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bioRxiv2018

Significant antitumour effect of an antibody against TMEM180, a new cancer-specific molecule

The present state of therapy for colorectal cancer (CRC) is far from satisfactory, highlighting the need for new targets for this disease. We identified a new colorectal cancer (CRC)-specific molecule, TMEM180, a predicted eleven-pass transmembrane protein that apparently functions as a cation symporter. Our anti-TMEM180 monoclonal antibody (mAb) eradicated SW480 CRC xenografts in mice. The TMEM180 promoter region contains ten hypoxia-responsive element consensus sequences; accordingly SW480 cells upregulated TMEM180 under low-oxygen conditions. TMEM180 expression in SW480 cells was positively correlated with anchorage-independent colony formation and tumourigenesis. TMEM180-positive SW480 cells resided at the tumour-stroma interface manifested by SMA-positive fibroblasts, also known as the tumour niche. Some clusters of TMEM180-positive cells adjacent to the niche were integrin 6-positive. These data indicate that TMEM180 represents a possible cancer stem cell marker and that a mAb against this protein could be used as antibody-based therapeutic against CRC.

cancer biology↗

bioRxiv2018

Quantitative mass spectrometry to interrogate proteomic heterogeneity in metastatic lung adenocarcinoma and validate a novel somatic mutation CDK12-G879V

Lung cancer is the leading cause of cancer death both in men and women. Tumor heterogeneity is an impediment to targeted treatment of all cancers, including lung cancer. Here, we sought to characterize changes in tumor proteome and phosphoproteome by longitudinal, prospective collection of tumor tissue of an exceptional responder lung adenocarcinoma patient who survived with metastatic lung adenocarcinoma for more than seven years with HER2-directed therapy in combination with chemotherapy. We employed \"Super-SILAC\" and TMT labeling strategies to quantify the proteome and phosphoproteome of a lung metastatic site and ten different metastatic progressive lymph nodes collected across a span of seven years, including five lymph nodes procured at autopsy. We identified specific signaling networks enriched in lung compared to the lymph node metastatic sites. We correlated the changes in protein abundance with changes in copy number alteration (CNA) and transcript expression. To further interrogate the mass spectrometry data, patient-specific database was built incorporating all the somatic variants identified by whole genome sequencing (WGS) of genomic DNA from the lung, one lymph node metastatic site and blood. An extensive validation pipeline was built for confirmation of variant peptides. We validated 360 spectra corresponding to 55 germline and 6 somatic variant peptides. Targeted MRM assays demonstrated expression of two novel variant somatic peptides, CDK12-G879V and FASN-R1439Q, with expression in lung and lymph node metastatic sites, respectively. CDK12 G879V mutation likely results in a nonfunctional CDK12 kinase and chemotherapy susceptibility in lung metastatic sites. Knockdown of CDK12 in lung adenocarcinoma cells results in increased chemotherapy sensitivity, explaining the complete resolution of the lung metastatic sites in this patient.

cancer biology↗

bioRxiv2018

A pipeline for rapidly generating genetically engineered mouse models of pancreatic cancer using in vivo CRISPR-Cas9 mediated somatic recombination

Genetically engineered mouse models (GEMMs) that recapitulate the major genetic drivers in pancreatic ductal adenocarcinoma (PDAC) have provided unprecedented insights into the pathogenesis of this lethal neoplasm. Nonetheless, generating an autochthonous model is an expensive, time consuming and labor intensive process, particularly when tissue specific expression or deletion of compound alleles are involved. In addition, many of the current PDAC GEMMs cause embryonic, pancreas-wide activation or loss of driver alleles, neither of which reflects the cognate human disease scenario. The advent of CRISPR/Cas9 based gene editing can potentially circumvent many of the aforementioned shortcomings of conventional breeding schema, but ensuring the efficiency of gene editing in vivo remains a challenge. Here we have developed a pipeline for generating PDAC GEMMs of complex genotypes with high efficiency using a single \"workhorse\" mouse strain expressing Cas9 in the adult pancreas under a p48 promoter. Using adeno-associated virus (AAV) mediated delivery of multiplexed guide RNAs (sgRNAs) to the adult murine pancreas of p48-Cre; LSL-Cas9 mice, we confirm our ability to express an oncogenic Kras G12D allele through homology-directed repair (HDR), in conjunction with CRISPR-induced disruption of cooperating alleles (Trp53, Lkb1 and Arid1A). The resulting GEMMs demonstrate a spectrum of precursor lesions (pancreatic intraepithelial neoplasia [PanIN] or Intraductal papillary mucinous neoplasm [IPMN] with eventual progression to PDAC. Next generation sequencing of the resulting murine PDAC confirms HDR of oncogenic KrasG12D allele at the endogenous locus, and insertion deletion (\"indel\") and frameshift mutations of targeted tumor suppressor alleles. By using a single \"workhorse\" mouse strain and optimal AAV serotype for in vivo gene editing with combination of driver alleles, we have created a facile autochthonous platform for interrogation of the PDAC genome.

