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Results for “Cancer Biology”

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bioRxiv2018

A Biomechanical Model of Tumor-induced Intracranial Pressure and Edema in Brain Tissue

Brain tumor growth and tumor-induced edema result in increased intracranial pressure (ICP), which, in turn, is responsible for conditions as benign as headaches and vomiting, or as severe as seizures, neurological damage, or even death. Therefore, it has been hypothesized that tracking ICP dynamics may offer improved prognostic potential in terms of early detection of brain cancer and better delimitation of the tumor boundary. However, translating such theory into clinical practice remains a challenge, in part, due to an incomplete understanding of how ICP correlates with tumor grade. Here, we propose a multiphase mixture model that describes the biomechanical response of healthy brain tissue - in terms of changes in ICP and edema - to a growing tumor. The model captures ICP dynamics within the diseased brain and accounts for the ability/inability of healthy tissue to compensate for this pressure. We propose parameter regimes that distinguish brain tumors by grade thereby providing critical insight into how ICP dynamics vary by severity of disease. In particular, we offer an explanation for clinically observed phenomena such as lack of symptoms in low grade glioma patients versus a rapid onset of symptoms in those with malignant tumors. Our model also takes into account the effects tumor-derived proteases may have on ICP levels and extent of tumor invasion. This work represents an important first step towards understanding the mechanisms that underlie the onset of edema and ICP in cancer-afflicted brains. Continued modeling effort in this direction has the potential to make an impact in the field of brain cancer diagnostics.

cancer biology↗

bioRxiv2018

Topological Data Analysis of PAM50 and 21-Gene Breast Cancer Assays

We introduce a classification of breast tumors into 7 classes which are more clearly defined by interpretable mRNA signatures along the PAM50 gene set than the 5 traditional PAM50 intrinsic subtypes. Each intrinsic subtype is partially concordant with one of our classes, and the 2 additional classes correspond to division of the classes concordant with the Luminal B and the Normal intrinsic subtypes along expression of the Her2 gene group. Our Normal class shows similarity with the myoepithelial mammary cell phenotype, including TP63 expression (specificity: 80.8% and sensitivity: 82.8%), and exhibits the best overall survival (89.6% at 5 years). Though Luminal A tumors are traditionally considered the least aggressive, our analysis shows that only the Luminal A tumors which are now classified as myoepithelial have this phenotype, while tumors in our luminal class (concordant with Luminal A) may be more aggressive than previously thought. We also find that patients with Basal tumors surviving to 48 months exhibit favorable survival rates when certain markers for B-lymphocytes are present and poor survival rates when they are absent, which is consistent with recent findings.

cancer biology↗

bioRxiv2018

Relating evolutionary selection and mutant clonal dynamics in normal epithelia

Cancer develops from mutated cells in normal tissues. Whether somatic mutations alter normal cell dynamics is key to understanding cancer risk and guiding interventions to reduce it. An analysis of the first incomplete moment of size distributions of clones carrying cancer-associated mutations in normal human eyelid skin gives a good fit with neutral drift, arguing mutations do not affect cell fate. However, this suggestion conflicts with genetic evidence in the same dataset that argues for strong positive selection of a subset of mutations. This implies cells carrying these mutations have a competitive advantage over normal cells, leading to large clonal expansions within the tissue. In normal epithelium, clone growth is constrained by the limited size of the proliferating compartment and competition with surrounding cells. We show that if these factors are taken into account, the first incomplete moment of the clone size distribution is unable to exclude non-neutral behavior. Furthermore, experimental factors can make a non-neutral clone size distribution appear neutral. We validate these principles with a new experimental data set showing that when experiments are appropriately designed, the first incomplete moment can be a useful indicator of non-neutral competition. Finally, we discuss the complex relationship between mutant clone sizes and genetic selection.\n\nSignificance StatementAging normal epithelial tissues are extensively colonised by clones carrying cancer associated mutations. Insight into the emergence of mutant clones is key to guide cancer prevention. However, the statistical evidence as to whether mutant clones emerge by neutral competition or due to a competitive advantage conferred by mutation is conflicted. We reconcile this apparent contradiction by demonstrating that the previously presented metrics for measuring neutrality from clone sizes are dependent on the spatial constraints imposed by the tissue structure and experimental design. Furthermore, we show that clonal competition within a recently reported dataset of healthy human oesophageal tissue is non-neutral. Finally, we discuss how discrepancies between measures of clone size and genetic selection can provide insight into early carcinogenesis.

