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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2017

Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer.

Breast cancer remains the leading cause of cancer death in women due to metastasis and the development of resistance to established therapies. Macrophages are the most abundant immune cells in the breast tumor microenvironment and can both inhibit and support cancer progression. Thus, gaining a better understanding of how macrophages support cancer could lead to the development of more effective therapies. In this study, we find that breast cancer associated macrophages express high levels of insulin-like growth factors 1 and 2 (IGFs) and are the main source of IGFs within both primary and metastatic tumours. 75% of breast cancer patients show activation of Insulin/IGF-1 receptor signaling and this correlates with increased macrophage infiltration and advanced tumor stage. In patients with invasive breast cancer, activation of Insulin/IGF-1 receptors increased to 87%. Blocking IGF in combination with paclitaxel, a chemotherapeutic agent commonly used to treat breast cancer, showed a significant reduction in tumor cell proliferation and lung metastasis in a pre-clinical breast cancer model compared to paclitaxel monotherapy. Our findings provide the rationale for further developing the combination of paclitaxel with IGF blockers for the treatment of invasive breast cancer, and Insulin/IGF1R activation and IGF+ stroma cells as potential biomarker candidates for further evaluation.

cancer biology↗

bioRxiv2017

Single-Cell RNAseq analysis of infiltrating neoplastic cells at the migrating front of human glioblastoma

Glioblastoma is the most common primary brain cancer in adults and is notoriously difficult to treat due to its diffuse nature. We performed single-cell RNAseq on 3589 cells in a cohort of four patients. We obtained cells from the tumor core as well as surrounding peripheral tissue. Our analysis revealed cellular variation in the tumors genome and transcriptome, We were able to identify infiltrating neoplastic cells in regions peripheral to the core lesions. Despite the existence of significant heterogeneity among neoplastic cells, we found that infiltrating GBM cells share a consistent gene signature between patients, suggesting a common mechanism of infiltration. Additionally, in investigating the immunological response to the tumors, we found transcriptionally distinct myeloid cell populations residing in the tumor core and the surrounding peritumoral space. Our data provide a detailed dissection of GBM cell types, revealing an abundance of novel information about tumor formation and migration.

cancer biology↗

bioRxiv2017

Chemotherapeutic dose scheduling based on tumor growth rates: the case for low dose metronomic high entropy therapies

We extend classical tumor regression models, such as the Norton-Simon hypothesis, from instantaneous regression rates (i.e. the derivative) to the cumulative effect (i.e. the integral) over one (or many) cycles of chemotherapy. To achieve this end, we use a stochastic Moran process model of tumor cell kinetics, coupled with a prisoners dilemma game-theoretic cell-cell interaction model to design chemotherapeutic strategies tailored to different tumor growth characteristics. Using the Shannon entropy as a novel tool to quantify the success of dosing strategies, we contrast maximum tolerated dose (MTD) strategies as compared with low dose, high density metronomic strategies (LDM) for tumors with different growth rates. Our results show that LDM strategies can outperform MTD strategies in total tumor cell reduction (TCR). The advantage is magnified for fast growing tumors that thrive on long periods of unhindered growth without chemotherapy drugs present and is not evident after a single cycle of chemotherapy, but grows after each subsequent cycle of repeated chemotherapy. The model supports the concept of designing different chemotherapeutic schedules for tumors with different growth rates and develops quantitative tools to optimize these schedules for maintaining low volume tumors. The evolutionary model we introduce in this paper is compared with regression data from murine models and shown to be in good agreement.\n\nMajor FindingsModel simulations show that metronomic (low dose, high density) therapies can outperform maximum tolerated dose (high dose, low density) therapies. This is due to the fact that tumor cell reduction is more sensitive to changes in dose density than changes in dose concentration, especially for faster growing tumors. This effect is negligible after a single cycle of chemotherapy, but magnified after many cycles. The model also allows for novel chemotherapeutic schedules and quantifies their performance according to tumor growth rate.

