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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.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 883 records · Page 49Linked to original sources

bioRxiv2018

Modelling bistable tumour population dynamics to design effective treatment strategies

Despite recent advances in targeted drugs and immunotherapy, cancer remains \"the emperor of all maladies\" due to inevitable emergence of resistance. Drug resistance is thought to be driven by mutations and/or dynamic plasticity that deregulate pathway activities and regulatory programs of a highly heterogeneous tumour. In this study, we propose a modelling framework to simulate population dynamics of heterogeneous tumour cells with reversible drug resistance. Drug sensitivity of a tumour cell is determined by its internal states, which are demarcated by coordinated activities of multiple interconnected oncogenic pathways. Transitions between cellular states depend on the effects of targeted drugs and regulatory relations between the pathways. Under this framework, we build a simple model to capture drug resistance characteristics of BRAF-mutant melanoma, where two cell states are described by two mutually inhibitory - main and alternative - pathways. We assume that cells with an activated main pathway are proliferative yet sensitive to the BRAF inhibitor, and cells with an activated alternative pathway are quiescent but resistant to the drug. We describe a dynamical process of tumour growth under various drug regimens using the explicit solution of mean-field equations. Based on these solutions, we compare efficacy of three treatment strategies: static treatments with continuous and constant dosages, periodic treatments with regular intermittent phases and drug holidays, and treatments derived from optimal control theory (OCT). Based on these analysis, periodic treatments outperform static treatments with a considerable margin, while treatments based on OCT outperform the best periodic treatment. Our results provide insights regarding optimal cancer treatment modalities for heterogeneous tumours, and may guide the development of optimal therapeutic strategies to circumvent drug resistance and due to tumour plasticity.

cancer biology↗

bioRxiv2018

Genome-wide silencing screen in mesothelioma cells reveals that loss of function of BAP1 induces chemoresistance to ribonucleotide reductase inhibition: implication for therapy

IntroductionLoss of function of BRCA1 associated protein 1 (BAP1) is observed in about 50% of malignant pleural mesothelioma (MPM) cases. The aim of this study was to investigate whether this aspect could be exploited for targeted therapy.\n\nMethodsA genetically engineered model was established expressing either functional or nonfunctional BAP1 and whole-genome siRNA screens were performed assessing impaired survival between the two cell lines. Cytotoxity induced by gemcitabine and hydroxyurea were assessed in a panel of BAP1-WT and BAP1-mut/del cell lines. Functional studies were carried out in BAP1 mut/del cell line reconstituted with BAP1 WT or BAP1 C91A (catalytically dead mutant) and in BAP1 WT cell line upon siRNA-mediated knock-down of BAP1.\n\nResultsThe whole-genome siRNA screen unexpectedly revealed 11 hits (FDR<0.05) more cytotoxic for BAP1-proficient cells. Two actionable targets, RRM1 and RRM2, were validated and their inhibition mediated by gemcitabine or hydroxyurea respectively, was more cytotoxic in BAP1-proficient cell lines. Upregulation of RRM2 upon gemcitabine and hydroxyurea was more profound in BAP1 mut/del cell lines. Increased lethality mediated by gemcitabine and hydroxyurea was observed in NCI-H2452 cells reconstituted with BAP1 WT but not with C91A mutant and upregulation of RRM2 in NCI-H2452-BAP1 WT spheroids was modest compared to control or C91A mutant. Finally, the opposite was observed after BAP1 knockdown in BAP1-proficient SPC111 cell line.\n\nConclusionWe found that BAP1 is involved in the regulation of RRM2 levels during replication stress. These observations reveal a potential therapeutic approach where MPM patients to be stratified depending on BAP status for gemcitabine treatment.

cancer biology↗

bioRxiv2018

High-throughput Automated Single Cell Imaging Analysis Reveals Dynamics Of Glioblastoma Stem Cell Population During State Transition

