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Results for “Cancer Biology”

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bioRxiv2018

APOBEC-mediated DNA alterations: a possible new mechanism of carcinogenesis in EBV-positive gastric cancer

Mechanisms of viral oncogenesis are diverse and include the off-target activity of enzymes expressed by the infected cells, which evolved to target viral genomes for controlling their infection. Among these enzymes, the single-strand DNA editing capability of APOBECs represent a well-conserved viral infection response that can also cause untoward mutations in host DNA. Here we show, after evaluating somatic single-nucleotide variations and transcriptome data in 240 gastric cancer samples, a positive correlation between APOBEC3s mRNA-expression and the APOBEC-mutation signature, both increased in EBV+ tumors. The correlation was reinforced by the observation of APOBEC-mutations preferentially occuring in transcriptionally-active loci. The EBV-infection and APOBEC3 mutation-signature axis was confirmed in a validation cohort of 112 gastric cancer patients. Our findings suggest that APOBEC3 upregulation in EBV+ cancer may boost the mutation load, providing further clues to the mechanisms of EBV-induced gastric carcinogenesis. After further validation, this EBV-APOBEC axis may prove to be a secondary driving force in the mutational evolution of EBV+ gastric tumors, whose consequences in terms of prognosis and treatment implications should be vetted.

cancer biology↗

bioRxiv2018

AICAR induces apoptosis and inhibits migration of prostate cancer cells through an AMPK/mTOR-dependent pathway

AICAR (5-aminoimidazole-4-carbox-amide-1-{beta}-D-ribofuranoside), an AMP-activated protein kinase (AMPK) agonist, has demonstrated antitumor activities for several types of cancers. However, the activity of AICAR on the cell growth and metastasis of prostate cancer has not been extensively studied. Herein we examine the effects of AICAR on the cell growth and metastasis of prostate cancer cells, 22RV1 cells. Cell growth was performed by MTT assay and soft agar assay. Cell apoptosis was examined by Annexin V/PI staining and PARP cleavage Western blot. Cell migration was evaluated by wound-healing assay. The expression of EMT-related protein and the activity of the AMPK/ mTOR-dependent pathway were analyzed by Western blot. In addition, we also tested the effect of AICAR on the chemosensitivity to docetaxel using MTT assay. Our results indicated that AICAR inhibits cell growth, induces apoptosis, attenuates TGF-{beta}-induced cell migration and EMT-related protein expression, and enhances the chemosensitivity to docetaxel through regulating the AMPK/mTOR-dependent pathway. Collectively, these findings support AICAR as a potential therapeutic agent for the treatment of prostate cancer.

cancer biology↗

bioRxiv2018

Electrochemotherapy with bleomycin associated with doxorubicin induces tumor regression and decreases the proliferative index in canine cutaneous squamous cell carcinomas

Canine cutaneous squamous cell carcinoma (cSCC) is the most common skin cancer in dogs, and due to its low metastatic rate, local treatments such as electrochemotherapy (ECT) promote disease control or even complete remission and increase the survival time in most cases. This study aimed to evaluate the expression of BAX, Bcl-2, and Ki67 and clinical parameters in dogs with cSCC subjected to ECT. A prospective clinical nonrandomized study was performed in dogs with naturally occurring cSCC treated with ECT. Eighteen lesions (from 11 dogs) were selected, independent of breed, sex and age. The ECT protocol consisted of bleomycin plus doxorubicin followed by electric pulses characterized by 8 biphasic electric pulses lasting 100 ms, 1 Hz and 1000 V/cm. Among the 18 lesions, the lesion volume significantly decreased after treatment (p=0.04). The tumor size at D0 had no impact on survival time or prognosis (P>0.05). A decreased mitotic index was observed at compared with D0 (P=0.019). We also observed more intratumoral necrosis at D21 compared to D0 (P=0.041). The median expression level of Ki67 was 277.96 at D0 and 193.92 at D21. Thus, tumor samples had a lower proliferative index after ECT (D21) (P=0.031). The survival times of subjects with Ki67 values lower and higher than the Ki67 median value were not significantly different (P>0.05). Regarding apoptotic markers, there was no significant difference in BAX or Bcl-2 expression between D0 and D21 (P>0.05) or in overall survival between subjects with different levels of apoptotic markers. Furthermore, a positive correlation was observed between BAX and Bcl-2 before ECT (D0) (P=0.0379, r=0.5067). In conclusion, there was no change in BAX and Bcl-2 protein expression levels in response to ECT at the time points evaluated, and ECT was able to reduce tumor volume and cellular proliferation in cSCC.