cancer biology↗

bioRxiv2017

PI3Kδ inhibition supports memory T cells with enhanced antitumor fitness

Phosphatidylinositol-3-kinase p110{delta} (PI3K{delta}) inhibition by Idelalisib (CAL-101) in hematological malignancies directly induces apoptosis in cancer cells and disrupts immunological tolerance by depleting regulatory T cells (Tregs). Yet, little is known about the direct impact of PI3K{delta} blockade on effector T cells from CAL-101 therapy. Herein, we demonstrate a direct effect of p110{delta} inactivation via CAL-101 on murine and human CD8+ T cells that promotes a strong undifferentiated memory phenotype (elevated CD62L/CCR7, CD127 and Tcf7). These CAL-101 T cells also persisted longer after transfer and exerted stronger antitumor immunity compared to traditionally expanded CD8+ T cells in two solid tumor models. Thus, this report describes a novel direct enhancement of CD8+ T cell memory by a p110{delta} inhibitor that leads to markedly improved tumor regression. This finding has significant implications to improve outcomes from next generation cancer immunotherapies.\n\nHighlightsO_LIIn vitro blockade of PI3K p110{delta} with CAL-101 endows antitumor T cells with a stronger memory phenotype than those treated with AKTi\nC_LIO_LIThe strong memory phenotype of CAL-101 treated cells translates into improved survival of mice bearing aggressive tumors after adoptive transfer of these T cells\nC_LIO_LIHuman CAR engineered T cells treated with CAL-101 possess an enhanced memory phenotype and robust antitumor efficacy\nC_LIO_LIThe antitumor efficacy of CAL-101 primed T cells is not mediated by high CD62L or CD127 expression, but is likely driven by their stem memory phenotype\nC_LI\n\neTOC BlurbBowers et al report a novel function of PI3K blockade using the p110{delta} subunit inhibitor CAL-101 to induce memory and antitumor potency in CD8+ T cells. Ex vivo treatment of T cells with CAL-101 leads to improved antitumor control and subject survival in both murine transgenic T cell and human CAR T cell models.

cancer biology↗

bioRxiv2017

Fibroblasts cell lines misclassified as cancer cell lines

Large collections of immortalized cancer cell lines have been widely used as model systems for cancer research and drug discovery. Some of these models however display more fibroblast-like than cancer-like characteristics based on their genetic and genomic characterization. The correct annotation of these cell lines remains a challenge. Here, we report the outcome of our analysis on a large cancer cell line collection, where we found a subset of cell lines misclassified.

cancer biology↗

bioRxiv2017

Modelling glioblastoma tumour-host cell interactions using adult brain organotypic slice co-culture

Glioblastoma (GBM) is an aggressive incurable brain cancer. The cells that fuel the growth of tumours resemble neural stem cells found in the developing and adult mammalian forebrain. These are referred to as GBM stem cells (GSCs). Similar to neural stem cells, GSCs exhibit a variety of phenotypic states: dormant, quiescent, proliferative and differentiating. How environmental cues within the brain influence these distinct states is not well understood. Laboratory models of GBM tumours can be generated using either genetically engineered mouse models, or via intracranial transplantation of cultured tumour initiating cells (mouse or human). Unfortunately, these approaches are expensive, time-consuming, low-throughput and ill-suited for monitoring of live cell behaviours. Here we explored whole adult brain coronal organotypic slices as a complementary strategy to remove the experimental bottleneck. Mouse adult brain slices remain viable in a neural stem cell serum-free basal media for several weeks. GSCs can therefore be easily microinjected into specific anatomical sites ex vivo. We demonstrated distinct responses of engrafted GSCs to different microenvironments in the brain. Within the subependymal zone - one of the adult neural stem cell niches - a subset of injected tumour cells could effectively engraft and respond to endothelial niche signals. GSCs transplanted slices were treated with the anti-mitotic drug temozolomide as proof-of-principle of the utility in modelling responses to existing treatments. Thus, engraftment of mouse or human GSCs onto whole brain coronal organotypic brain slices provides a convenient experimental model for studies of GSC-host interactions and preclinical testing of candidate therapeutic agents.

cancer biology↗

bioRxiv2017

Patient-derived xenografts undergo murine-specific tumor evolution

Patient-derived xenografts (PDXs) have become a prominent model for studying human cancer in vivo. The underlying assumption is that PDXs faithfully represent the genomic features of primary tumors, retaining their molecular characteristics throughout propagation. However, the genomic stability of PDXs during passaging has not yet been evaluated systematically. Here we monitored the dynamics of copy number alterations (CNAs) in 1,110 PDX samples across 24 cancer types. We found that new CNAs accumulated quickly, such that within four passages an average of 12% of the genome was affected by newly acquired CNAs. Selection for preexisting minor clones was a major contributor to these changes, leading to both gains and losses of CNAs. The rate of CNA acquisition in PDX models was correlated with the extent of both aneuploidy and genetic heterogeneity observed in primary tumors of the same tissue. However, the specific CNAs acquired during PDX passaging differed from those acquired during tumor evolution in patients, suggesting that PDX tumors are subjected to distinct selection pressures compared to those that exist in human hosts. Specifically, several recurrent CNAs observed in primary tumors gradually disappeared in PDXs, indicating that events undergoing positive selection in humans can become dispensable during propagation in mice. Finally, we found that the genomic stability of PDX models also affected their responses to chemotherapy and targeted drugs. Our findings thus highlight the need to couple the timing of PDX molecular characterization to that of drug testing experiments. These results suggest that while PDX models are powerful tools, they should be used with caution.