Cancer stem cells (CSCs) are a heterogeneous and dynamic population that stands at the top of tumor cellular hierarchy and is responsible for maintenance of the tumor microenvironment. As methods of CSC isolation and functional interrogation advance, there is a need for a reliable and accessible quantitative approach to assess heterogeneity and state transition dynamics in CSCs. We developed a High-throughput Automated Single Cell Imaging Analysis (HASCIA) approach for quantitative assessment of protein expression with single cell resolution and applied the method to investigate spatiotemporal factors that influence CSC state transition using glioblastoma (GBM) CSC as a model system. We were able to validate the quantitative nature of this approach through comparison of the protein expression levels determined by HASCIA to those determined by immunoblotting. A virtue of HASCIA was exemplified by detection of a subpopulation of SOX2-low cells, which expanded in fraction size during state transition. HASCIA also revealed that CSCs were committed to loose stem cell state at an earlier time point than the average SOX2 level decreased. Functional assessment of stem cell frequency in combination with quantification of SOX2 expression by HASCIA defined a stable cut-off of SOX2 expression level for stem cell state. We also developed an approach to assess local cell density and found that denser monolayer areas possess higher average levels of SOX2, higher cell diversity and a presence of a sub-population of slowly proliferating SOX2-low CSCs. HASCIA is an open source software that facilitates understanding the dynamics of heterogeneous cell population such as that of CSCs and their progeny. It is a powerful and easy-to-use image analysis and statistical analysis tool available at https://hascia.lerner.ccf.org.

cancer biology↗

bioRxiv2018

Rho-mediated MRTF and YAP1 activation contributes to BRAF inhibitor resistance in Sox9High/Sox10Low melanoma cells.

Over half of cutaneous melanoma tumors have BRAFV600E/K mutations. Acquired resistance to BRAF inhibitors (BRAFi) remains a major hurdle in attaining durable therapeutic responses. In this study we demonstrate that approximately 50-60% of melanoma cell lines with acquired vemurafenib resistance activate the RhoA family signaling pathway. RhoAHigh BRAFi-resistant cells are sensitive to the combination of ROCK inhibitors and vemurafenib. Further, these RhoAHigh cells have >100-fold increase in Sox9 expression and >100-fold decrease in Sox10 expression. Two transcriptional co-activators downstream of RhoA, MRTF and YAP1, are activated in Sox9High/Sox10Low BRAFi-resistant cells. Pharmacological inhibition of these transcriptional mechanisms re-sensitizes the cells to vemurafenib. Analysis of human BRAFi-resistant tumors reveals that many resistant tumors show gene expression signatures consistent with increased RhoA activation or activation of the transcriptional co-activators MRTF and YAP1. A subset of melanoma tumors in the TCGA dataset with low Sox10 expression also have elevated RhoA, MRTF, and YAP1 activation signatures. Taken together, these results support the concept of targeting RhoA-regulated gene transcription pathways as a promising approach for treating or preventing BRAFi-resistance in melanoma.

cancer biology↗

bioRxiv2018

Isoform switching as a mechanism of acquired resistance to isocitrate dehydrogenase inhibition

Somatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase (IDH1 or IDH2, respectively) contribute to oncogenesis via production of the metabolite 2-hydroxyglutarate (2HG). Isoform-selective IDH inhibitors suppress 2HG production and induce clinical responses in patients with IDH1- and IDH2-mutant malignancies. Despite the promising activity of IDH inhibitors, the mechanisms that mediate resistance to IDH inhibition are poorly understood. Here, we describe four clinical cases that identify mutant IDH isoform switching, either from mutant IDH1 to mutant IDH2 or vice versa, as a mechanism of acquired clinical resistance to IDH inhibition in solid and liquid tumors.\n\nSignificanceIDH-mutant cancers can develop resistance to isoform-selective IDH inhibition by \"isoform switching\" from mutant IDH1 to mutant IDH2 or vice versa, thereby restoring 2-hydroxyglutarate (2HG) production by the tumor. These findings underscore a role for continued 2HG production in tumor progression and suggest therapeutic strategies to prevent or overcome resistance.

cancer biology↗

bioRxiv2018

A Novel Scavenging Tool for Cancer Biomarker Discovery based on the Blood-Circulating Nanoparticle Protein Corona

