interest, we identify a previously unrecognised strong association between the rs78378222[C] SNP in the 3' untranslated region (3'-UTR) of TP53 and both increased risk for developing non-melanomatous skin cancer (OR=1.36 (95% 1.31 to 1.41), adjusted p=7.62E), brain malignancy (OR=3.12 (2.22 to 4.37), adjusted p=1.43E) and increased standing height (adjusted p=2.18E, beta=0.073±0.007), lean body mass (adjusted p=8.34E, beta=0.073±0.005) and basal metabolic rate (adjusted p=1.13E, beta=0.076±0.006), thus offering a novel genetic link between these anthropometric traits and cancer risk.

Conclusion: Our results clearly demonstrate that heritable variants in key cancer genes can associate with both differential cancer risk and anthropometric traits in the general population, thereby lending support for a genetic basis for linking these human phenotypes.
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http://dx.doi.org/10.1136/jmedgenet-2019-106799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142426PMC
June 2021

Role of gene signatures combined with pathology in classification of oropharynx head and neck cancer.

Sci Rep 2020 06 23;10(1):10226. Epub 2020 Jun 23.

Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales, Australia.

Treatment personalisation remains an unmet need in oropharynx cancer (OPC). We aimed to determine whether gene expression signatures improved upon clinico-pathological predictors of outcome in OPC. The clinico-pathological predictors, AJCC version 7 (AJCC 7), AJCC 8, and a clinical algorithm, were assessed in 4 public series of OPC (n = 235). Literature review identified 16 mRNA gene expression signatures of radiosensitivity, HPV status, tumour hypoxia, and microsatellite instability. We quality tested signatures using a novel sigQC methodology, and added signatures to clinico-pathological variables as predictors of survival, in univariate and multivariate analyses. AJCC 7 Stage was not predictive of recurrence-free survival (RFS) or overall survival (OS). AJCC 8 significantly predicted RFS and OS. Gene signature quality was highly variable. Among HPV-positive cases, signatures for radiosensitivity, hypoxia, and microsatellite instability revealed significant underlying inter-tumour biological heterogeneity, but did not show prognostic significance when adjusted for clinical covariates. Surprisingly, among HPV-negative cases, a gene signature for HPV status was predictive of survival, even after adjustment for clinical covariates. Across the whole series, several gene signatures representing HPV and microsatellite instability remained significant in multivariate analysis. However, quality control and independent validation remain to be performed to add prognostic information above recently improved clinico-pathological variables.
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http://dx.doi.org/10.1038/s41598-020-66983-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311543PMC
June 2020

Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin.

Br J Cancer 2020 01 10;122(2):258-265. Epub 2019 Dec 10.

Department of Oncology, University of Oxford, Churchill Hospital, Oxford, OX3 7LE, UK.

Background: Epidemiological studies suggest that metformin may reduce the incidence of cancer in patients with diabetes and multiple late phase clinical trials assessing the potential of repurposing this drug are underway. Transcriptomic profiling of tumour samples is an excellent tool to understand drug bioactivity, identify candidate biomarkers and assess for mechanisms of resistance to therapy.

Methods: Thirty-six patients with untreated primary breast cancer were recruited to a window study and transcriptomic profiling of tumour samples carried out before and after metformin treatment.

Results: Multiple genes that regulate fatty acid oxidation were upregulated at the transcriptomic level and there was a differential change in expression between two previously identified cohorts of patients with distinct metabolic responses. Increase in expression of a mitochondrial fatty oxidation gene composite signature correlated with change in a proliferation gene signature. In vitro assays showed that, in contrast to previous studies in models of normal cells, metformin reduces fatty acid oxidation with a subsequent accumulation of intracellular triglyceride, independent of AMPK activation.

Conclusions: We propose that metformin at clinical doses targets fatty acid oxidation in cancer cells with implications for patient selection and drug combinations.

Clinical Trial Registration: NCT01266486.
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http://dx.doi.org/10.1038/s41416-019-0665-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986920PMC
January 2020

Identification of anticancer drugs to radiosensitise -wild-type and mutant colorectal cancer.

Cancer Biol Med 2019 May;16(2):234-246

NIHR University College London Hospitals Biomedical Research Centre, UCL Cancer Institute, University College London, London WC1E 6DD, UK.