cancer biology↗

bioRxiv2017

Diagnostic and Prognostic Implications of Ribosomal Protein Transcript Coordination in Human Cancers

Ribosomes, the organelles responsible for the translation of mRNA, are comprised of rRNA and ~80 ribosomal proteins (RPs). Although canonically assumed to be maintained in equivalent proportions, some RPs have been shown to possess differential expression across tissue types. Dysregulation of RP expression occurs in a variety of human diseases, notably in many cancers, and altered expression of some RPs correlates with different tumor phenotypes and patient survival. To investigate the impact of global RP transcript (RPT) expression patterns on tumor phenotypes, we analyzed RPT expression of ~10,000 human tumors and 700 normal tissues with t-distributed stochastic neighbor embedding (t-SNE). We show here that normal tissues and cancers possess readily discernible RPT expression patterns. In tumors, this patterning is distinct from normal tissues, distinguishes tumor subtypes from one another, and in many cases correlates with molecular, pathological, and clinical features, including survival. Collectively, RPT expression can be used as a powerful and novel method of tumor classification, offering a potential clinical tool for prognosis and therapeutic stratification.

cancer biology↗

bioRxiv2017

c-Myc Represses Transcription of the Epstein-Barr Virus Latent Membrane Protein 1 Early After Primary B Cell Infection

Recent evidence has shown that the EBV oncogene LMP1 is not expressed at high levels early after EBV-infection of primary B cells, despite its being essential for the long-term outgrowth of immortalized lymphoblastoid cell lines (LCLs). In this study, we found that expression of LMP1 increased fifty-fold between seven days post infection and the LCL state. Metabolic labeling of nascently transcribed mRNA indicated this was primarily a transcription-mediated event. EBNA2, the key viral transcription factor regulating LMP1, and CTCF, an important chromatin insulator, were recruited to the LMP1 locus similarly early and late after infection. However, the activating histone H3K9Ac mark was enriched at the LMP1 promoter in LCLs relative to early-infected B cells. We found that high c-Myc activity in EBV-infected lymphoma cells as well as overexpression of c-Myc in an LCL model system repressed LMP1 transcription. Finally, we found that chemical inhibition of c-Myc expression both in LCLs and early after primary B-cell infection increased LMP1 expression. These data support a model in which high levels of endogenous c-Myc activity induced early after primary B-cell infection directly represses LMP1 transcription.\n\nIMPORTANCEEBV is a highly successful pathogen that latently infects greater than 90% of adults worldwide and is also causally associated with a number of B-cell malignancies. EBV expresses a set of viral oncoproteins and non-coding RNAs during the latent life cycle with the potential to promote cancer. Critical among these is the viral latent membrane protein, LMP1. Prior work suggests that LMP1 is essential for EBV to immortalize B cells, but our recent work indicates that LMP1 is not produced at high levels during the first few weeks after infection. Here, we show that the transcription of LMP1 can be negatively regulated by a host transcription factor, c-Myc. Ultimately, understanding the regulation of EBV-encoded oncogenes will allow us to better treat cancers that rely on these viral products for survival.

cancer biology↗

bioRxiv2017

Suppression of Transposable Elements in Leukemic Stem Cells

Genomic transposable elements (TEs) comprise nearly half of the human genome. The expression of TEs is considered potentially hazardous, as it can lead to insertional mutagenesis and genomic instability. However, recent studies have revealed that TEs are involved in immune-mediated cell clearance. Hypomethylating agents can increase the expression of TEs in cancer cells, inducing viral mimicry, causing interferon signalling and cancer cell killing. To investigate the role of TEs in the pathogenesis of acute myeloid leukaemia (AML), we studied TE expression in several cell fractions of AML while tracking its development (pre-leukemic haematopoietic stem cells, leukemic stem cells [LSCs], and leukemic blasts). LSCs, which are resistant to chemotherapy and serve as reservoirs for relapse, showed significant suppression of TEs and interferon pathways. Similarly, high-risk cases of myelodysplastic syndrome (MDS) showed far greater suppression of TEs than low-risk cases. We propose TE suppression as a mechanism for immune escape in AML and MDS. Repression of TEs co-occurred with the upregulation of several genes known to modulate TE expression, such as RNA helicases and autophagy genes. Thus, we have identified potential pathways that can be targeted to activate cancer immunogenicity via TEs in AML and MDS.

