SEARCH · Search bioRxiv

Results for “Cancer Biology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 505 records · Page 28Linked to original sources

bioRxiv2017

Adaptive dynamics of unstable cancer populations: the canonical equation

In most instances of tumour development, genetic instability plays a role in allowing cancer cell populations to respond to selection barriers, such as physical constraints or immune responses, and rapidly adapt to an always changing environment. Modelling instability is a nontrivial task, since by definition evolving changing instability leads to changes in the underlying landscape. In this paper we explore mathematically a simple version of unstable tumor progression using the formalism of Adaptive Dynamics (AD) where selection and mutation are explicitly coupled. Using a set of basic fitness landscapes, the so called canonical equation for the evolution of genetic instability on a minimal scenario associated to a population of unstable cells is derived. The implications and potential extensions of this model are discussed.

cancer biology↗

bioRxiv2017

A repetitive mutation and selection system for bacterial evolution to increase the specific affinity to pancreatic cancer cells.

It is difficult to target and kill cancer cells. One possible approach is to mutate bacteria to enhance their binding to cancer cells. In this study, Gram-negative bacteria Escherichia coli and Gram-positive bacteria Bacillus subtilis were randomly mutated, and then were positively and negatively selected for binding cancer and normal cells. With repetitive mutation and selection both bacteria successfully evolved to increase affinity to the pancreatic cancer cell line (Mia PaCa-2) but not normal cells (HPDE: immortalized human pancreatic ductal epithelial cell line). The mutant E. coli and B. subtilis strains could bind to Mia PaCa-2 cells about 10 and 25 times more than to HPDE cells. The selected E. coli, strain had mutations in biofilm-related genes and the regulatory region for a type I pilus gene. Consistent with type I pili involvement, mannose could inhibit the binding to cells. However, the results suggest that weak but specific binding is involved in the initial step of adhesion. To kill Mia PaCa-2 cells, hemolysin was expressed in the mutant strain. The hemolysin that was released from the mutant strain could kill Mia PaCa-2 cells. This type of mutation/selection strategy may be applicable to other combinations of cancer cells and bacterial species.

cancer biology↗

bioRxiv2017

PPARD regulation in gastric progenitor cells drives gastric tumorigenesis in mice

Little is known about the cell origin of gastric cancer. Peroxisome proliferator-activated receptor-delta (PPARD) is a druggable ligand-activated nuclear receptor that impacts protumorigenic cellular events. However, PPARDs role in tumorigenesis, especially gastric tumorigenesis, remains to be defined. We found that targeting PPARD overexpression in murine gastric progenitor cells (GPC), via a villin promoter, spontaneously induced gastric tumorigenesis that progressed to invasive adenocarcinoma. PPARD overexpression in GPC upregulated tumorigenic proinflammatory cytokine and CD44 expression, expanded GPC population in vivo, enhanced GPC self-renewal and proliferation in organoid cultures, and endowed these cells with tumorigenic properties. Our findings identify PPARD as a driver of gastric tumorigenesis via GPC transformation.

cancer biology↗

bioRxiv2017

miR-16 suppresses growth of rhabdoid tumor cells

BackgroundRhabdoid tumor is a highly aggressive pediatric cancer characterized by biallelic loss and/or mutation of SMARCB1. Outcomes remain poor, and there are no established ways to target the tumorigenic pathways driven by SMARCB1 inactivation. SMARCB1 loss leads to an increase in cyclin D transcription.\n\nProcedureWe characterized the cell line WT-CLS1, which has been described previously as Wilms tumor, by whole-exome sequencing, RNA-seq, and xenograft histology. We measured the effect of microRNA overexpression on WT-CLS1, BT-12, and CHLA-06-ATRT.\n\nResultsWe found that WT-CLS1 demonstrates the histological, mutational, and transcriptional hallmarks of rhabdoid tumor. Because the microRNAs let-7 and miR-16 can target cyclin D genes, we next overexpressed each of these microRNAs in WT-CLS1. We found that miR-16 reduced cell accumulation. This was accompanied by a decrease in proliferation markers and an increase in apoptosis markers. These results were replicated in the BT-12 and CHLA-06-ATRT cell lines.\n\nConclusionsThe loss-of-function SMARCB1 mutation found in WT-CLS1, in conjunction with immunohistochemical and gene expression analysis, warrants reclassification of this cell line as rhabdoid tumor. Proliferation of WT-CLS1 and other rhabdoid tumor cell lines is significantly abrogated by miR-16 overexpression. Further studies are necessary to gain insight into the potential for miR-16 to be used as a novel therapeutic in rhabdoid tumor.\n\nAbbreviations

cancer biology↗

bioRxiv2017

Cholesterol Synthesis Pathway Genes in Prostate Cancer are consistently downregulated when tissue confounding is minimized.