Objective: Patients with -mutant colorectal cancer (CRC) have a poor prognosis. Molecular status is not currently used to select which drug to use in combination with radiotherapy. Our aim was to identify drugs that radiosensitise CRC cells with known status.

Methods: We screened 298 oncological drugs with and without ionising radiation in colorectal cancer cells isogenic for . Hits from rank product analysis were validated in a 16-cell line panel of human CRC cell lines, using clonogenic survival assays and xenograft models .

Results: Most consistently identified hits were drugs targeting cell growth/proliferation or DNA damage repair. The most effective class of drugs that radiosensitised wild-type and mutant cell lines was PARP inhibitors. In clonogenic survival assays, talazoparib produced a radiation enhancement ratio of 1.9 in DLD1 (-wildtype) cells and 1.8 in RKO ( V600E) cells. In DLD1 xenografts, talazoparib significantly increased the inhibitory effect of radiation on tumour growth ( ≤ 0.01).

Conclusions: Our method for screening large drug libraries for radiosensitisation has identified PARP inhibitors as promising radiosensitisers of colorectal cancer cells with wild-type and mutant backgrounds.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2018.0284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713640PMC
May 2019

E2F1 proteolysis via SCF-cyclin F underlies synthetic lethality between cyclin F loss and Chk1 inhibition.

EMBO J 2019 10 19;38(20):e101443. Epub 2019 Aug 19.

Department of Oncology, Medical Research Council Institute for Radiation Oncology, University of Oxford, Oxford, UK.

Cyclins are central engines of cell cycle progression in conjunction with cyclin-dependent kinases (CDKs). Among the different cyclins controlling cell cycle progression, cyclin F does not partner with a CDK, but instead forms via its F-box domain an SCF (Skp1-Cul1-F-box)-type E3 ubiquitin ligase module. Although various substrates of cyclin F have been identified, the vulnerabilities of cells lacking cyclin F are not known. Thus, we assessed viability of cells lacking cyclin F upon challenging them with more than 180 different kinase inhibitors. The screen revealed a striking synthetic lethality between Chk1 inhibition and cyclin F loss. Chk1 inhibition in cells lacking cyclin F leads to DNA replication catastrophe. Replication catastrophe depends on accumulation of the transcription factor E2F1 in cyclin F-depleted cells. We find that SCF-cyclin F controls E2F1 ubiquitylation and degradation during the G2/M phase of the cell cycle and upon challenging cells with Chk1 inhibitors. Thus, Cyclin F restricts E2F1 activity during the cell cycle and upon checkpoint inhibition to prevent DNA replication stress. Our findings pave the way for patient selection in the clinical use of checkpoint inhibitors.
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http://dx.doi.org/10.15252/embj.2018101443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792013PMC
October 2019

MITF controls the TCA cycle to modulate the melanoma hypoxia response.

Pigment Cell Melanoma Res 2019 11 8;32(6):792-808. Epub 2019 Jul 8.

Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

In response to the dynamic intra-tumor microenvironment, melanoma cells adopt distinct phenotypic states associated with differential expression of the microphthalmia-associated transcription factor (MITF). The response to hypoxia is driven by hypoxia-inducible transcription factors (HIFs) that reprogram metabolism and promote angiogenesis. HIF1α indirectly represses MITF that can activate HIF1α expression. Although HIF and MITF share a highly related DNA-binding specificity, it is unclear whether they co-regulate subset of target genes. Moreover, the genomewide impact of hypoxia on melanoma and whether melanoma cell lines representing different phenotypic states exhibit distinct hypoxic responses is unknown. Here we show that three different melanoma cell lines exhibit widely different hypoxia responses with only a core 23 genes regulated in common after 12 hr in hypoxia. Surprisingly, under hypoxia MITF is transiently up-regulated by HIF1α and co-regulates a subset of HIF targets including VEGFA. Significantly, we also show that MITF represses itself and also regulates SDHB to control the TCA cycle and suppress pseudo-hypoxia. Our results reveal a previously unsuspected role for MITF in metabolism and the network of factors underpinning the hypoxic response in melanoma.
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http://dx.doi.org/10.1111/pcmr.12802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777998PMC
November 2019

Guidelines for using sigQC for systematic evaluation of gene signatures.

Nat Protoc 2019 05 10;14(5):1377-1400. Epub 2019 Apr 10.