The prominent discrepancy between the significant investment towards plasma biomarker discovery and the very low number of biomarkers currently in clinical use stresses the need for novel discovery technologies. The discovery of protein biomarkers present in human blood by proteomics is tremendously challenging, owing to the large dynamic concentration range of blood proteins. Here, we describe the use of blood-circulating lipid-based nanoparticles (NPs) as a scavenging tool to comprehensively analyse the blood circulation proteome. We aimed to exploit the spontaneous interaction of NPs with plasma proteins once injected in the bloodstream, known as protein corona and to facilitate the discovery of previously unreported biomarker molecules for cancer diagnostics. We employed two different tumor models, a subcutaneous melanoma model (B16-F10) and human lung carcinoma xenograft model (A549) and comprehensively compared by mass spectrometry the in vivo protein coronas formed onto clinically used liposomes, intravenously administered in healthy and tumor-bearing mice. The results obtained demonstrated the ability of blood-circulating liposomes to surface-capture and amplify low molecular weight (MW) and low abundant tumor specific proteins (intracellular products of tissue leakage) that could not be detected by plasma analysis, performed in comparison. Most strikingly, the NP (liposomal) corona formed in the xenograft model was found to consist of murine host response proteins, as well as human proteins released from the inoculated and growing human cancer cells. This study offers direct evidence that the in vivo NP protein corona could be deemed as a valuable tool of the blood proteome in experimental disease models to allow the discovery of potential biomarkers.\n\nToC Graphic\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC=\"FIGDIR/small/382192_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (29K):\norg.highwire.dtl.DTLVardef@130bde1org.highwire.dtl.DTLVardef@102058aorg.highwire.dtl.DTLVardef@1b9e61dorg.highwire.dtl.DTLVardef@1b29ba1_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2018

Universal cancer tasks, evolutionary tradeoffs, and the functions of driver mutations

Recent advances have led to an appreciation of the vast molecular diversity of cancer. Detailed data has enabled powerful methods to sort tumors into groups with benefits for prognosis and treatment. We are still missing, however, a general theoretical framework to understand the diversity of tumor gene-expression and mutations. To address this, we present a framework based on multi-task evolution theory, using the fact that tumors evolve in the body, and that tumors are faced with multiple tasks that contribute to their fitness. In accordance with the theory, we find that tradeoff between tasks constrains tumor gene-expression to a continuum bounded by a polyhedron. The vertices of the polyhedron are gene-expression profiles each specializing in one task, allowing the tasks to be identified. We find five universal cancer tasks across tissue-types: cell-division, biomass & energy, lipogenesis, immune-interaction and invasion & tissue remodeling. Tumors whose gene-expression lies close to a vertex are task specialists. We find evidence that such specialists are more sensitive to drugs that interfere with this task. We find that driver mutations, but not passenger mutations, tune gene-expression towards specialization in specific tasks. This approach can integrate additional types of molecular data into a theoretically-based framework for understanding tumor diversity.

cancer biology↗

bioRxiv2018

A molecular inversion probe and sequencing-based microsatellite instability assay for high throughput cancer diagnostics and Lynch syndrome screening

BackgroundClinical guidelines recommend microsatellite instability (MSI) and BRAF V600E testing of all colorectal cancers (CRCs) to screen for Lynch syndrome (LS), a hereditary predisposition to cancer. MSI is also associated with response to immunotherapy. However, uptake of MSI testing is poor and current assays are not suitable for high throughput diagnostics.\n\nWe aimed to develop a cheap and scalable sequencing assay for MSI classification, which is robust to variables in clinical samples and simultaneously tests for BRAF V600E to streamline the LS screening pipeline.\n\nMethods24 short (7-12bp) microsatellites and the BRAF V600E locus were amplified in multiplex using single molecule molecular inversion probes (smMIPs) and sequenced using the Illumina MiSeq platform. Reads were aligned to reference genome hg19. An MSI classifier was trained from 98 CRCs and validated in 99 independent CRCs collected in pathology laboratories in Edinburgh, Spain and Newcastle.\n\nResultsThe smMIP-based MSI assay has 100% accuracy for MSI status relative to MSI Analysis System (Promega). MSI classification is reproducible (100% concordance) and is robust to sample variables, detecting less than 5% MSI-high content in template DNA and giving reliable classification from sequencing only 75 DNA molecules per marker. BRAF V600E was detected with mutant allele frequencies down to 1.7%.\n\nConclusionsOur short microsatellite, smMIP-based, MSI assay provides a cheap and fully automatable assessment of MSI status and BRAF mutation. It is readily scalable to high throughput cancer diagnostics, and is suitable both as a companion diagnostic for immunotherapy and for streamlined LS screening.