cancer biology↗

bioRxiv2018

Dynamic urinary proteomic analysis in a Walker 256 intracerebral tumor model

Patients with primary and metastatic brain cancer have an extremely poor prognosis, mostly due to the late diagnosis of disease. Urine, which lacks homeostatic mechanisms, is an ideal biomarker source that accumulates early and highly sensitive changes to provides information about the early stage of disease. A rat model mimicking the local tumor growth process in the brain was established with intracerebral Walker 256 (W256) cell injection. Urine samples were collected on days 3, 5 and 8 after injection and then analyzed by LC-MS/MS. In the intracerebral W256 model, no obvious clinical manifestations changes or abnormal MRI signals were found on days 3 and 5; at these time points, nine proteins were changed significantly in the urine of all 8 tumor rats. On day 8, when tumors were detected by MRI, twenty-five differential proteins were identified, including 10 proteins that have been reported to be closely related to tumor metastasis or brain tumors. The differential urinary proteomes were compared with those from the subcutaneous W256 model and the intracerebral C6 model. Few differential proteins overlapped. Specific differential protein patterns were observed among the three models, indicating that the urinary proteome can reflect the difference when tumor cells with different growth characteristics are inoculated into the brain and when identical tumor cells are inoculated into different areas, specifically, the subcutis and the brain.

cancer biology↗

bioRxiv2018

Mesenchymal stromal cells release CXCL1/2/8 and induce chemoresistance and macrophage polarization

Factors released by surrounding cells such as cancer-associated mesenchymal stromal cells (CA-MSCs) are involved in tumor progression and chemoresistance. We determine the mechanisms by which a naive MSC could become a CA-MSC and characterize CA-MSCs. Ovarian tumor cells (OTC) trigger the transformation of MSCs to CA-MSCs expressing different pro-tumoral, genes and secreting high amounts of CXCR1/2 ligands (CXCL1, CXCL2 and IL-8) implicated in the chemoresistance of cancer cells. CXCR1/2 ligands can also inhibit the immune response against OTC. Indeed, through their released factors, CA-MSCs can trigger the differentiation of monocytes to pro-tumoral M2 phenotype macrophages known to promote the tumor progression. When CXCR1/2 receptors are inhibited, these CA-MSC-activated macrophages lose their M2 functions and acquire an anti-tumoral phenotype. Both ex vivo and in vivo a CXCR1/2 inhibitor can sensitize OTC to carboplatin even in the presence of a pro-tumoral microenvironment. This inhibitor can circumvent the pro-tumoral effects of CA-MSCs. As high concentrations of CXCR1/2 ligands in blood from patients can be associated with chemoresistance, CXCR1/2 inhibition could be a potential therapeutic strategy to revert chemoresistance.

cancer biology↗

bioRxiv2018

Active Receptor Tyrosine Kinases, but not Brachyury, are sufficient to trigger chordoma in zebrafish

The aberrant activation of developmental processes triggers diverse cancer types. Chordoma is a rare, aggressive tumor arising from transformed notochord remnants. Several potentially oncogenic factors, including several receptor tyrosine kinase (RTK) genes, have been found deregulated in chordoma, yet causation remains uncertain. In particular, sustained expression of the developmental notochord transcription factor Brachyury is hypothesized as key driver of chordoma; nonetheless, experimental evidence for an oncogenic role of Brachyury in chordoma and its prognostic impact remains missing. Here, we developed and applied a zebrafish chordoma model to identify the notochord-transforming potential of implicated genes in vivo. We find that Brachyury, including a form with augmented transcriptional activity, is insufficient to initiate notochord hyperplasia. In contrast, the chordoma-implicated RTKs EGFR and KDR/VEGFR2 are sufficient to transform notochord cells within two to five days of development. Transcriptome and structural analysis of transformed notochords revealed that the aberrant activation of RTK/Ras signaling attenuates processes required for notochord differentiation, including of the unfolded protein response. Our results provide first in vivo indication against a tumor-initiating potential of Brachyury in the notochord, and imply activated RTK signaling as possibly initiating event in chordoma. These results provide a mechanistic framework for the pursuit of chemotherapeutic compounds to combat this aggressive tumor type.