Computational Biology and Integrative Genomics Lab, MRC/CRUK Oxford Institute and Department of Oncology, University of Oxford, Oxford, UK.

With the increased use of next-generation sequencing generating large amounts of genomic data, gene expression signatures are becoming critically important tools for the interpretation of these data, and are poised to have a substantial effect on diagnosis, management, and prognosis for a number of diseases. It is becoming crucial to establish whether the expression patterns and statistical properties of sets of genes, or gene signatures, are conserved across independent datasets. Conversely, it is necessary to compare established signatures on the same dataset to better understand how they capture different clinical or biological characteristics. Here we describe how to use sigQC, a tool that enables a streamlined, systematic approach for the evaluation of previously obtained gene signatures across multiple gene expression datasets. We implemented sigQC in an R package, making it accessible to users who have knowledge of file input/output and matrix manipulation in R and a moderate grasp of core statistical principles. SigQC has been adopted in basic biology and translational studies, including, but not limited to, the evaluation of multiple gene signatures for potential clinical use as cancer biomarkers. This protocol uses a previously obtained signature for breast cancer metastasis as an example to illustrate the critical quality control steps involved in evaluating its expression, variability, and structure in breast tumor RNA-sequencing data, a different dataset from that in which the signature was originally derived. We demonstrate how the outputs created from sigQC can be used for the evaluation of gene signatures on large-scale gene expression datasets.
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http://dx.doi.org/10.1038/s41596-019-0136-8DOI Listing
May 2019

Adaptation to HIF1α Deletion in Hypoxic Cancer Cells by Upregulation of GLUT14 and Creatine Metabolism.

Mol Cancer Res 2019 07 18;17(7):1531-1544. Epub 2019 Mar 18.

Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.

Hypoxia-inducible factor 1α is a key regulator of the hypoxia response in normal and cancer tissues. It is well recognized to regulate glycolysis and is a target for therapy. However, how tumor cells adapt to grow in the absence of HIF1α is poorly understood and an important concept to understand for developing targeted therapies is the flexibility of the metabolic response to hypoxia via alternative pathways. We analyzed pathways that allow cells to survive hypoxic stress in the absence of HIF1α, using the HCT116 colon cancer cell line with deleted HIF1α versus control. Spheroids were used to provide a 3D model of metabolic gradients. We conducted a metabolomic, transcriptomic, and proteomic analysis and integrated the results. These showed surprisingly that in three-dimensional growth, a key regulatory step of glycolysis is Aldolase A rather than phosphofructokinase. Furthermore, glucose uptake could be maintained in hypoxia through upregulation of GLUT14, not previously recognized in this role. Finally, there was a marked adaptation and change of phosphocreatine energy pathways, which made the cells susceptible to inhibition of creatine metabolism in hypoxic conditions. Overall, our studies show a complex adaptation to hypoxia that can bypass HIF1α, but it is targetable and it provides new insight into the key metabolic pathways involved in cancer growth. IMPLICATIONS: Under hypoxia and HIF1 blockade, cancer cells adapt their energy metabolism via upregulation of the GLUT14 glucose transporter and creatine metabolism providing new avenues for drug targeting.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-0315DOI Listing
July 2019

Modeling genotypes in their microenvironment to predict single- and multi-cellular behavior.

Gigascience 2019 03;8(3)

Computational Biology and Integrative Genomics, MRC/CRUK Oxford Institute, Departmemt of Oncology, University of Oxford, Old Road Campus, Oxford, Oxfordshire, OX3 7DQ, UK.

A cell's phenotype is the set of observable characteristics resulting from the interaction of the genotype with the surrounding environment, determining cell behavior. Deciphering genotype-phenotype relationships has been crucial to understanding normal and disease biology. Analysis of molecular pathways has provided an invaluable tool to such understanding; however, typically it does not consider the physical microenvironment, which is a key determinant of phenotype. In this study, we present a novel modeling framework that enables the study of the link between genotype, signaling networks, and cell behavior in a three-dimensional microenvironment. To achieve this, we bring together Agent-Based Modeling, a powerful computational modeling technique, and gene networks. This combination allows biological hypotheses to be tested in a controlled stepwise fashion, and it lends itself naturally to model a heterogeneous population of cells acting and evolving in a dynamic microenvironment, which is needed to predict the evolution of complex multi-cellular dynamics. Importantly, this enables modeling co-occurring intrinsic perturbations, such as mutations, and extrinsic perturbations, such as nutrient availability, and their interactions. Using cancer as a model system, we illustrate how this framework delivers a unique opportunity to identify determinants of single-cell behavior, while uncovering emerging properties of multi-cellular growth. This framework is freely available at http://www.microc.org.
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http://dx.doi.org/10.1093/gigascience/giz010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423375PMC
March 2019

Pan-cancer characterisation of microRNA across cancer hallmarks reveals microRNA-mediated downregulation of tumour suppressors.