cancer biology↗

bioRxiv2018

Mathematical Modeling Reveals the Factors Involved in the Phenomena of Cancer Stem Cells Stabilization

Cancer Stem Cells (CSC), a subset of cancer cells resembling normal stem cells with self-renewal and asymmetric division capabilities, are present at various but low proportions in many tumors and are thought to be responsible for tumor relapses following conventional cancer therapies. In vitro, most intriguingly, when isolated, CSCs return to their original proportion level as shown by various investigators. This phenomenon still remains to be explained.\n\nWe suggest a mathematical model of cancer cell population dynamics, based on the main parameters of cell population dynamics, including the proliferation rates, the rates of cell death and the frequency of symmetric and asymmetric cell divisions both in CSCs and in non-CSCs. This model should help elucidating some important factors underlying the dynamics of the two populations, first of all, the phenomena of cancer stem cell population stabilization.\n\nAuthor SummaryCancer Stem Cells (CSC) present a subset of cancer cells which is thought to be responsible for tumor growth. That is why CSC are also named \"tumor initiation cells\". Additionally, it was shown that CSC are resistant to chemo- and radio-therapies which suggests that these cells can be responsible for tumor relapses after these treatments. Experimental data in cancer cell lines have shown the intriguing phenomena of CSC population stability, which means that isolated CSC population rapidly stabilizes at its characteristic level (the relative proportion of CSC in a whole cancer population). We suggest a mathematical model of cancer cell population dynamics, based on experimentally measured dynamics of CSC population stabilization and including main parameters of cell population growth.\n\nWe have computationally predicted probability of different scenarios of cancer cell behavior for each experimental case with measurable growth parameters. Moreover, we provide an analytical tool for elucidating important biochemical factors responsible for a particular dynamics of CSC population.\n\nThe results may have important implications in therapeutic, because the destroying of a set of factors underlying CSC stability may help to avoid tumor relapses.

cancer biology↗

bioRxiv2018

Genetic mechanisms of primary chemotherapy resistance in pediatric acute myeloid leukemia: A report from the TARGET initiative

Acute myeloid leukemias (AML) are characterized by mutations of tumor suppressor and oncogenes, involving distinct genes in adults and children. While certain mutations have been associated with the increased risk of AML relapse, the genomic landscape of primary chemotherapy resistant AML is not well defined. As part of the TARGET initiative, we performed whole-genome DNA and transcriptome (RNA and miRNA) sequencing analysis of pediatric AML with failure of induction chemotherapy. We identified at least three genetic groups of patients with induction failure, including those with NUP98 rearrangements, somatic mutations of WT1 in the absence of NUP98 mutations, and additional recurrent variants including those in KMT2C and MLLT10. Comparison of specimens before and after chemotherapy revealed distinct and invariant gene expression programs. While exhibiting overt therapy resistance, these leukemias nonetheless showed diverse forms of clonal evolution upon chemotherapy exposure. This included selection for mutant alleles of FRMD8, DHX32, PIK3R1, SHANK3, MKLN1, as well as persistence of WT1 and TP53 mutant clones, and elimination or contraction of FLT3, PTPN11, and NRAS mutant clones. These findings delineate genetic mechanisms of primary chemotherapy resistance in pediatric AML, which should inform improved approaches for its diagnosis and therapy.

cancer biology↗

bioRxiv2018

Mathematical Details on a Cancer Resistance Model

The primary factor limiting the success of chemotherapy in cancer treatment is the phenomenon of drug resistance. We have recently introduced a framework for quantifying the effects of induced and non-induced resistance to cancer chemotherapy [11, 10]. In this work, we expound on the details relating to an optimal control problem outlined in [10]. The control structure is precisely characterized as a concatenation of bang-bang and path-constrained arcs via the Pontryagin Maximum Principle and differential Lie algebra techniques. A structural identifiability analysis is also presented, demonstrating that patient-specific parameters may be measured and thus utilized in the design of optimal therapies prior to the commencement of therapy. For completeness, a detailed analysis of existence results is also included.