cancer biology↗

bioRxiv2018

CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation

The cyclin-dependent kinase 12 (CDK12) modulates transcription elongation by phosphorylating the carboxy-terminal domain of RNA polymerase II and appears to selectively affect the expression of DNA damage response (DDR) and mRNA processing genes. Yet, the mechanism(s) by which it achieves this selectivity remains unclear. Using a highly selective CDK12/13 inhibitor, THZ531, and nascent RNA sequencing, we show that CDK12 inhibition results in gene length-dependent elongation defects, leading to premature cleavage and polyadenylation (PCPA) as well as loss of expression of long (>45 kb) genes, a substantial proportion of which participate in the DDR. This early termination phenotype correlated with an increased proportion of intronic polyadenylation sites, a feature that was especially prominent among DDR genes. Finally, phosphoproteomic analysis indicated that pre-mRNA processing factors, including those involved in PCPA, are direct phosphotargets of CDKs 12 and 13. These results support a model in which DDR genes are uniquely susceptible to CDK12 inhibition due primarily to their relatively longer lengths and lower ratios of U1 snRNP binding to intronic polyadenylation sites.

cancer biology↗

bioRxiv2018

A cell-of-origin epigenetic tracer reveals clinically distinct subtypes of high grade serous ovarian cancer

High grade serous ovarian cancer (HGSOC) is a major unmet need in oncology. The persistent uncertainty on its originating tissue has contributed to hamper the discovery of oncogenic pathways and effective therapies. Here we define the DNA methylation print that distinguishes the human fimbrial (FI) and ovarian surface epithelia (OSE) and develop a robust epigenetic cell-of-origin tracer that stratifies HGSOC in FI-and OSE-originated tumors across all available cohorts. We translate this origin-based stratification into a clinically actionable transcriptomic signature, demonstrating its prognostic impact on patients survival and identifying novel network level dysregulations specific for the two disease subtypes.

cancer biology↗

bioRxiv2018

Single cell derived organoids capture the self-renewing subpopulations of metastatic ovarian cancer

High Grade Serous Ovarian cancer (HGSOC) is a major unmet need in oncology, due to its precocious dissemination and the lack of meaningful human models for the investigation of disease pathogenesis in a patient-specific manner. To overcome this roadblock, we present a new method to isolate and grow single cells directly from patients ascites, establishing the conditions for propagating them as single-cell derived ovarian cancer organoids (scOCOs). By single cell RNA sequencing (scRNAseq) we define the cellular composition of metastatic ascites and trace its propagation in 2D and 3D culture paradigms, finding that scOCOs retain and amplify key subpopulations from the original patients samples and recapitulate features of the original metastasis that do not emerge from classical 2D culture, including retention of individual patients specificities. By enabling the enrichment of uniquely informative cell subpopulations from HGSOC metastasis and the clonal interrogation of their diversity at the functional and molecular level, this method transforms the prospects of precision oncology for ovarian cancer.