Nat Commun 2018 12 7;9(1):5228. Epub 2018 Dec 7.

Department of Oncology, Medical Sciences Division, University of Oxford, Oxford, OX3 7DQ, UK.

microRNAs are key regulators of the human transcriptome across a number of diverse biological processes, such as development, aging and cancer, where particular miRNAs have been identified as tumour suppressive and oncogenic. In this work, we elucidate, in a comprehensive manner, across 15 epithelial cancer types comprising 7316 clinical samples from the Cancer Genome Atlas, the association of miRNA expression and target regulation with the phenotypic hallmarks of cancer. Utilising penalised regression techniques to integrate transcriptomic, methylation and mutation data, we find evidence for a complex map of interactions underlying the relationship of miRNA regulation and the hallmarks of cancer. This highlighted high redundancy for the oncomiR-1 cluster of oncogenic miRNAs, in particular hsa-miR-17-5p. In addition, we reveal extensive miRNA regulation of tumour suppressor genes such as PTEN, FAT4 and CDK12, uncovering an alternative mechanism of repression in the absence of mutation, methylation or copy number changes.
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http://dx.doi.org/10.1038/s41467-018-07657-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286392PMC
December 2018

The many faces of mathematical modelling in oncology.

Br J Radiol 2019 Jan 28;92(1093):20180856. Epub 2018 Nov 28.

CRUK/MRC Oxford Institute, Department of Oncology, Medical Science Division, University of Oxford , Oxford , United Kingdom.

The application of modelling to solve problems in biology and medicine, and specifically in oncology and radiation therapy, is increasingly established and holds big promise. We provide an overview of the basic concepts of the field and its current state, along with new tools available and future directions for research. We will outline radiobiology models, examples of other anticancer therapy models, multiscale modelling, and we will discuss mechanistic and phenomenological approaches to modelling.
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http://dx.doi.org/10.1259/bjr.20180856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435080PMC
January 2019

Endogenous miRNA sponges mediate the generation of oscillatory dynamics for a non-coding RNA network.

J Theor Biol 2019 11 30;481:54-60. Epub 2018 Oct 30.

Departments of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, United States. Electronic address:

Oscillations are crucial to the normal function of living organisms, across a wide variety of biological processes. In eukaryotes, oscillatory dynamics are thought to arise from interactions at the protein and RNA levels; however, the role of non-coding RNA in regulating these dynamics remains understudied. In this work, we show how non-coding RNA acting as microRNA (miRNA) sponges in a conserved miRNA - transcription factor feedback motif, can give rise to oscillatory behaviour, and how to test for this experimentally. Control of these non-coding RNA can dynamically create oscillations or stability, and we show how this behaviour predisposes to oscillations in the stochastic limit. These results, supported by emerging evidence for the role of miRNA sponges in development, point towards key roles of different species of miRNA sponges, such as circular RNA, potentially in the maintenance of yet unexplained oscillatory behaviour. These results help to provide a paradigm for understanding functional differences between the many redundant, but distinct RNA species thought to act as miRNA sponges in nature, such as long non-coding RNA, pseudogenes, competing mRNA, circular RNA, and3' UTRs.
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http://dx.doi.org/10.1016/j.jtbi.2018.10.055DOI Listing
November 2019

Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer.

Cell Metab 2018 11 20;28(5):679-688.e4. Epub 2018 Sep 20.

Department of Oncology, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.