cancer biology↗

bioRxiv2018

Quantitative Assessment of Colorectal Cancer Progression: a Comparative Study of Linear and Nonlinear Microscopy Techniques

BACKGROUND AND AIMSColorectal cancer (CRC) is a disease that can be prevented if is diagnosed and treated at pre-invasive stages. Thus, the monitoring of colonic cancer progression can improve the early diagnosis and detection of malignant lesions in the colon. This monitoring should be performed with appropriate image techniques and be accompanied by proper quantification to minimize subjectivity. We have monitored the mice CRC progression by image deconvolution, two-photon emission fluorescence (TPEF) and second harmonic generation (SHG) microscopies and present different quantization indices for diagnosis.\n\nMETHODSThe Azoxymethane (AOM) / dextran sodium sulfate (DSS) protocol was used. 35 eight-week old male BALB/cCmedc mice were used and distal colon segments were dissected at day zero and fourth, eighth, sixteen, and twenty weeks after injection. These segments were observed with linear and nonlinear optical microscopies and several parameters were used for quantification.\n\nRESULTSCrypt diameter higher than 0.08 mm and increased fluorescence signal intensity in linear images; as well as aspect relation above 0.7 and altered organization reflexed by high-energy values obtained from SHG images, away from those obtained in normal tissues.\n\nCONCLUSIONThe combination of linear and nonlinear signals improve the detection and classification of pathological changes in crypt morphology/distribution and collagen fiber structure/arrangement. In combination with standard screening approaches for CRC, the proposed methods improve the detection of the disease in its early stages, thereby increasing the chances of successful treatment.

cancer biology↗

bioRxiv2018

Activation of TAp73 and inhibition of thioredoxin reductase for improved cancer therapy in TP53 mutant pancreatic tumors

The p73 is a tumor suppressor that compensates for p53 loss and induces apoptosis in tumors in response to genotoxic stress or small-molecule treatments.\n\nPancreatic ductal adenocarcinoma (PDAC) has a late onset of the disease, responds poorly to the existing therapies and has very low overall survival rates.\n\nHere, using drug-repurposing approach, we found that protoporphyrin IX (PpIX) and benzoporphyrin derivative monoacid ring A (BPD) activate p73 and induce apoptosis in pancreatic cancer cells. PpIX and BPD induce reactive oxygen species and inhibit thioredoxin reductase 1 (TrxR1). Thus, PpIX and BPD target cancer cells vulnerabilities namely activate TAp73 tumor suppressor and inhibit oncogenic TrxR1. Our findings, may contribute to faster repurposing of PpIX and BPD to treat pancreatic tumors.\n\nLay AbstractDespite the efforts, pancreatic cancer remains among the most aggressive tumors. Late diagnoses often linked with the asymptomatic disease progression make it extremely difficult to cure. We have used drugs that are already in clinics and applied in photodynamic therapy of cancer and showed that the compounds induce death of cancer cells. The mechanism is via activation of p73 tumor suppressor and inhibition oncogenic thioredoxin reductase. Molecules that in parallel induce two pathways leading to cell death might be very promising candidates for improved cancer therapy in pancreatic cancer patients.