cancer biology↗

bioRxiv2018

Opposing Roles of the Fork-head box genes FoxM1 and FoxA2 in Hepatocellular Carcinoma

The fork-head box transcription factor FoxMl is essential for hepatocellular carcinoma (HCC) development and its overexpression coincides with poor prognosis. Here, we show that the mechanisms by which FoxM1 drives HCC progression involve overcoming the inhibitory effects of the liver differentiation gene FoxA2. First, the expression patterns of FoxM1 and FoxA2 in human HCC are opposite. We show that FoxM1 represses expression of FoxA2 in G1 phase, a phase in the cell cycle in which cells can undergo differentiation. Repression of FoxA2 in G1 phase is important, as it is capable of inhibiting expression of the pluripotency genes that are expressed mainly in S/G2 phases. Using a transgenic mouse model for oncogenic Ras-driven HCC, we provide genetic evidence for a repression of FoxA2 by FoxM1. Conversely, FoxA2 inhibits expression of FoxM1, and inhibits FoxM1-induced tumorigenicity of HCC cells. Moreover, expression of FoxA2 in mouse liver expressing activated Ras inhibits FoxM1 expression and inhibits HCC progression. The observations provide strong genetic evidence for an opposing role of FoxM1 and FoxA2 in HCC progression.\n\nAUTHOR SUMMARYLiver cancer remains untreatable because it is diagnosed at a stage when the cancer is aggressive and resistant to therapeutics. The mechanism that drives aggressive liver cancer is poorly understood. These cancers are made up of poorly differentiated cancer cells. Interestingly, the FoxM1 gene is overexpressed in the aggressive liver cancers. Although FoxM1 is important for expression of the proliferation genes, it does not explain why it is overexpressed mainly in the undifferentiated cancers. The current study addresses this puzzle. Our previous studies demonstrated that FoxM1 increases expression of the pluripotency genes that are expressed mainly in the stem-like cells. In the current manuscript we show that, in addition to activating the pluripotency genes, FoxM1 inhibits expression of the liver differentiation gene FoxA2. Overexpression of FoxM1 is important for this inhibition function, as it involves the retinoblastoma family of proteins, which are often inactivated in cancer cells, and thus, are of low-abundance. Moreover, the inhibition of FoxA2 is significant because FoxA2 could inhibit expression of the pluripotency genes as well as FoxM1. The observations provide new insights into how FoxM1 drives progression of aggressive liver cancer.

cancer biology↗

bioRxiv2018

Novel allosteric mechanism of p53 activation by small molecules for targeted anticancer therapy

Given the immense significance of p53 restoration for anti-cancer therapy, elucidation of the mechanisms of action of p53-activating molecules is of the utmost importance. Here we report a discovery of novel allosteric modulation of p53 by small molecules, which is an unexpected turn in the p53 story. We identified a structural element involved in p53 regulation, whose targeting by RITA, PpIX and licofelone block the binding of p53 inhibitors, MDM2 and MDMX. Deletion and mutation analysis followed by molecular modeling, identified the key p53 residues S33 and S37 targeted by RITA and PpIX. We propose that the binding of small molecules to the identified site induces a conformational trap preventing p53 from the interaction with MDM2 and MDMX. These results point to a high potential of allosteric activators. Our study provides the basis for the development of therapeutics with a novel mechanism of action, thus extending the p53 pharmacological potential.

cancer biology↗

bioRxiv2018

Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine-resistance in breast cancer