Late-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time points to profile the bioactivity of metformin in primary breast cancer. We show metformin reduces the levels of mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumors. Two tumor groups are identified with distinct metabolic responses, an OXPHOS transcriptional response (OTR) group for which there is an increase in OXPHOS gene transcription and an FDG response group with increased 18-FDG uptake. Increase in proliferation, as measured by a validated proliferation signature, suggested that patients in the OTR group were resistant to metformin treatment. We conclude that mitochondrial response to metformin in primary breast cancer may define anti-tumor effect.
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http://dx.doi.org/10.1016/j.cmet.2018.08.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224605PMC
November 2018

Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer.

EBioMedicine 2018 May 23;31:182-189. Epub 2018 Apr 23.

Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester M20 4BX, UK; NIHR Manchester Biomedical Research Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, UK. Electronic address:

Background: Hypoxia is associated with a poor prognosis in prostate cancer. This work aimed to derive and validate a hypoxia-related mRNA signature for localized prostate cancer.

Method: Hypoxia genes were identified in vitro via RNA-sequencing and combined with in vivo gene co-expression analysis to generate a signature. The signature was independently validated in eleven prostate cancer cohorts and a bladder cancer phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON).

Results: A 28-gene signature was derived. Patients with high signature scores had poorer biochemical recurrence free survivals in six of eight independent cohorts of prostatectomy-treated patients (Log rank test P < .05), with borderline significances achieved in the other two (P < .1). The signature also predicted biochemical recurrence in patients receiving post-prostatectomy radiotherapy (n = 130, P = .007) or definitive radiotherapy alone (n = 248, P = .035). Lastly, the signature predicted metastasis events in a pooled cohort (n = 631, P = .002). Prognostic significance remained after adjusting for clinic-pathological factors and commercially available prognostic signatures. The signature predicted benefit from hypoxia-modifying therapy in bladder cancer patients (intervention-by-signature interaction test P = .0026), where carbogen and nicotinamide was associated with improved survival only in hypoxic tumours.

Conclusion: A 28-gene hypoxia signature has strong and independent prognostic value for prostate cancer patients.
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http://dx.doi.org/10.1016/j.ebiom.2018.04.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014579PMC
May 2018

Clinical whole-genome sequencing from routine formalin-fixed, paraffin-embedded specimens: pilot study for the 100,000 Genomes Project.

Genet Med 2018 10 1;20(10):1196-1205. Epub 2018 Feb 1.

Genomics England, William Harvey Research Institute, Queen Mary University of London, London, UK.

Purpose: Fresh-frozen (FF) tissue is the optimal source of DNA for whole-genome sequencing (WGS) of cancer patients. However, it is not always available, limiting the widespread application of WGS in clinical practice. We explored the viability of using formalin-fixed, paraffin-embedded (FFPE) tissues, available routinely for cancer patients, as a source of DNA for clinical WGS.

Methods: We conducted a prospective study using DNAs from matched FF, FFPE, and peripheral blood germ-line specimens collected from 52 cancer patients (156 samples) following routine diagnostic protocols. We compared somatic variants detected in FFPE and matching FF samples.

Results: We found the single-nucleotide variant agreement reached 71% across the genome and somatic copy-number alterations (CNAs) detection from FFPE samples was suboptimal (0.44 median correlation with FF) due to nonuniform coverage. CNA detection was improved significantly with lower reverse crosslinking temperature in FFPE DNA extraction (80 °C or 65 °C depending on the methods). Our final data showed somatic variant detection from FFPE for clinical decision making is possible. We detected 98% of clinically actionable variants (including 30/31 CNAs).

Conclusion: We present the first prospective WGS study of cancer patients using FFPE specimens collected in a routine clinical environment proving WGS can be applied in the clinic.
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http://dx.doi.org/10.1038/gim.2017.241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520241PMC
October 2018

miR-139-5p Modulates Radiotherapy Resistance in Breast Cancer by Repressing Multiple Gene Networks of DNA Repair and ROS Defense.

Cancer Res 2018 01 27;78(2):501-515. Epub 2017 Nov 27.

St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.