cancer biology↗

bioRxiv2018

Failure of complex systems, cascading disasters, and the onset of disease

Complex systems can fail through different routes, often progressing through a series of (rate-limiting) steps and modified by environmental exposures. The onset of disease, cancer in particular, is no different. Multi-stage models provide a simple but very general mathematical framework for studying the failure of complex systems, or equivalently, the onset of disease. They include the Armitage-Doll multi-stage cancer model as a particular case, and have potential to provide new insights into how failures and disease, arise and progress. A method described by E.T. Jaynes is developed to provide an analytical solution for a large class of these models, and highlights connections between the convolution of Laplace transforms, sums of random variables, and Schwinger/Feynman parameterisations. Examples include: exact solutions to the Armitage-Doll model, the sum of Gamma-distributed variables with integer-valued shape parameters, a clonal-growth cancer model, and a model for cascading disasters. Applications and limitations of the approach are discussed in the context of recent cancer research. The model is sufficiently general to be used in many contexts, such as engineering, project management, disease progression, and disaster risk for example, allowing the estimation of failure rates in complex systems and projects. The intended result is a mathematical toolkit for applying multi-stage models to the study of failure rates in complex systems and to the onset of disease, cancer in particular.

cancer biology↗

bioRxiv2018

The CIC-DUX4 fusion oncoprotein drives metastasis and tumor growth via distinct downstream regulatory programs and therapeutic targets in sarcoma

Transcription factor fusion genes create oncoproteins that drive oncogenesis, and represent challenging therapeutic targets. Understanding the molecular targets by which such fusion oncoproteins promote malignancy offers an approach to develop rational treatment strategies to improve clinical outcomes. CIC-DUX4 is a transcription factor fusion that defines certain undifferentiated round cell sarcomas with high metastatic propensity and poor clinical outcomes. The molecular targets regulated by the CIC-DUX4 oncoprotein that promote this aggressive malignancy remain largely unknown. We show that increased expression of ETV4 and CCNE1 occurs via neo-morphic, direct effects of CIC-DUX4 and drives tumor metastasis and survival, respectively. We demonstrate a molecular dependence on the CCNE-CDK2 cell cycle complex that renders CIC-DUX4 tumors sensitive to inhibition of the CCNE-CDK2 complex, highlighting a therapeutic strategy for CIC-DUX4 tumors. Our findings highlight a paradigm of functional diversification of transcriptional repertoires controlled by a genetically-aberrant transcriptional regulator, with therapeutic implications.

cancer biology↗

bioRxiv2018

Towards multi-drug adaptive therapy

A new ecologically inspired paradigm in cancer treatment known as \"adaptive therapy\" capitalizes on competitive interactions between drug-sensitive and drug-resistant subclones. The goal of adaptive therapy is to maintain a controllable stable tumor burden by allowing a significant population of treatment sensitive cells to survive. These, in turn, suppress proliferation of the less fit resistant populations. However, there remain several open challenges in designing adaptive therapies, particularly in extending these therapeutic concepts to multiple treatments. We present a cancer treatment case study (metastatic castrate resistant prostate cancer) as a point of departure to illustrate three novel concepts to aid the design of multi-drug adaptive therapies. First, frequency-dependent \"cycles\" of tumor evolution can trap tumor evolution in a periodic, controllable loop. Second, the availability and selection of treatments may limit the evolutionary \"absorbing region\" reachable by the tumor. Third, the velocity of evolution significantly influences the optimal timing of drug sequences.