Tumor hypoxia is associated with poor patient outcomes in estrogen receptor- (ER) positive breast cancer. Hypoxia is known to affect tumor growth by reprogramming metabolism and regulating amino acid (AA) uptake. Here we show that the glutamine transporter, SNAT2, is the AA transporter most frequently induced by hypoxia in breast cancer and it is regulated by HIF1 both in-vitro and in-vivo in xenografts. SNAT2 induction in MCF7 cells was also regulated by ER but it became predominantly a HIF-1-dependent gene under hypoxia. Relevant to this, binding sites for both HIF-1 and ER overlap in SNAT2s cis-regulatory elements. In addition, the downregulation of SNAT2 by the ER antagonist fulvestrant was reverted in hypoxia.\n\nOverexpression of SNAT2 in-vitro to recapitulate the levels induced by hypoxia caused enhanced growth, particularly after ER inhibition, in hypoxia, or when glutamine levels were low. SNAT2 upregulation in-vivo caused complete resistance to anti-estrogen and, partially, anti-VEGF therapies. Finally, high SNAT2 expression levels correlate with HIF-1 and worse outcome in patients given anti-estrogen therapy. Our findings show a switch in regulation of SNAT2 between ER and HIF-1, leading to endocrine resistance in hypoxia. Development of drugs targeting SNAT2 may be of value for a subset of hormone-resistant breast cancer.

cancer biology↗

bioRxiv2018

Molecular Heterogeneity and Early Metastatic Clone Selection in Testicular Germ Cell Cancer Development

BackgroundTesticular germ cell cancer (TGCC), being the most frequent malignancy in young Caucasian males, is initiated from an embryonic germ cell. This study determines intratumor heterogeneity to unravel tumor progression from initiation till metastasis.\n\nMethodsIn total 42 purified samples of four treatment-resistant nonseminomatous TGCC (NS) were investigated, including the precursor germ cell neoplasia in situ (GCNIS) and metastatic specimens, using whole genome- and targeted sequencing. Their evolution was reconstructed.\n\nResultsIntratumor molecular heterogeneity did not correspond to the supposed primary tumor histological evolution. Metastases after systemic treatment could be derived from cancer stem cells not identified in the primary cancer. GCNIS mostly lacked the molecular marks of the primary NS and comprised dominant clones that failed to progress. A BRCA-like mutational signature was observed without evidence for direct involvement of BRCA1 and BRCA2 genes.\n\nConclusionsOur data strongly support the hypothesis that NS is initiated by whole genome duplication, followed by chromosome copy number alterations in the cancer stem cell population, and accumulation of low numbers of somatic mutations. These observations of heterogeneity at all stages of tumorigenesis should be considered when treating patients with GCNIS-only disease, or with clinically overt NS.

cancer biology↗

bioRxiv2018

Risk factors contributing to Bacteraemia at a Tertiary Cancer Center in South Asia

ContextCancer patients are immunocompromised due to their medical condition resulting in neutropenia, increased exposure to intravascular devices (IVDs) and prolonged hospital stays. These conditions are established risk factors in causing bacteraemia. Bateraemia is a contributing factor towards increased rates of morbidity and mortality in several countries including Sri Lanka.\n\nAimsThe current study evaluates the risk factors such as demographic factors, neutrophil counts, presence of an IVD and length of hospitalization that would contribute to the development of bacteraemia among cancer patients at the Apeksha Hospital - Maharagama, Sri Lanka.\n\nResultsA higher prevalence of bacteraemia compared to other countries (13.7%) was reported with the highest frequency identified from oncology wards. Patients above 60 years with carcinomas were revealed to be more susceptible. A length of hospital stay exceeding three days was a statistically significant factor in causing bacteraemia. Gram-negative organisms accounted for majority of the infections while Acinetobacter species were more frequently isolated from IVDs.\n\nConclusionsIt could be suggested that additional care and sterility measures be taken when carrying out invasive procedures in such patients. Precautions could be taken in managing patients with a hospital stay exceeding 3 days as they have been identified as a risk group in acquiring nosocomial infections

cancer biology↗

bioRxiv2018

Inducible formation of leading cells driven by CD44 switching gives rise to collective invasion