Radiotherapy is essential to the treatment of most solid tumors and acquired or innate resistance to this therapeutic modality is a major clinical problem. Here we show that miR-139-5p is a potent modulator of radiotherapy response in breast cancer via its regulation of genes involved in multiple DNA repair and reactive oxygen species defense pathways. Treatment of breast cancer cells with a miR-139-5p mimic strongly synergized with radiation both and , resulting in significantly increased oxidative stress, accumulation of unrepaired DNA damage, and induction of apoptosis. Several miR-139-5p target genes were also strongly predictive of outcome in radiotherapy-treated patients across multiple independent breast cancer cohorts. These prognostically relevant miR-139-5p target genes were used as companion biomarkers to identify radioresistant breast cancer xenografts highly amenable to sensitization by cotreatment with a miR-139-5p mimetic. The microRNA described in this study offers a potentially useful predictive biomarker of radiosensitivity in solid tumors and a generally applicable druggable target for tumor radiosensitization. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-3105DOI Listing
January 2018

IGF-1R associates with adverse outcomes after radical radiotherapy for prostate cancer.

Br J Cancer 2017 Nov 3;117(11):1600-1606. Epub 2017 Oct 3.

Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.

Background: Activated type 1 insulin-like growth factor receptors (IGF-1Rs) undergo internalisation and nuclear translocation, promoting cell survival. We previously reported that IGF-1R inhibition delays DNA damage repair, sensitising prostate cancer cells to ionising radiation. Here we tested the clinical relevance of these findings.

Methods: We assessed associations between IGF-1R and clinical outcomes by immunohistochemistry in diagnostic biopsies of 136 men treated with 55-70 Gy external beam radiotherapy for prostate cancer, comparing results with publicly available transcriptional data in surgically treated patients.

Results: Following radiotherapy, overall recurrence-free survival was shorter in patients whose tumours contained high total, cytoplasmic and internalised (nuclear/cytoplasmic) IGF-1R. High total IGF-1R associated with high primary Gleason grade and risk of metastasis, and cytoplasmic and internalised IGF-1R with biochemical recurrence, which includes patients experiencing local recurrence within the radiation field indicating radioresistance. In multivariate analysis, cytoplasmic, internalised and total IGF-1R were independently associated with risk of overall recurrence, and cytoplasmic IGF-1R was an independent predictor of biochemical recurrence post radiotherapy. Insulin-like growth factor receptors expression did not associate with biochemical recurrence after radical prostatectomy.

Conclusions: These data reveal increased risk of post-radiotherapy recurrence in men whose prostate cancers contain high levels of total or cytoplasmic IGF-1R.
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http://dx.doi.org/10.1038/bjc.2017.337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729437PMC
November 2017

Gemcitabine-Induced TIMP1 Attenuates Therapy Response and Promotes Tumor Growth and Liver Metastasis in Pancreatic Cancer.

Cancer Res 2017 11 1;77(21):5952-5962. Epub 2017 Aug 1.

Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom.

Gemcitabine constitutes one of the backbones for chemotherapy treatment in pancreatic ductal adenocarcinoma (PDAC), but patients often respond poorly to this agent. Molecular markers downstream of gemcitabine treatment in preclinical models may provide an insight into resistance mechanisms. Using cytokine arrays, we identified potential secretory biomarkers of gemcitabine resistance (response) in the transgenic KRasG12D; Trp53R172H; Pdx-1 Cre (KPC) mouse model of PDAC. We verified the oncogenic role of the cytokine tissue inhibitor of matrix metalloproteinases 1 (TIMP1) in primary pancreatic tumors and metastases using both techniques and animal models. We identified potential pathways affected downstream of TIMP1 using the Illumina Human H12 array. Our findings were validated in both primary and metastatic models of pancreatic cancer. Gemcitabine increased inflammatory cytokines including TIMP1 in the KPC mouse model. TIMP1 was upregulated in patients with pancreatic intraepithelial neoplasias grade 3 and PDAC lesions relative to matched normal pancreatic tissue. In addition, TIMP1 played a role in tumor clonogenic survival and vascular density, while TIMP1 inhibition resensitized tumors to gemcitabine and radiotherapy. We observed a linear relationship between TIMP-1 expression, liver metastatic burden, and infiltration by CD11bGr1 myeloid cells and CD4CD25FOXP3 Tregs, whereas the presence of tumor cells was required for immune cell infiltration. Overall, our results identify TIMP1 upregulation as a resistance mechanism to gemcitabine and provide a rationale for combining chemo/radiotherapy with TIMP1 inhibitors in PDAC. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-2833DOI Listing
November 2017

TOPK modulates tumour-specific radiosensitivity and correlates with recurrence after prostate radiotherapy.

Br J Cancer 2017 Aug 4;117(4):503-512. Epub 2017 Jul 4.

CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.

Background: Tumour-specific radiosensitising treatments may enhance the efficacy of radiotherapy without exacerbating side effects. In this study we determined the radiation response following depletion or inhibition of TOPK, a mitogen-activated protein kinase kinase family Ser/Thr protein kinase that is upregulated in many cancers.

Methods: Radiation response was studied in a wide range of cancer cell lines and normal cells using colony formation assays. The effect on cell cycle progression was assessed and the relationship between TOPK expression and therapeutic efficacy was studied in a cohort of 128 prostate cancer patients treated with radical radiotherapy.

Results: TOPK knockdown did not alter radiation response in normal tissues, but significantly enhanced radiosensitivity in cancer cells. This result was recapitulated in TOPK knockout cells and with the TOPK inhibitor, OTS964. TOPK depletion altered the G/S transition and G/M arrest in response to radiation. Furthermore, TOPK depletion increased chromosomal aberrations, multinucleation and apoptotic cell death after irradiation. These results suggest a possible role for TOPK in the radiation-induced DNA damage checkpoints. These findings have clinical relevance, as elevated TOPK protein expression was associated with poorer clinical outcomes in prostate cancer patients treated with radical radiotherapy.

Conclusions: This study demonstrates that TOPK disruption may cause tumour-specific radiosensitisation in multiple different tumour types.
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http://dx.doi.org/10.1038/bjc.2017.197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558685PMC
August 2017

In vitro downregulated hypoxia transcriptome is associated with poor prognosis in breast cancer.

Mol Cancer 2017 06 15;16(1):105. Epub 2017 Jun 15.

Department of Electronic and Computer Engineering, Brunel University London, Uxbridge, Middlesex, UB8 3PH, UK.

Background: Hypoxia is a characteristic of breast tumours indicating poor prognosis. Based on the assumption that those genes which are up-regulated under hypoxia in cell-lines are expected to be predictors of poor prognosis in clinical data, many signatures of poor prognosis were identified. However, it was observed that cell line data do not always concur with clinical data, and therefore conclusions from cell line analysis should be considered with caution. As many transcriptomic cell-line datasets from hypoxia related contexts are available, integrative approaches which investigate these datasets collectively, while not ignoring clinical data, are required.

Results: We analyse sixteen heterogeneous breast cancer cell-line transcriptomic datasets in hypoxia-related conditions collectively by employing the unique capabilities of the method, UNCLES, which integrates clustering results from multiple datasets and can address questions that cannot be answered by existing methods. This has been demonstrated by comparison with the state-of-the-art iCluster method. From this collection of genome-wide datasets include 15,588 genes, UNCLES identified a relatively high number of genes (>1000 overall) which are consistently co-regulated over all of the datasets, and some of which are still poorly understood and represent new potential HIF targets, such as RSBN1 and KIAA0195. Two main, anti-correlated, clusters were identified; the first is enriched with MYC targets participating in growth and proliferation, while the other is enriched with HIF targets directly participating in the hypoxia response. Surprisingly, in six clinical datasets, some sub-clusters of growth genes are found consistently positively correlated with hypoxia response genes, unlike the observation in cell lines. Moreover, the ability to predict bad prognosis by a combined signature of one sub-cluster of growth genes and one sub-cluster of hypoxia-induced genes appears to be comparable and perhaps greater than that of known hypoxia signatures.

Conclusions: We present a clustering approach suitable to integrate data from diverse experimental set-ups. Its application to breast cancer cell line datasets reveals new hypoxia-regulated signatures of genes which behave differently when in vitro (cell-line) data is compared with in vivo (clinical) data, and are of a prognostic value comparable or exceeding the state-of-the-art hypoxia signatures.
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http://dx.doi.org/10.1186/s12943-017-0673-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472949PMC
June 2017

Depletion of signal recognition particle 72kDa increases radiosensitivity.

Cancer Biol Ther 2017 06 11;18(6):425-432. Epub 2017 May 11.

a Cancer Research UK/ MRC Oxford Institute for Radiation Oncology, Gray Laboratories, Department of Oncology , University of Oxford , Oxford , UK.