cancer biology↗

bioRxiv2017

Recasting the cancer stem cell hypothesis: unification using a continuum model of microenvironmental forces

Since the first evidence for cancer stem cells in leukemia, experimentalists have sought to identify tumorigenic subpopulations in solid tumors. In parallel, scientists have argued over the implications of the existence of this subpopulation. On one side, the cancer stem cell hypothesis posits that a small subset of cells within a tumor are responsible for tumorigenesis and are capable of recapitulating the entire tumor on their own. Under this hypothesis, a tumor may be conceptualized as a series of coupled compartments, representing populations of progressively differentiated cell types, starting from stem cells. The allure of this model is that it elegantly explains our therapeutic failures: we have been targeting the wrong cells. Alternatively, the stochastic model states that all cells in a tumor can have stem-like properties, and have an equally small capability of forming a tumor. As tumors are, by nature, heterogeneous, there is ample evidence to support both hypotheses. We propose a mechanistic mathematical description that integrates these two theories, settling the dissonance between the schools of thought and providing a road map for integrating disparate experimental results into a single theoretical framework. We present experimental results from clonogenic assays that demonstrate the importance of defining this novel formulation, and the clarity that is provided when interpreting these results through the lens of this formulation.

cancer biology↗

bioRxiv2017

Insulin Does Not Augment In Vitro Tumor Growth Under A Hyperglycemia-Mimicking Milieu And In A Calorie Restriction-Resembling Manner

BackgroundWhether insulin enhances or represses tumor cell proliferation remains debating and inconclusive although epidemiological data indicated insulin use raises a risk of cancer incidence in patients with diabetes mellitus (DM).\n\nMethodology/Principle FindingsWe cultured rat pituitary adenoma cells in a high-glucose medium to simulate hyperglycemia occurring in DM patients. Upon incubation with or without insulin, repressed tumor cell proliferation and downregulated tumor marker expression occur accompanying with mitigated oxidative stress and compromised apoptosis. Mechanistically, insulin resistance-abrogated glucose uptake was suggested to create an intracellular low-glucose milieu, leading to cellular starvation resembling calorie restriction (CR). While downregulation of insulin-like growth factor 1 (IGF-1) occurring in CR was validated, oncogene downregulation and tumor suppressor gene upregulation seen in CR was also replicated by NOS2 knockdown.\n\nConclusions/SignificanceCellular starvation can exert CR-like anti-tumor effects regardless of insulin presence or absence.

cancer biology↗

bioRxiv2017

Targeting posttranslational modifications of RioK1 inhibits the progression of colorectal and gastric cancers

RioK1 has recently been shown to play important roles in cancers, but its posttranslational regulation is largely unknown. Here we report that RioK1 is methylated at K411 by SETD7 methyltransferase, and that lysine-specific demethylase 1 (LSD1) reverses its methylation. The mutated RioK1 (K411R) that cannot be methylated exhibits a longer half-life than does the methylated RioK1. FBXO6 specifically interacts with K411-methylated RioK1 through its FBA domain to induce RioK1 ubiquitination. Casein kinase 2 (CK2) phosphorylates RioK1 at T410, which stabilizes RioK1 by antagonizing K411 methylation and impeding the recruitment of FBXO6 to RioK1. Functional experiments demonstrate the RioK1 methylation reduces the tumor growth and metastasis in CRC and GC. Importantly, the protein levels of CK2 and LSD1 show an inverse correlation with FBXO6 and SETD7 expression in human CRC tissues. Therefore, this study highlights the importance of a RioK1 methylation-phosphorylation switch in determining CRC and GC development.

cancer biology↗

bioRxiv2017

Expanding primary cells from mucoepidermoid and other salivary gland neoplasms for genetic and chemosensitivity testing