cancer biology↗

bioRxiv2018

MLL-AF9 Initiates Transformation From Fast-Proliferating Myeloid Progenitors

Cancer is a hyper-proliferative clonal disease. Whether the proliferative state originates from the cell-of-origin or emerges later remains elusive. By tracking de novo transformation from normal hematopoietic progenitors expressing an acute myeloid leukemia (AML) oncogene MLL-AF9, we reveal that the cell cycle rate heterogeneity among granulocyte-macrophage progenitors (GMPs) determines their probability of transformation. An intrinsic fast cell cycle kinetics at the time of oncogene expression provide permissiveness for transformation, with the fastest cycling 3% of GMPs ([~]0.006% of bone marrow nucleated cells) acquiring malignancy with nearly 100% efficiency. Molecularly, we propose that MLL-AF9 preserves the gene expression of the cellular states in which it is expressed. As such, when expressed in the naturally-existing, rapidly-cycling myeloid progenitors, this cell state is perpetuated, yielding malignancy. Our work elucidates one of the earliest steps toward malignancy and suggests that modifying the cycling state of the cell-of-origin could be an effective approach to prevent malignancy.

cancer biology↗

bioRxiv2018

A cross-cancer metastasis signature in the microRNA-mRNA axis of paired tissue samples

In the progression of cancer, cells acquire genetic mutations that cause uncontrolled growth. Over time, the primary tumour may undergo additional mutations that allow for the cancerous cells to spread throughout the body as metastases. Since metastatic development typically results in markedly worse patient outcomes, research into the identity and function of metastasisassociated biomarkers could eventually translate into clinical diagnostics or novel therapeutics. Although the general processes underpinning metastatic progression are understood, no consistent nor clear cross-cancer biomarker profile has yet emerged. However, the literature suggests that some microRNAs (miRNAs) may play an important role in the metastatic progression of several cancer types. Using a subset of The Cancer Genome Atlas (TCGA) data, we performed an integrated analysis of mRNA and miRNA expression with paired metastatic and primary tumour samples to interrogate how the miRNA-mRNA regulatory axis influences metastatic progression. From this, we successfully built mRNAand miRNA-specific classifiers that can discriminate pairs of metastatic and primary samples across 11 cancer types. In addition, we identified a number of miRNAs whose metastasis-associated dysregulation could predict mRNA metastasis-associated dysregulation. Among the most predictive miRNAs, we found several previously implicated in cancer progression, including miR-301b, miR-1296, and miR-423. Taken together, our results suggest that cross-cancer metastatic samples have unique biomarker signatures when compared with paired primary tumours, and that these miRNA biomarkers can be used to predict both metastatic status and mRNA expression.

cancer biology↗

bioRxiv2018

Single-cell Transcriptomics reveals multi-step adaptations to endocrine therapy

Resistant tumours are thought to arise from the action of Darwinian selection on genetically heterogenous cancer cell populations. However, simple clonal selection is inadequate to describe the late relapses often characterising luminal breast cancers treated with endocrine therapy (ET), suggesting a more complex interplay between genetic and non-genetic factors. Partially, this is due to our limited understanding on the effect of ET at the single cell level. In the present study, we dissect the contributions of clonal genetic diversity and transcriptional plasticity during the early and late phases of ET at single-cell resolution. Using single-cell RNA-sequencing and imaging we disentangle the transcriptional variability of plastic cells and define a rare sub-population of pre-adapted (PA) cells which undergoes further transcriptomic reprogramming and copy number changes to acquire full resistance. PA cells show reduced oestrogen receptor activity but increased features of quiescence and migration. We find evidence for sub-clonal expression of this PA signature in primary tumours and for dominant expression in clustered circulating tumour cells. We propose a multi-step model for ET resistance development and advocate the use of stage-specific biomarkers.

cancer biology↗

bioRxiv2018

Epigenetic mutational landscape in breast cancer: role of the histone methyltransferase gene KMT2D in triple negative tumors