cancer biology↗

bioRxiv2018

Genome-wide Estrogen Receptor-alpha activation is sustained, not cyclical

Estrogen Receptor- (ER) is the key driver of 75% of all breast cancers. Upon stimulation by its ligand estra-2-diol, ER forms a transcriptionally active complex binding chromatin. Previous studies have reported that ER binding follows a cyclical binding pattern with a periodicity of 90 minutes. However, these studies have been limited to individual ER target genes and most were done without replicates. Thus, the robustness and generality of ER cycling are not well understood.\n\nHere we present a comprehensive genome-wide analysis of the time dependence of ER binding affinity up to 90 minutes after activation, based on 6 replicates at 10 time points using our previously reported method for precise quantification of binding, Parallel-Factor ChIP-seq (pfChIP-seq). In contrast to previously described cyclical binding, our approach identifies a unidirectional sustained increase in ER binding affinity, as well as a class of estra-2-diol independent binding sites. Our results are corrob-orated by a quantitative re-analysis of data from multiple independent studies.\n\nOur new model reconciles the results of multiple conflicting studies into the activation of ER at the TFF1 promoter. We provide a detailed understanding of ERs response to estra-2-diol in the context of the receptors fundamental role as both the main driver and therapeutic target of breast cancer.

cancer biology↗

bioRxiv2018

Investigation of the Relationship between Markers of Systemic Inflammatory Response and Head and Neck Tumor Characteristics

BackgroundMarkers of systemic inflammation have been hypothesized to reflect the underlying tumor microenvironment, and have recently been shown to be associated with advanced tumor grade, T and N stages.\n\nAims/ObjectiveThe objective of this study was to evaluate the relationship between head and neck cancer (HNC) tumor characteristics and routine pretreatment inflammatory markers: the platelet lymphocyte ratio (PLR), the neutrophil to lymphocyte ratio (NLR), and the lymphocyte to monocyte ratio (LMR).\n\nMaterials and MethodsThis is a retrospective cohort study. The tumor characteristics collected were tumor differentiation, T stage, N stage. The relationship between the inflammatory markers and tumor characteristics was analyzed.\n\nResultsA total of 122 patients were enrolled from 2010-2016. An elevated PLR was found to be significantly associated with advanced T stage (rho=0.191, p=0.00347), and N stage (ANOVA, p=0.005). None of the other inflammatory markers (NLR, LMR) were associated with T stage or N stage. No markers were associated with tumor differentiation.\n\nConclusion and significanceWe found that an PLR is significantly associated with advanced tumor and nodal stage. We were unable to find any tumor associations with the other inflammatory markers (NLR, LMR).

cancer biology↗

bioRxiv2018

Context dependent roles for RB-E2F transcriptional regulation in tumor suppression

RB-E2F transcriptional control plays a key role in regulating the timing of cell cycle progression from G1 to S-phase in response to growth factor stimulation. Despite this role, it is genetically dispensable for cell cycle exit in primary fibroblasts in response to growth arrest signals. Mice engineered to be defective for RB-E2F transcriptional control at cell cycle genes were also found to live a full lifespan with no susceptibility to cancer. Based on this background we sought to probe the vulnerabilities of RB-E2F transcriptional control defects found in Rb1R461E,K542E mutant mice (Rb1G) through genetic crosses with other mouse strains. We generated Rb1G/G mice in combination with Trp53 and Cdkn1a deficiencies, as well as in combination with KrasG12D. The Rb1G mutation enhanced Trp53 cancer susceptibility, but had no effect in combination with Cdkn1a deficiency or KrasG12D. Collectively, this study indicates that compromised RB-E2F transcriptional control is not uniformly cancer enabling, but rather has potent oncogenic effects when combined with specific vulnerabilities.

cancer biology↗

bioRxiv2018

Toll-Like Receptor-4 Disruption Suppresses Adipose Tissue Remodeling and Increases Survival During Cancer Cachexia Syndrome