The relationship between cholesterol and prostate cancer has been extensively studied for decades, where high levels of cellular cholesterol are generally associated with cancer progression and less favorable outcomes. However, the role of in vivo cellular cholesterol synthesis in this process is unclear, and data on the transcriptional activity of cholesterol synthesis pathway genes in tissue from prostate cancer patients are inconsistent. A common problem with cancer tissue data from patient cohorts is the presence of heterogeneous tissue which confounds molecular analysis of the samples. In this study we present a method to minimize systematic confounding from stroma tissue in seven patient cohorts consisting of 1713 prostate cancer and 230 normal tissue samples. When confounding was minimized, differential gene expression analysis over all cohorts showed robust and consistent downregulation of nearly all genes in the cholesterol synthesis pathway. Additional analysis also identified cholesterol synthesis as the most significantly altered metabolic pathway in prostate cancer. This surprising observation is important for our understanding of how prostate cancer cells regulate cholesterol levels in vivo. Moreover, we show that tissue heterogeneity explains the lack of consistency in previous expression analysis of cholesterol synthesis genes in prostate cancer.

cancer biology↗

bioRxiv2017

Identification of USP7 as an essential component to maintain integrity and function of non-canonical PRC1.1 in leukemia

Acute myeloid leukemia (AML) is a highly heterogeneous disease in which genetic and epigenetic changes disturb regulatory mechanisms controlling stem cell fate and maintenance. AML still remains difficult to treat, in particular in poor risk AML patients carrying TP53 mutations. Here, we identify the deubiquitinase USP7 as an integral member of non-canonical PRC1.1 and show that targeting of USP7 provides an alternative therapeutic approach for AML. USP7 inhibitors effectively induced apoptosis in (primary) AML cells, also independent of the USP7-MDM2-TP53 axis, whereby survival of both the cycling as well as quiescent populations was affected. MLL-AF9-induced leukemia was significantly delayed in vivo in human leukemia xenografts. We previously showed that non-canonical PRC1.1 is critically important for leukemic stem cell self-renewal, and that genetic knockdown of the PRC1.1 chromatin binding component KDM2B abrogated leukemia development in vitro and in vivo [1]. Here, by performing KDM2B interactome studies in TP53mut cells we identify that USP7 is an essential component of PRC1.1 and is required for its stability and function. USP7 inhibition results in disassembly of the PRC1.1 complex and consequently loss of binding to its target loci. Loss of PRC1.1 binding coincided with reduced H2AK119ub and H3K27ac levels and diminished gene transcription, whereas H3K4me3 levels remained unaffected. Our studies highlight the diverse functions of USP7 and link it to Polycomb-mediated epigenetic control. USP7 inhibition provides an efficient therapeutic approach for AML, also in the most aggressive subtypes with mutations in TP53.\n\nKey pointsO_LIUSP7 is a therapeutic target in leukemia, including poor risk TP53mut AML.\nC_LIO_LIUSP7 is an essential component of non-canonical PRC1.1 and is required for its stability and function.\nC_LI

cancer biology↗

bioRxiv2017

Prevention and reversion of pancreatic tumorigenesis through a differentiation-based mechanism

Activating mutations in Kras are nearly ubiquitous in human pancreatic cancer and initiate precancerous pancreatic intraepithelial neoplasia (PanINs) when induced in adult murine acinar cells. PanINs normally take months to form, but can be rapidly induced by genetic deletion of acinar cell differentiation factors such as Ptf1a, suggesting that loss of mature cell identity is a rate-limiting step in pancreatic tumor initiation. Using a novel genetic mouse model that allows for independent control of oncogenic Kras and Ptf1a expression, we demonstrate that maintained activity of Ptf1a is sufficient to eliminate Kras-driven tumorigenesis, even in the presence of tumor-promoting inflammation. Furthermore, reintroduction of Ptf1a into established PanINs reverts their phenotype in vivo. Our results suggest that reactivation of an endogenous differentiation program can prevent and reverse oncogenesis in cells harboring tumor driving mutations, thus introducing a novel paradigm for solid tumor prevention and treatment.