PurposeEpigenetic regulating proteins like histone methyltransferases produce variations in several functions, some of them associated with the generation of oncogenic processes. Mutations of genes involved in these functions have been recently associated with cancer, and strategies to modulate their activity are currently in clinical development.\n\nMethodsBy using data extracted from the METABRIC study, we searched for mutated genes linked with detrimental outcome in invasive breast carcinoma (n = 772). Then, we used downstream signatures for each mutated gene to associate that signature with clinical prognosis using the online tool \"Genotype-2-Outcome\" (http://www.g-2-o.com). Next, we performed functional annotation analyses to classify genes by functions, and focused on those associated with the epigenetic machinery.\n\nResultsWe identified KMT2D, SETD1A and SETD2, included in the lysine methyltransferase activity function, as linked with poor prognosis in invasive breast cancer. KMT2D, which codes for a histone methyltransferase that acts as a transcriptional regulator, was mutated in 6% of triple negative breast tumors and found to be linked to poor survival. Genes regulated by KMT2D included RAC3, KRT23, or KRT14, among others, which are involved in cell communication and signal transduction. Finally, low expression of KMT2D at the transcriptomic level, which mirror what happens when KMT2D is mutated and functionally inactive, confirmed its prognostic value.\n\nConclusionIn the present work, we describe epigenetic modulating genes which are found to be mutated in breast cancer. We identify the histone methyltransferase KMT2D, which is mutated in 6% of triple negative tumors and linked with poor survival.

cancer biology↗

bioRxiv2018

Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition

Renal medullary carcinoma (RMC) is a rare and deadly kidney cancer in patients of African descent with sickle cell trait. Through direct-to-patient outreach, we developed genomically faithful patient-derived models of RMC. Using whole genome sequencing, we identified intronic fusion events in one SMARCB1 allele with concurrent loss of the other allele, confirming that SMARCB1 loss occurs in RMC. Biochemical and functional characterization of these RMC models revealed that RMC depends on the loss of SMARCB1 for survival and functionally resemble other cancers that harbor loss of SMARCB1, such as malignant rhabdoid tumors or atypical teratoid rhabdoid tumors. We performed RNAi and CRISPR-Cas9 loss of function genetic screens and a small-molecule screen and identified UBE2C as an essential gene in SMARCB1 deficient cancers. We found that the ubiquitin-proteasome pathway was essential for the survival of SMARCB1 deficient cancers in vitro and in vivo. Genetic or pharmacologic inhibition of this pathway leads to G2/M arrest due to constitutive accumulation of cyclin B1. These observations identify a synthetic lethal relationship that may serve as a therapeutic approach for patients with SMARCB1 deficient cancers.

cancer biology↗

bioRxiv2018

CCN4 shifts melanoma cells from a fragile proliferative state to a resilient metastatic state

While deregulated intracellular signaling initiates melanoma, intercellular crosstalk within the tumor microenvironment, often coordinated by soluble factors, is essential for melanoma progression and metastasis. One such secreted matricellular protein, cellular communication network factor 4 (CCN4), stimulates metastasis in other malignancies. Here, we report that CCN4 expression is associated progressively with reduced overall survival in patients with primary melanomas. To reveal the roles of CCN4 in melanoma progression, we used mouse melanoma models and knocked out Ccn4 using a homology-directed repair CRISPR/CAS9 system to generate pools of Ccn4-knockout cells. In vitro assays supported previous findings using clones generated using a double nickase-based CRISPR/CAS9 system that CCN4 promoted an epithelial - mesenchymal-like transition in melanoma cells and stimulated invasion and metastasis. We also found that, while Ccn4 knockout enhanced cell growth in optimal 2D culture conditions, the knockout suppressed certain cell survival signaling pathways and rendered cells less resistant to stress conditions. Tumor cell growth assays at sub-optimal conditions in vitro, quantitative analysis of tumor growth assays in vivo, and transcriptomics analysis of human melanoma cell lines suggested that CCN4 repressed cell growth and simultaneously enhanced cell survival. The collective role of CCN4 suggests a potential therapeutic target for limiting metastatic invasion in melanoma and a biomarker for metastatic potential.

cancer biology↗

bioRxiv2018

Podoplanin interaction with caveolin-1 promotes tumour cell migration and invasion