Cancer-induced cachexia, characterized by systemic inflammation, body weight loss, adipose tissue (AT) remodeling and muscle wasting, is a malignant metabolic syndrome with undefined etiology. Here, we show that Toll-like receptor 4 (TLR4) mediates AT remodeling, in particular, AT browning and inflammatory response in mice bearing Lewis lung carcinoma (LLC). LLC tumor-bearing (TB) TLR4-/- mice were spared from AT remodeling due to a reduced macrophage infiltration and adipocyte atrophy. TLR4-/- mice were also resistant to cold-induced browning of subcutaneous AT (scAT). Importantly, pharmacological inhibition of TLR4 reproduced the main protective effect against AT remodeling found in TLR4-/- TB mice. Moreover, the treatment was effective in prolonging the survival and attenuating tumor mass growth when compared to non-treated-TB animals. Further, tumor-induced elevation of circulating pro-inflammatory cytokines was similarly abolished in both genetic ablation and pharmacological inhibition of TLR4. These data suggest that TLR4 is a critical mediator and a promising therapeutic target for cancer-induced AT remodeling.\n\nHIGHLIGHTSO_LIGenetic ablation and pharmacological inhibition of TLR4 attenuate adipose tissue remodeling during cancer-associated cachexia;\nC_LIO_LITLR4 suppression play an essential role in the browning phenotype induced by cachexia;\nC_LIO_LIAdministration of TLR4 drug inhibitor increase survival and reduces tumor mass growth in tumor bearing mice;\nC_LIO_LITLR4 pathway is a promising target for cancer-cachexia therapeutic intervention.\nC_LI

cancer biology↗

bioRxiv2018

Bcl-xL inhibition enhances Dinaciclib-induced cell death in soft-tissue sarcomas.

Soft-tissue sarcomas (STS) are an uncommon and heterogeneous group of malignancies that result in high mortality. Metastatic STS have very bad prognosis due to the lack of effective treatments. Dinaciclib is a model drug for the family of CDK inhibitors. Its main targets are cell cycle regulator CDK1 and protein synthesis controller CDK9. We present data supporting Dinaciclib ability to inactivate in vitro different STS models at nanomolar concentrations. Moreover, the different rhythms of cell death induction allow us to further study into the mechanism of action of the drug. Cell death was found to respond to the mitochondrial pathway of apoptosis. Anti-apoptotic Bcl-xL was identified as the key regulator of this process. Bcl-xL showed a slower decay curve after protein synthesis disruption that in tolerant cell lines was enough to delay apoptosis, as its action cannot be countered by the relative low levels of pro-apoptotic BH3 proteins BIM and PUMA. Combination of Dinaciclib with BH3-mimetics led to quick and massive apoptosis induction in vitro, but in vivo assessment was prevented due to liver toxicity. Additionally, Bcl-xL inhibitor A-1331852 also synergized with conventional chemotherapy drugs as Gemcitabine. Thus, Bcl-xL targeted therapy arises as a major opportunity to the treatment of STS.

cancer biology↗

bioRxiv2018

Quantifying the fitness of tissue-specific evolutionary trajectories by harnessing cancer’s repeatability at the genetic level

Cancer is a potentially lethal disease, in which patients with nearly identical genetic backgrounds can develop a similar pathology through distinct combinations of genetic alterations. We aimed to reconstruct the evolutionary process underlying tumour initiation, using the combination of convergence and discrepancies observed across 2,742 cancer genomes from 9 tumour types. We developed a framework using the repeatability of cancer development to score the local malignant adaptation (LMA) of genetic clones, as their potential to malignantly progress and invade their environment of origin. Using this framework, we found that pre-malignant skin and colorectal lesions appeared specifically adapted to their local environment, yet insufficiently for full cancerous transformation. We found that metastatic clones were more adapted to the site of origin than to the invaded tissue, suggesting that genetics may be more important for local progression than for the invasion of distant organs. In addition, we used network analyses to investigate evolutionary properties at the system-level, highlighting that different dynamics of malignant progression can be modelled by such a framework in tumour-type-specific fashion. We find that occurrence-based methods can be used to specifically recapitulate the process of cancer initiation and progression, as well as to evaluate the adaptation of genetic clones to given environments. The repeatability observed in the evolution of most tumour types could therefore be harnessed to better predict the trajectories likely to be taken by tumours and pre-neoplastic lesions in the future.

cancer biology↗

bioRxiv2018

Repression of Transcription Factor AP-2 Alpha by Peroxisome Proliferator Activated Receptor Gamma Reveals a Novel Transcriptional Circuit in basal-squamous Bladder Cancer