cancer biology↗

bioRxiv2017

Peptidomimetic blockade of MYB in acute myeloid leukemia

Aberrant gene expression is a hallmark of acute leukemias. However, therapeutic strategies for its blockade are generally lacking, largely due to the pharmacologic challenges of drugging transcription factors. MYB-driven gene trans-activation with CREB-binding protein (CBP)/P300 is required for the initiation and maintenance of a variety of acute lymphoblastic and myeloid leukemias, including refractory MLL-rearranged leukemias. Using structure-guided molecular design, we developed a prototypical peptidomimetic inhibitor MYBMIM that interferes with the assembly of the molecular MYB:CBP/P300 complex at micromolar concentrations and rapidly accumulates in the nuclei of AML cells. We found that treatment of AML cells with MYBMIM, led to the displacement of the MYB:CBP/P300 complex in cells, displacement of MYB from oncogenic enhancers and promoters enriched for MYB binding sites, and downregulation of MYB-dependent gene expression, including of MYC and BCL2 oncogenes. Both human MLL-rearranged and non-rearranged AML cells, underwent mitochondrial apoptosis in response to MYBMIM treatment, which could be partially rescued by ectopic expression of BCL2. We observed that MYBMIM treatment impeded leukemia growth and extended survival of immunodeficient mice engrafted with primary patient-derived MLL-rearranged leukemia cells. These findings emphasize the exquisite dependence of human AML on MYB:CBP/P300 transcriptional dysregulation, and establish a pharmacologic approach for its therapeutic blockade.

cancer biology↗

bioRxiv2017

Acute myeloid/T-lymphoblastic leukemia (AMTL): A distinct category of acute leukemias with common pathogenesis in need of improved therapy

Advances in the immunophenotypic and cytogenetic classification of acute leukemias have led to improved clinical outcomes for a substantial fraction of patients. However, resistance to chemotherapy remains a major barrier to cure for patients with specific subsets of acute myeloid and lymphoblastic leukemias. Here, we propose that a molecularly distinct subtype of acute leukemia with shared myeloid and T-cell lymphoblastic features, which we term acute myeloid/T-lymphoblastic leukemia (AMTL), and has been divided between 3 diagnostic categories owing to variable expression of markers deemed to be defining of myeloid and T-cell lymphoid lineages. This new diagnostic group is supported by the i) shared hematopoietic ontogeny in which myeloid differentiation potential is specifically retained during early T-cell lymphoid development, ii) recognition of cases of AML with hallmarks of T-cell development such as clonal rearrangements of the T-cell receptor genes, and iii) identification of common gene mutations in subsets of AML and T-ALL cases. This proposed diagnostic entity overlaps with early T-cell precursor (ETP) T-ALL and T-cell/myeloid mixed phenotype acute leukemias (MPAL), and also includes a subset of leukemias currently classified as AML with hallmarks of T-lymphoblastic development. AMTLs express variable levels of both T-cell and myeloid-specific markers, such as CD3 and myeloperoxidase, and additionally have shared gene mutations including WT1, PHF6, RUNX1 and BCL11B. The proposed classification of AMTL as a distinct entity should enable prospective diagnosis and development of improved therapies for patients whose treatment is inadequate with current approaches.

cancer biology↗

bioRxiv2017

BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous cell carcinoma

Patients diagnosed with lung squamous cell carcinoma (LUSC) have limited targeted therapeutic options. We report here the identification and characterisation of the transcriptional regulator, BCL11A, as a LUSC oncogene. Analysis of cancer genomics datasets revealed BCL11A to be upregulated in LUSC but not lung adenocarcinoma (LUAD). We demonstrated that knockdown of BCL11A in LUSC cell lines abolished xenograft tumour growth and its overexpression in vivo led to lung airway hyperplasia and the development of reserve cell hyperplastic lesions. In addition, deletion of Bcl11a in the tracheal basal cells abolished the development of tracheosphere organoids while its overexpression led to solid tracheospheres with a squamous phenotype. At the molecular level we found BCL11A to be a target of SOX2 and we show that it is required for the oncogenic role of SOX2 in LUSC. Furthermore, we showed that BCL11A and SOX2 interact at the protein level and that together they co-regulated the expression of several transcription factors. We demonstrate that pharmacological inhibition of SETD8, a gene co-regulated by BCL11A and SOX2, alone or in combination with cisplatin treatment, shows significant selectivity to LUSC in comparison to LUAD cells. Collectively, these results indicate that the disruption of the BCL11A-SOX2 transcriptional program provides a future framework for the development of targeted therapeutic intervention for LUSC patients.