Podoplanin, a highly O-glycosylated type-1 transmembrane glycoprotein, found in lymphatic endothelial cells, podocytes, alveolar epithelial cells and lymph node fibroblasts is also expressed by tumour cells, and is correlated with more aggressive disease. Despite numerous studies documenting podoplanin expression, the mechanisms underlying its tumour-promoting functions remain unclear. Using a murine melanoma cell line that endogenously expresses podoplanin, we demonstrate interactions with proteins necessary for cytoskeleton reorganization, adhesion and matrix degradation, and endocytosis/receptor recycling but also identify a novel interaction with caveolin-1. We generated a panel of podoplanin and caveolin-1 variants to determine the molecular interactions and functional consequences of these interactions. Complementary in vitro and in vivo systems confirmed the existence of a functional cooperation in which surface expression of both full length, signalling competent podoplanin and caveolin-1 are necessary to induce directional migration and invasion, which is executed via PAK1 and ERK1 pathways. Our findings establish that podoplanin signalling mediates the invasive properties of melanoma cells in a caveolin-1 dependent manner.\n\nSummary StatementThis manuscript describes a new interaction and functional cooperation between podoplanin and caveolin1 that drives tumour cell invasion into surrounding tissues.

cancer biology↗

bioRxiv2018

The consensus molecular classification of muscle-invasive bladder cancer

Muscle-Invasive Bladder Cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, yielding diverse sets of subtypes, which hampers the clinical implications of such knowledge. Here, we report the results of a large international effort to reach a consensus on MIBC molecular subtypes. Using 1750 MIBC transcriptomes and a network-based analysis of six independent MIBC classification systems, we identified a consensus set of six molecular classes: Luminal Papillary (24%), Luminal Non-Specified (8%), Luminal Unstable (15%), Stroma-rich (15%), Basal/Squamous (35%), and Neuroendocrine-like (3%). These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics. This consensus system offers a robust framework that will enable testing and validating predictive biomarkers in future clinical trials.

cancer biology↗

bioRxiv2018

Induction of AMPK activation by N,N-Diarylurea FND-4b decreases growth and increases apoptosis in triple negative and estrogen-receptor positive breast cancers

PurposeTriple negative breast cancer (TNBC) is the most lethal and aggressive subtype of breast cancer. AMP-activated protein kinase (AMPK) is a major energy regulator that suppresses tumor growth, and 1-(3-chloro-4-((trifluoromethyl)thio)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea (FND-4b) is a novel AMPK activator that inhibits growth and induces apoptosis in colon cancer. The purpose of this project was to test the effects of FND-4b on AMPK activation, proliferation, and apoptosis in breast cancer with a particular emphasis on TNBC.\n\nMaterials and methods(i) Estrogen-receptor positive breast cancer (ER+BC; MCF-7, and T-47D), TNBC (MDA-MB-231 and HCC-1806), and breast cancer stem cells were treated with FND-4b for 24h. Immunoblot analysis assessed AMPK, acetyl-CoA carboxylase (ACC), ribosomal protein S6, cyclin D1, and cleaved PARP. (ii) Sulforhodamine B growth assays were performed after treating ER+BC and TNBC cells with FND-4b for 72h. Proliferation was also assessed by counting cells after 72h of FND-4b treatment. (iii) Cell death ELISA assays were performed after treating ER+BC and TNBC cells with FND-4b for 72h.\n\nResults(i) FND-4b increased AMPK activation with concomitant decreases in ACC activity, phosphorylated S6, and cyclin D1 in all subtypes. (ii) FND-4b decreased proliferation in all cells, while dose-dependent growth decreases were found in ER+BC and TNBC. (iii) Increases in apoptosis were observed in ER+BC and the MDA-MB-231 cell line with FND-4b treatment.\n\nConclusionsOur findings indicate that FND-4b decreases proliferation for a variety of breast cancers by activating AMPK and has notable effects on TNBC. The growth reductions were mediated through decreases in fatty acid synthesis (ACC), mTOR signaling (S6), and cell cycle flux (cyclin D1). ER+BC cells were more susceptible to FND-4b-induced apoptosis, but MDA-MB-231 cells still underwent apoptosis with higher dose treatment. Further development of FND compounds could result in a novel therapeutic for TNBC.

cancer biology↗