cancer biology↗

bioRxiv2018

ESCRT-III accumulates in micronuclei with ruptured nuclear envelopes

1.Micronuclei represent the cellular attempt to compartmentalize DNA to maintain genomic integrity threatened by mitotic errors and genotoxic events. Micronuclei show aberrant nuclear envelopes that collapse, generating damaged DNA and promoting complex genome alterations. However, ruptured micronuclei also provide a pool of cytosolic DNA that stimulates anti-tumour immunity, revealing the complexity of micronuclei impact on tumour progression.\n\nThe ESCRT-III complex ensures nuclear envelope (NE) resealing during late mitosis and NE repair in interphase. Therefore, ESCRT-III activity maybe crucial for maintaining the integrity of other genomic structures enclosed by a nuclear envelope. ESCRT-III activity at the nuclear envelope is coordinated by the subunit CHMP7.\n\nWe show that CHMP7 and ESCRT-III protects against the genomic instability associated with micronuclei formation. Loss of ESCRT-III activity increases the population of micronuclei with ruptured nuclear envelopes, in interphase cells. Surprisingly, ESCRT-III is retained at acentric micronuclei suggesting that ESCRT-III cannot repair these structures. Depletion of CHMP7 expression removes ESCRT-III accumulations at ruptured micronuclei, and removes the population of micronuclei with damaged DNA also containing a sensor for cytosolic DNA.\n\nThus, ESCRT-III activity appears to protect from the consequence of genomic instability in a dichotomous fashion. Membrane repair activity prevents the occurrence of MN with weak envelopes; conversely, aberrant membrane remodelling at micronuclei generates a steady state pool of cytosolic DNA that may contribute to sustaining pro-inflammatory pathways in cancer cells.

cancer biology↗

bioRxiv2018

MiR-195 regulates mitochondrial function by targeting mitofusin-2 in breast cancer cells

Mitochondrial dynamics is a highly dysregulated process in cancer. Apoptosis and mitochondrial fission are two concurrent events wherein increased mitochondrial fragmentation serves as a hallmark of apoptosis. We have shown earlier that miR-195 exerts pro-apoptotic effects in breast cancer cells. Herein, we have demonstrated miR-195 as a modulator of mitochondrial dynamics and function. Imaging experiments upon miR-195 treatment have shown that mitochondria undergo extensive fission. We validated mitofusin2 as a potential target of miR-195. Which may provide a molecular explanation for the respiratory defects induced by miR-195 over-expression in breast cancer cells? Active, but not total, mitochondrial mass, was reduced with increasing levels of miR-195. We have further shown that miR-195 enhances mitochondrial SOD-2 expression but does not affect PINK1 levels in breast cancer cells. Collectively, we have revealed that miR-195 is a modulator of mitochondrial dynamics by targeting MFN2 thereby impairing mitochondrial function. Concomitantly, it enhances the scavenger of reactive oxygen species (SOD-2) to maintain moderate levels of oxidative stress. Our findings suggest a therapeutic potential of miR-195 in both ER-positive as well as ER-negative breast cancer cells.

cancer biology↗

bioRxiv2018

Reproducing Transformation of Indolent B-cell Lymphoma by T-cell Immunosuppression of L.CD40 Mice.

Transformation of an indolent B-cell lymphoma is associated with a more aggressive clinical course and poor survival. The role of immune surveillance in the transformation of a B-cell indolent lymphoma towards a more aggressive form is poorly documented. To experimentally address this question, we used the L.CD40 mouse model, which is characterized by B-cell specific continuous CD40 signaling, responsible for spleen indolent clonal or oligoclonal B-cell lymphoma after one year in 60% cases. Immunosuppression was obtained either by T/NK cell depletion or by treatment with the T-cell immunosuppressive drug cyclosporin A. Immunosuppressed L.CD40 mice had larger splenomegaly with increased numbers of B-cells in both spleen and peripheral blood. High-throughput sequencing of immunoglobulin variable segments revealed that clonal expansion was increased in immunosuppressed L.CD40 mice. Tumor B cells of immunosuppressed mice were larger with an immunoblastic aspect, both on blood smears and spleen tissue sections, with increased proliferation rate and increased numbers of activated B-cells. Collectively, these features suggest that immune suppression induced a shift from indolent lymphomas into aggressive ones. Thus, as a preclinical model, immunosuppressed L.CD40 mice reproduce aggressive transformation of an indolent B-cell tumor and highlight the role of the immune surveillance in its clinical course, opening new perspective for immune restoration therapies.\n\nSummary statementHighlighting the role of immune surveillance, transformation of indolent B-cell lymphoma into an aggressive malignancy is experimentally reproduced after T-cell immune suppression in the L.CD40 preclinical mouse model.