Restricted availability of cell and animal models is a rate-limiting step for investigation of salivary gland neoplasm pathophysiology and therapeutic response. Conditionally reprogrammed cell (CRC) technology enables establishment of primary epithelial cell cultures from patient material. This study tested a translational workflow for acquisition, expansion and testing of CRC-derived primary cultures of salivary gland neoplasms from patients presenting to an academic surgical practice. Results showed cultured cells were sufficient for epithelial cell-specific transcriptome characterization to detect candidate therapeutic pathways and fusion genes in addition to screening for cancer-risk-associated single nucleotide polymorphisms (SNPs) and driver gene mutations through exome sequencing. Focused study of primary cultures of a low-grade mucoepidermoid carcinoma demonstrated Amphiregulin-Mechanistic Target of Rapamycin-AKT/Protein kinase B (AKT) pathway activation, identified through bioinformatics and subsequently confirmed as present in primary tissue and preserved through different secondary 2D and 3D culture media and xenografts. Candidate therapeutic testing showed that the allosteric AKT inhibitor MK2206 reproducibly inhibited cell survival across different culture formats. In contrast, the cells appeared resistant to the adenosine triphosphate competitive AKT inhibitor GSK690693. Procedures employed here illustrate an approach for reproducibly obtaining material for pathophysiological studies of salivary gland neoplasms, and other less common epithelial cancer types, that can be executed without compromising pathological examination of patient specimens. The approach permits combined genetic and cell-based physiological and therapeutic investigations in addition to more traditional pathologic studies and can be used to build sustainable bio-banks for future inquiries.

cancer biology↗

bioRxiv2017

A quantitative chemotherapy genetic interaction map reveals new factors associated with PARP inhibitor resistance

Nearly every cancer patient is treated with chemotherapy yet our understanding of factors that dictate response and resistance to such agents remains limited. We report the generation of a quantitative chemical-genetic interaction map in human mammary epithelial cells that charts the impact of knockdown of 625 cancer and DNA repair related genes on sensitivity to 29 drugs, covering all classes of cancer chemotherapeutics. This quantitative map is predictive of interactions maintained in cancer cell lines and can be used to identify new cancer-associated DNA repair factors, predict cancer cell line responses to therapy and prioritize drug combinations. We identify that GPBP1 loss in breast and ovarian cancer confers resistance to cisplatin and PARP inhibitors through the regulation of genes involved in homologous recombination. This map may help navigate patient genomic data and optimize chemotherapeutic regimens by delineating factors involved in the response to specific types of DNA damage.

cancer biology↗

bioRxiv2017

SVclone: inferring structural variant cancer cell fraction

We present SVclone, a computational method for inferring the cancer cell fraction of structural variant breakpoints from whole-genome sequencing data. We validate our approach using simulated and real tumour samples, and demonstrate its utility on 2,778 whole-genome sequenced tumours. We find a subset of liver, breast and ovarian cancer cases with decreased overall survival that have subclonally enriched copy-number neutral rearrangements, an observation that could not be discovered with currently available methods.

cancer biology↗

bioRxiv2017

Whole chromosome loss in tetraploid cells confers tumorigenic potential in a mouse allograft model

Whole chromosome gains or losses (aneuploidy) are a hallmark of ~70% of human tumors. Modeling the consequences of aneuploidy has relied on perturbing spindle assembly checkpoint (SAC) components but interpretations of these experiments are clouded by the multiple functions of these proteins. Here we used a Cre recombinase-mediated chromosome loss strategy to individually delete mouse chromosomes 9, 10, 12 or 14 in tetraploid immortalized murine embryonic fibroblasts. While the aneuploid cells generally display a growth disadvantage in vitro, they grow significantly better in low adherence sphere-forming conditions and 3 of the 4 lines are transformed in vivo, forming large and invasive tumors in immunocompromised mice. The aneuploid cells display increased chromosomal instability and DNA damage, a mutator phenotype associated with tumorigenesis in vivo. Thus, these studies demonstrate a causative role for whole chromosome loss in tumorigenesis and may shed light on the early consequences of aneuploidy in mammalian cells.

cancer biology↗

bioRxiv2017

The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space

Glioblastoma is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the role of the epigenome in glioblastoma disease progression. Here, we present genome-scale maps of the DNA methylation dynamics in matched primary and recurring glioblastoma tumors, based on a national population registry and a comprehensively annotated clinical cohort. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected formalin-fixed paraffin-embedded (FFPE) samples, and we validate bisulfite sequencing as a multi-purpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional tumor characteristics. Based on these data, we identified characteristic differences between primary and recurring tumors, links between DNA methylation and the tumor microenvironment, and an association of epigenetic tumor heterogeneity with patient survival. In summary, this study provides a resource for dissecting DNA methylation heterogeneity in genetically diverse and heterogeneous tumors, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology in a representative national cohort, leveraging samples and data collected as part of routine clinical practice.

cancer biology↗