cancer biology↗

bioRxiv2017

Magnetic resonance imaging for characterization of a chick embryo model of cancer cell metastases

BackgroundMetastasis is the most common cause of death for cancer patients, hence its study has rapidly expanded over the past few years. To fully understand all the steps involved in metastatic dissemination, in vivo models are required, of which murine ones are the most common. Therefore pre-clinical imaging methods have mainly been developed for small mammals. However, the potential of preclinical imaging techniques such as magnetic resonance imaging (MRI) to monitor cancer growth and metastasis in non-mammalian in vivo models is not commonly used. We have here used MRI to measure primary neuroblastoma tumour size and presence of metastatic dissemination in a chick embryo model. We compared its sensitivity and accuracy to end-point fluorescence detection.\n\nMethodsHuman neuroblastoma cells were labelled with GFP and micron-sized iron particles (MPIOs) and implanted on the extraembryonic chorioallantoic membrane of the chick embryo at E7. T2 RARE, T2 weighted FLASH as well as time-of-flight MR angiography imaging was applied at E14. Primary tumours as well as metastatic deposits in the chick embryo were dissected post imaging to compare with MRI results.\n\nResultsMPIO labelling of neuroblastoma cells allowed in ovo observation of the primary tumour and tumour volume measurement non-invasively over time. Moreover, T2 weighted and FLASH imaging permitted the detection of very small metastatic deposits in the chick embryo.\n\nConclusionsThe use of contrast agents enabled the detection of metastatic deposits of neuroblastoma cells in a chick embryo model, thereby reinforcing the potential of this cost efficient and convenient, 3R compliant, in vivo model for cancer research.

cancer biology↗

bioRxiv2017

Quantitative relationships for radiation induced chromosome instability: data analysis

The experimental observations demonstrate that different cell lines reveal various shape of dynamic curves for radiation-induced chromosomal instability (RICI). We analyzed our own and published data on RICI for three cell lines, CHO-K1, V79 and TK6, on the basis of the mechanistic RICI model. We demonstrate that all three dynamic curves can be successfully described by the proposed model with partially cell line specific parameters.

cancer biology↗

bioRxiv2017

The urinary microbiome associated with bladder cancer

Recent findings suggest that microorganisms inhabiting the human body can influence the development of cancer, but the role of microorganisms in bladder cancer pathogenesis has not been explored yet. The aim of this study was to characterize and compare the urinary microbiome of bladder cancer patients with those of healthy controls. Bacterial communities present in urine specimens collected from male patients diagnosed with primary or recurrent, non-muscle invasive bladder cancers, and from healthy, age-matched individuals were analysed using 16S Illumina MiSeq sequencing. Our result show that the most abundant phylum in both groups was Firmicutes, followed by Actinobacteria, Bacteroidetes and Proteobacteria. While microbial diversity and overall microbiome composition were not significantly different between bladder cancer and healthy samples, we identified specific operational taxonomic units (OTUs) that were significantly more abundant (p < 0.05) in either type of samples. Among those that were significantly enriched in the bladder cancer group, we identified an OTU belonging to genus Fusobacterium, a possible protumorigenic pathogen. Three OTUs more abundant in healthy urines were from genera Veillonella, Streptococcus and Corynebacterium. Detected microbiome changes suggest that microbiome may be a factor in bladder cancer pathology, and the clinical implications of reported results remain to be explored.

cancer biology↗

bioRxiv2017

Dose response relationships for gamma radiation induced chromosomal instability

Different cell lines demonstrate various dose response for radiation-induced chromosomal instability (RICI). To clarify the origin of differences we analyzed own and published data on RICI for four cell lines, V79, TK6, WTK1 and CHO-K1 on the basis of the mechanistic RICI model. We conclude that observable dose-response shapes, both plateau-like and strong dose dependent behavior, may be jointly explained by the same model of RICI. Mechanistic modeling reveals that a variation of certain set of RICI parameters leads to strong modification of dose-response curve.

cancer biology↗

bioRxiv2017

Modularity of the metabolic gene network as a prognostic biomarker for hepatocellular carcinoma