cancer biology↗

bioRxiv2018

miR-425 suppresses EMT and inhibits the development of TNBC (triple-negative breast cancer) by targeting TGF-β 1/SMAD 3 signaling pathway

BackgroundEMT has the crucial effect on the progression and metastasis of tumor. This work will elucidate the role of miR-425 in EMT and development of TNBC.\n\nMethodsThe differential miRNA expression among non-tumor, para-tumor (adjacent tissue of tumor) and tumor tissues was analyzed. The luciferase activities of TGF-{beta}1 3 UTR treated with miR-425 were determined. Then human breast cancer cell lines were dealt with mimics or inhibitors of miR-425, and then the cell proliferation and migration, invasion ability were assessed. The expression of TGF-{beta}1 and markers of epithelial cell and mesenchymal cell were analyzed. The influences of miR-425 on development of TNBC through inducing EMT by targeting TGF-{beta} 1 and TGF-{beta}1/SMAD3 signaling pathway in TNBC cell lines were investigated. Furthermore, Xenograft mice were used to explore the potential roles of miR-425 on EMT and development of TNBC in vivo.\n\nResultsCompared with non-tumor tissues, 9 miRNAs were upregulated and 3 miRNAs were down-regulated in tumor tissues. The relative expression of miR-425 in tumor tissues was obviously much lower than that in para-tumor and non-tumor tissues. MiR-425 suppressed TGF-{beta}1 expression, additionally inhibited expression of mesenchymal cell markers, while exerted effects on cell proliferation and migration of TNBC cell lines. Moreover, the agomir of miR-425 could protect against development process in murine TNBC xenogarft model.\n\nConclusionsOur results demonstrated that miR-425 targets to TGF-{beta}1, and was a crucial suppressor on EMT and development of TNBC through inhibiting TGF-{beta}1/SMAD3 signaling pathway. It suggested that aim at TGF-{beta}1/SMAD3 signaling pathway by enhancing relative miR-425 expression, was a feasible therapy strategy for TNBC.

cancer biology↗

bioRxiv2018

Machine learning enables detection of early-stage colorectal cancer by whole-genome sequencing of plasma cell-free DNA

BackgroundBlood-based methods using cell-free DNA (cfDNA) are under development as an alternative to existing screening tests. However, early-stage detection of cancer using tumor-derived cfDNA has proven challenging because of the small proportion of cfDNA derived from tumor tissue in early-stage disease. A machine learning approach to discover signatures in cfDNA, potentially reflective of both tumor and non-tumor contributions, may represent a promising direction for the early detection of cancer.\n\nMethodsWhole-genome sequencing was performed on cfDNA extracted from plasma samples (N=546 colorectal cancer and 271 non-cancer controls). Reads aligning to protein-coding gene bodies were extracted, and read counts were normalized. cfDNA tumor fraction was estimated using IchorCNA. Machine learning models were trained using k-fold cross-validation and confounder-based cross-validation to assess generalization performance.\n\nResultsIn a colorectal cancer cohort heavily weighted towards early-stage cancer (80% stage I/II), we achieved a mean AUC of 0.92 (95% CI 0.91-0.93) with a mean sensitivity of 85% (95% CI 83-86%) at 85% specificity. Sensitivity generally increased with tumor stage and increasing tumor fraction. Stratification by age, sequencing batch, and institution demonstrated the impact of these confounders and provided a more accurate assessment of generalization performance.\n\nConclusionsA machine learning approach using cfDNA achieved high sensitivity and specificity in a large, predominantly early-stage, colorectal cancer cohort. The possibility of systematic technical and institution-specific biases warrants similar confounder analyses in other studies. Prospective validation of this machine learning method and evaluation of a multi-analyte approach are underway.

cancer biology↗

bioRxiv2018

Transcriptional heterogeneity in cancer-associated regulatory T cells is predictive of survival.