Collective invasion into adjacent tissue is a hallmark of luminal breast cancer, with about 20% of cases that eventually undergo metastasis. It remained unclear how less aggressive luminal-like breast cancer transit to invasive cancer. Our study revealed that CD44hi cancer cells are the leading subpopulation in collective invading cancer cells, which could efficiently lead the collective invasion of CD44lo/follower cells. CD44hi/leading subpopulation showed specific gene signature of a cohort of hybrid epithelial/mesenchymal state genes and key functional co-regulators of collective invasion, which was distinct from CD44lo/follower cells. However, the CD44hi/leading cells, in partial-EMT state, were readily switching to CD44lo phenotype along with collective movements and vice versa, which is spontaneous and sensitive to tumor microenvironment. The CD44lo-to-CD44hi conversion is accompanied with a shift of CD44s-to-CD44v, but not corresponding to the conversion of non-CSC-to-CSC. Therefore, the CD44hi leader cells are not a stable subpopulation in breast tumors. This plasticity and ability to generate CD44hi carcinoma cells with enhanced invasion-initiating powers might be responsible for the transition from in situ to invasive behavior of luminal-type breast cancer.\n\nSignificanceNow, the mechanisms involved in local invasion and distant metastasis are still unclear. We identified a switch of CD44 that drives leader cell formation during collective invasion in luminal breast cancer. We provided evidence that interconversions between low and high CD44 states occur frequently during collective invasion. Furthermore, these findings demonstrated that the CD44hi/leader cells featuring partial EMT are inducible and attainable in response to tumor microenvironment. The CD44lo cancer cells are plastic that readily shift to CD44hi state, accompanied with shifts of CD44s-to-CD44v, thereby increasing tumorigenic and malignant potential. There are many \"non-invasiveness\" epithelial/follower cells with reversible invasive potential within an individual tumor, that casting some challenges on molecular targeting therapy.

cancer biology↗

bioRxiv2018

SP1 and STAT3 functionally synergize to induce the RhoU small GTPase and a subclass of non-canonical WNT responsive genes correlating with poor prognosis in breast cancer.

Breast cancer is a complex disease in which heterogeneity makes clinical management very challenging. Although breast cancer subtypes classified according to specific molecular features are associated to better or worse prognosis, the identification of specific markers predicting disease outcome within the single subtypes still lags behind. Both the non-canonical WNT and the STAT3 pathways are often constitutively activated in breast tumors, and both can induce the small GTPase RhoU gene transcription. Here we show that RhoU transcription can be triggered by both canonical and non-canonical WNT ligands via the activation of JNK and the recruitment of the SP1 transcription factor to the RhoU promoter, identifying for the first time SP1 as a JNK-dependent mediator of WNT signaling. RhoU down-regulation by silencing or treatment with JNK, SP1 or STAT3 inhibitors lead to impaired cell migration in basal-like MDA-MB-231 cells, which display constitutive activation of both the non-canonical WNT and STAT3 pathways. These data suggest that STAT3 and SP1 can cooperate to induce high RhoU expression and enhance migration of breast cancer cells. In vivo binding of both factors characterizes a group of SP1/STAT3 responsive genes belonging to the non-canonical WNT and the IL-6/STAT3 pathways. High expression of this signature is significantly correlated with poor prognosis across all profiled patients. Thus, concomitant binding of both STAT3 and SP1 defines a subclass of genes contributing to breast cancer aggressiveness, suggesting the relevance of developing novel targeted therapies combining inhibitors of the STAT3 and WNT pathways or of their downstream mediators.\n\nNovelty and ImpactThe WNT and STAT3 pathways are often activated in breast tumors, but whether they can cooperate towards aggressiveness is not presently known. Here the authors show that WNT ligands can elicit the activation of the transcription factor SP1, which cooperates with STAT3 to induce a subset of non-canonical WNT and IL-6/STAT3 genes. Expression of this gene signature correlates with bad prognosis in breast cancer, suggesting coordinated interference with both TFs as a novel therapeutic option.

cancer biology↗

bioRxiv2018

HIF-2α drives an intrinsic vulnerability to ferroptosis in clear cell renal cell carcinoma