The identification of genetic determinants that underpin tumor radioresistance can help the development of targeted radiosensitizers or aid personalization of radiotherapy treatment. Here we identify signal recognition particle 72kDa (SRP72) as a novel gene involved in radioresistance. Knockdown of SRP72 resulted in significant radiosensitization of HeLa (cervical), PSN-1 (pancreatic), and T24 (bladder), BT-549 (breast) and MCF7 (breast) tumor lines as measured by colony formation assays. SRP72 depletion also resulted in the radiosensitization of normal lung fibroblast cell lines (HFL1 and MRC-5), demonstrating that the effect is not restricted to tumor cells. Increased radiosensitivity was not due to impaired DNA damage signaling or repair as assessed by γ-H2AX foci formation. Instead SRP72 depletion was associated with elevated levels of apoptosis after irradiation, as measured by caspase 3/7 activity, PARP-cleavage and Annexin-V staining, and with an induction of the unfolded protein response. Together, our results show that SRP72 is a novel gene involved in radioresistance.
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http://dx.doi.org/10.1080/15384047.2017.1323587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536942PMC
June 2017

A Gene Signature for Selecting Benefit from Hypoxia Modification of Radiotherapy for High-Risk Bladder Cancer Patients.

Clin Cancer Res 2017 Aug 11;23(16):4761-4768. Epub 2017 Apr 11.

Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, United Kingdom.

Hypoxia modification improves overall survival in muscle-invasive bladder cancer patients who undergo radiotherapy. There is evidence that hypoxic tumors benefit most from hypoxia modification. The study aimed to identify or derive a hypoxia gene signature that predicts benefit from hypoxia-modifying treatment in bladder cancer. Published hypoxia signatures were tested and a new one derived by analyzing bladder cancer transcriptomic data from public databases. Tumor samples were available from the BCON phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON). Gene expression data were generated for 151 tumors using Affymetrix Human 1.0 Exon ST arrays and used for independent validation. A 24-gene signature was derived, which was prognostic in four of six independent surgical cohorts ( = 679; meta HR, 2.32; 95% CI, 1.73-3.12; < 0.0001). The signature was also prognostic in BCON patients receiving radiotherapy alone ( = 75; HR for local relapse-free survival, 2.37; 95% CI, 1.26-4.47; = 0.0076). The signature predicted benefit from CON ( = 76; HR, 0.47; 95% CI, 0.26-0.86; = 0.015). Prognostic significance ( = 0.017) and predictive significance ( = 0.058) remained after adjusting for clinicopathologic variables. A test for interaction between hypoxia status and treatment arms was significant ( = 0.0094). A 24-gene hypoxia signature has strong and independent prognostic and predictive value for muscle-invasive bladder cancer patients. The signature can aid identification of patients likely to benefit from the addition of carbogen and nicotinamide to radiotherapy. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0038DOI Listing
August 2017

Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma.

Genes Dev 2017 01 17;31(1):18-33. Epub 2017 Jan 17.

Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.

The intratumor microenvironment generates phenotypically distinct but interconvertible malignant cell subpopulations that fuel metastatic spread and therapeutic resistance. Whether different microenvironmental cues impose invasive or therapy-resistant phenotypes via a common mechanism is unknown. In melanoma, low expression of the lineage survival oncogene microphthalmia-associated transcription factor (MITF) correlates with invasion, senescence, and drug resistance. However, how MITF is suppressed in vivo and how MITF-low cells in tumors escape senescence are poorly understood. Here we show that microenvironmental cues, including inflammation-mediated resistance to adoptive T-cell immunotherapy, transcriptionally repress MITF via ATF4 in response to inhibition of translation initiation factor eIF2B. ATF4, a key transcription mediator of the integrated stress response, also activates AXL and suppresses senescence to impose the MITF-low/AXL-high drug-resistant phenotype observed in human tumors. However, unexpectedly, without translation reprogramming an ATF4-high/MITF-low state is insufficient to drive invasion. Importantly, translation reprogramming dramatically enhances tumorigenesis and is linked to a previously unexplained gene expression program associated with anti-PD-1 immunotherapy resistance. Since we show that inhibition of eIF2B also drives neural crest migration and yeast invasiveness, our results suggest that translation reprogramming, an evolutionarily conserved starvation response, has been hijacked by microenvironmental stress signals in melanoma to drive phenotypic plasticity and invasion and determine therapeutic outcome.
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http://dx.doi.org/10.1101/gad.290940.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5287109PMC
January 2017
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