Regulatory T cells (Tregs) are a population of T cells that exert a suppressive effect on a variety of immune cells and non-immune cells. The suppressive effects of Tregs are detrimental to anti-tumor immunity. Recent investigations into cancer-associated Tregs have identified common expression patterns for tumor-infiltration, however the functional heterogeneity in tumor-infiltrating (TI) Treg is largely unknown. We performed single-cell sequencing on immune cells derived from renal clear cell carcinoma (ccRCC) patients, isolating 160 peripheral-blood (PB) Tregs and 574 TI Tregs. We identified distinct transcriptional TI Treg cell fates, with a suppressive subset expressing CD177. We demonstrate CD177+ TI-Tregs have preferential suppressive effects in vivo and ex vivo. Gene signatures derived the CD177+ Treg subset had superior ability to predict survival in ccRCC and seven other cancer types. Further investigation into the development and regulation of TI-Treg heterogeneity will be vital to the application of tumor immunotherapies that possess minimal side effects.

cancer biology↗

bioRxiv2018

B cells sustain inflammation and improve survival in human melanoma

Tumor associated inflammation is one of important predictors of response to immune checkpoint blockade. Understanding molecular processes that regulate tumor inflammation is key to improve the efficacy of checkpoint blockade. Established mechanisms that underlie therapy response and resistance have centered on anti-tumor T cell responses.\n\nWe show that tumor-associated B cells are vital to T cell functions. They promote recruitment of CD8+ T cells through plasmablast-like cells with expression of pro- and anti-inflammatory factors. Plasmablast-like cells are associated with improved survival of patients with metastatic melanoma and their response to checkpoint blockade. Plasmablast-like B cells express chemokines for T cell-attraction. Depletion of tumor-associated B cells by anti-CD20 immunotherapy of metastatic melanoma patients causes a remarkable decrease in tumor CD8+ T cells. These findings indicate that tumor-associated B cells orchestrate and sustain tumor inflammation, recruit CD8+ T effector cells and are key to therapeutic response and patients overall survival.

cancer biology↗

bioRxiv2018

Uncovering the signaling landscape controlling breast cancer cell migration identifies novel metastasis driver genes

Metastasis is the major cause of death in cancer patients and migration of cancer cells from the primary tumor to distant sites is the prerequisite of metastasis formation. Here we applied an imaging-based RNAi phenotypic cell migration screen using two highly migratory basal breast cancer cell lines (Hs578T and MDA-MB-231) to provide a repository for signaling determinants that functionally drive cancer cell migration. We screened ~4,200 individual target genes covering most cell signaling components and discovered 133 and 113 migratory modulators of Hs578T and MDA-MB-231, respectively, of which 43 genes were common denominators of cell migration. Interaction networks of candidate migratory modulators were in common with networks of different clinical breast cancer prognostic and metastasis classifiers. The splicing factors PRPF4B and BUD31 and the transcription factor BPTF were amplified in human primary breast tumors and the expression was associated with metastasis-free survival. Depletion of PRPF4B, BUD31 and BPTF caused primarily down-regulation of genes involved in focal adhesion and ECM-interaction pathways. PRPF4B was essential for triple negative breast cancer cell migration and critical for breast cancer metastasis formation in vivo, making PRPF4B a candidate for further drug development. Our systematic phenotypic screen provides an important repository of candidate metastasis drug targets.

cancer biology↗

bioRxiv2018

A serum-free and insulin-supplemented cell culture medium ensures fatty acid synthesis gene activation in cancer cells

While investigating the role played by de novo fatty acid biosynthesis (DNFA) in cancer cells, we sought a medium condition that would support cell proliferation without providing any serum lipids. Here we report that a defined serum free cell culture medium condition containing insulin, transferrin and selenium (ITS) supports controlled study of DNFA regulation in melanoma cell lines. This lipid-free ITS medium is able to support proliferation of melanoma cell lines that fulfill their lipid requirements via DNFA. We show that the ITS medium stimulates gene transcription in support of both DNFA and de novo cholesterol synthesis (DNCS), specifically mediated by SREBP1/2 in melanoma cells. We further found that the ITS medium promoted SREBP1 nuclear localization and occupancy on DNFA gene promoters. Our data show clear utility of this serum and lipid-free medium for melanoma cancer cell culture and lipid-related areas of investigation.

cancer biology↗