Kidney cancers are characterized by extensive metabolic reprogramming and resistance to a broad range of anti-cancer therapies. By interrogating the Cancer Therapeutics Response Portal compound sensitivity dataset, we show that cells of clear-cell renal cell carcinoma (ccRCC) possess a lineage-specific vulnerability to ferroptosis that can be exploited by inhibiting glutathione peroxidase 4 (GPX4). Using genome-wide CRISPR screening and lipidomic profiling, we reveal that this vulnerability is driven by the HIF-2-HILPDA pathway by inducing a polyunsaturated fatty acyl (PUFA)-lipid-enriched cell state that is dependent on GPX4 for survival and susceptible to ferroptosis. This cell state is developmentally primed by the HNF-1{beta}-1-Acylglycerol-3-Phosphate O-Acyltransferase 3 (AGPAT3) axis in the renal lineage. In addition to PUFA metabolism, ferroptosis is facilitated by a phospholipid flippase TMEM30A involved in membrane topology. Our study uncovers an oncogenesis-associated vulnerability, delineates the underlying mechanisms and suggests targeting GPX4 to induce ferroptosis as a therapeutic opportunity in ccRCC.\n\nHIGHLIGHTSO_LIccRCC cells exhibit strong susceptibility to GPX4 inhibition-induced ferroptosis\nC_LIO_LIThe GPX4-dependent and ferroptosis-susceptible state in ccRCC is associated with PUFA-lipid abundance\nC_LIO_LIThe HIF-2-HILPDA axis promotes the selective deposition of PUFA-lipids and ferroptosis susceptibility\nC_LIO_LIAGPAT3 selectively synthesizes PUFA-phospholipids and primes renal cells for ferroptosis\nC_LI

cancer biology↗

bioRxiv2018

Transposable Element Expression In Tumors Is Associated With Immune Infiltration And Increased Antigenicity

Profound loss of DNA methylation is a well-recognized hallmark of cancer. Given its role in silencing transposable elements (TEs), we hypothesized that extensive TE expression occurs in tumors with highly demethylated DNA. We developed REdiscoverTE, a computational method for quantifying genome-wide TE expression in RNA sequencing data. Using The Cancer Genome Atlas database, we observed increased expression of over 400 TE subfamilies, of which 262 appeared to result from a proximal loss of DNA methylation. The most recurrent TEs were among the evolutionarily youngest in the genome, predominantly expressed from intergenic loci, and associated with antiviral or DNA damage responses. Treatment of glioblastoma cells with a demethylation agent resulted in both increased TE expression and de novo presentation of TE-derived peptides on MHC class I molecules. Therapeutic reactivation of tumor-specific TEs may synergize with immunotherapy by inducing both inflammation and the display of potentially immunogenic neoantigens.\n\nOne Sentence SummaryTransposable element expression in tumors is associated with increased immune response and provides tumor-associated antigens

cancer biology↗

bioRxiv2018

Unjamming overcomes kinetic and proliferation arrest in terminally differentiated cells and promotes collective motility of carcinoma.

During wound repair, branching morphogenesis and carcinoma dissemination, cellular rearrangements are fostered by a solid-to-liquid transition known as unjamming. The biomolecular machinery behind unjamming, its physiological and clinical relevance remain, however, a mystery. Here, we combine biophysical and biochemical analysis to study unjamming in a variety of epithelial 2D and 3D collectives: monolayers, differentiated normal mammary cysts, spheroid models of breast ductal carcinoma in situ (DCIS), and ex vivo slices of orthotopically-implanted DCIS. In all cases, elevation of the small GTPase RAB5A sparks unjamming by promoting non-clathrin-dependent internalization of epidermal growth factor receptor that leads to hyper-activation of endosomally-confined ERK1/2 and phosphorylation of the actin nucleator WAVE2. Physically, activation of this pathway causes highly coordinated flocking of the cells, with striking rotational motion in 3D that eventually leads to matrix remodelling and collective invasiveness of otherwise jammed carcinoma. The identified endo-ERK1/2 pathway provides an effective switch for unjamming through flocking to promote epithelial tissues morphogenesis and carcinoma invasion and dissemination.

cancer biology↗