Abnormal metabolism is an emerging hallmark of cancer. Cancer cells utilize both aerobic glycolysis and oxidative phosphorylation (OXPHOS) for energy production and biomass synthesis. Understanding the metabolic reprogramming in cancer can help design therapies to target metabolism and thereby to improve prognosis. We have previously argued that more malignant tumors are usually characterized by a more modular expression pattern of cancer-associated genes. In this work, we analyzed the expression patterns of metabolism genes in terms of modularity for 371 hepatocellular carcinoma (HCC) samples from the Cancer Genome Atlas (TCGA). We found that higher modularity significantly correlated with glycolytic phenotype, later tumor stages, higher metastatic potential, and cancer recurrence, all of which contributed to poorer prognosis. Among patients with recurred tumor, we found the correlation of higher modularity with worse prognosis during early to mid-progression. Furthermore, we developed metrics to calculate individual modularity, which was shown to be predictive of cancer recurrence and patients survival and therefore may serve as a prognostic biomarker. Our overall conclusion is that more aggressive HCC tumors, as judged by decreased host survival probability, had more modular expression patterns of metabolic genes. These results may be used to identify cancer driver genes and for drug design.

cancer biology↗

bioRxiv2017

Aberrant splicing in B-cell acute lymphoblastic leukemia

Aberrant splicing is a hallmark of leukemias with mutations in splicing factor (SF)-encoding genes. Here we investigated its prevalence in pediatric B-cell acute lymphoblastic leukemias (B-ALL), where SFs are not mutated. By comparing them to normal pro-B cells, we found thousands of aberrant local splice variations (LSVs) per sample, with 279 LSVs in 241 genes present in every comparison. These genes were enriched in RNA processing pathways and encoded ~100 SFs, e.g. hnRNPA1. hnRNPA1 3UTR was pervasively misspliced, yielding the transcript subject to nonsense-mediated decay. Thus, we knocked it down in B-lymphoblastoid cells, identified 213 hnRNPA1-dependent splicing events, and defined the hnRNPA1 splicing signature in pediatric leukemias. One of its elements was DICER1, a known tumor suppressor gene; its LSVs were consistent with reduced translation of DICER1 mRNA. Additionally, we searched for LSVs in other leukemia and lymphoma drivers and discovered 81 LSVs in 41 genes. 77 LSVs were confirmed using two large independent B-ALL RNA-seq datasets. In fact, the twenty most common B-ALL drivers showed higher prevalence of aberrant splicing than of somatic mutations. Thus, post-transcriptional deregulation of SF can drive widespread changes in B-ALL splicing and likely contribute to disease pathogenesis.

cancer biology↗

bioRxiv2017

Cytokine response of acute myeloid leukemia cells has impact on patient prognosis: Insights from mathematical modeling

Acute myeloid leukemia (AML) is a heterogeneous disease. One reason for the heterogeneity may originate from inter-individual differences in the responses of leukemic cells to endogenous cytokines. On the basis of mathematical modeling, computer simulations and patient data, we have provided evidence that cytokine-independent leukemic cell proliferation is linked to early relapses and poor overall survival. Depending whether the model of cytokine-dependent or cytokine-independent leukemic cell proliferation fits to the clinical data, patients can be assigned to two groups that differ significantly with respect to overall survival. The modeling approach further enables us to identify parameter constellations that can explain unexpected responses of some patients to external cytokines such as blast crisis or remission without chemotherapy.

cancer biology↗

bioRxiv2017

Androgen receptor binding sites are highly mutated in prostate cancer

Androgen receptor (AR) signalling is essential to nearly all prostate cancer cells. Any alterations to AR-mediated transcription can have a profound effect on prostate carcinogenesis and tumour growth. While the AR protein has been extensively studied, little is know about mutations to the non-coding regions where AR binds to DNA. Using clinical whole genome sequencing, we demonstrate that AR binding sites have a dramatically increased rate of mutations that is greater than any other transcription factor and specific to only prostate cancer. Demonstrating this may be common to lineage-specific transcription factors, estrogen receptor binding sites had an elevated rate of mutations in breast cancer. Based on the mutations observed at the binding site of AR and other related transcription factors, we proposed that AR occupancy impairs access of base excision repair enzymes to endogenous DNA damage. Overall, this work demonstrates that non-coding AR binding sites are frequently mutated in prostate cancer and may potentially act as driver mutations.

cancer biology↗