The discovery of bladder cancer transcriptional subtypes provides an opportunity to identify high risk patients, and tailor disease management. Recent studies suggest tumor heterogeneity contributes to \"plasticity\" of molecular subtype during progression and following treatment. Nonetheless, the transcriptional drivers of the aggressive basal-squamous subtype remain unidentified. As PPAR{gamma} has been repeatedly implicated in the luminal subtype of bladder cancer, we hypothesized inactivation of this transcriptional master regulator during progression results in increased expression of basal-squamous specific transcription factors (TFs) which act to drive aggressive behavior. We initiated a pharmacologic and RNA-seq-based screen to identify PPAR{gamma}-repressed, basal-squamous specific TFs. Hierarchical clustering of RNA-seq data following treatment of a panel of human bladder cancer cell lines with a PPAR{gamma} agonist identified a number of TFs regulated by PPAR{gamma} activation, several of which are implicated in urothelial and squamous differentiation. One PPAR{gamma}-repressed TF implicated in squamous differentiation identified is Transcription Factor Activating Protein 2 alpha (TFAP2A). We show TFAP2A and its paralog TFAP2C are overexpressed in basal-squamous bladder cancer and in squamous areas of cystectomy samples, and that overexpression is associated with increased lymph node metastasis and distant recurrence, respectively. Biochemical analysis confirmed the ability of PPAR{gamma} activation to repress TFAP2A, while PPAR{gamma} antagonist studies indicate the requirement of a functional receptor. In vivo tissue recombination studies show TFAP2A and TFAP2C promote tumor growth in line with the aggressive nature of basal-squamous bladder cancer. Our findings suggest PPAR{gamma} inactivation, as well as TFAP2A and TFAP2C overexpression cooperate with other TFs to promote the basal-squamous transition.

cancer biology↗

bioRxiv2018

Detection of HPV16, HPV18, p16, and E6/E7 MRNA in Nasopharyngeal Cancer: A Systematic Review and Meta-Analysis

IntroductionHuman Papilloma Virus (HPV) associated head and neck cancers, particularly oropharyngeal cancers (OPC), have a superior prognosis to HPV negative cancers. A literature review did not find any studies that analyzed HPV 16, HPV 18 DNA and p16 in the nasopharynx subsite, although it has been reported in the oropharynx. The detection of HPV DNA and p16 in the nasopharynx could have implications for the treatment of NPC. To date no one has reported the detection or concordance rates of HPV associated markers in nasopharyngeal carcinoma (NPC).\n\nMethodsA literature search was undertaken on Medline, EMBASE, Scopus, and the Cochrane Library to identify studies that used PCR and ISH for detection of HPV DNA and p16 in the nasopharynx. We included studies published between 1992 and 2017 that reported the prognostic impact of HPV DNA and/or p16, treated HPV and p16 as categorical variables with at least 10 patients who tested for p16 and/or HPV16/HPV18 DNA in NPC, irrespective of HPV status. We then collected information from many parameters, and performed a meta-analysis to produce pooled prevalence estimates and explored sources of heterogeneity\n\nResults21 studies published between 1992 and 2017 were selected for meta-analysis, with sample sizes ranging from 10 to 1328. The total (random effects) pooled detection of any HPV marker in NPC patients was 19.7% (95% CI: 12.56 to 28.00). The total (random effects) pooled detection of p16 positivity in NPC patients was 23.98% (95% CI: 14.82 to 34.54). The total (random effects) pooled detection of HPV DNA in NPC patients, detected by ISH, was 14.43% (95% CI: 10.13 to 19.33) and for HPV DNA in NPC patients including E6/E7 was 18.13% (95% CI: 11.45 to 25.94). The total (random effects) pooled detection of HPV DNA in NPC patients was 18.13% (95% CI: 11.45 to 25.94). The total (random effects) pooled detection of EBV positivity in NPC patients was 76.21% (95% CI: 66.40 to 84.80). Heterogeneity was high for all of the results. The attributable fraction of p16+ and HPV DNA+ in NPC is 0.029. The attributable fraction of EBV positive and HPV - in NPC is 0.827. The attributable fraction of EBV negative and HPV - in NPC is 0.0639. The attributable fraction of EBV negative and HPV + in NPC is 0.085. The attributable fraction of EBV positive and HPV + in NPC is 0.023. The attributable fraction of HPV positive and mRNA+ in NPC was 0.115. The attributable fraction of p16 in NPC was 0.123.\n\nDiscussionThis is the first study that contributes to the concordance and detection rates of HPV related markers in NPC.\n\nLimitationsMost of the studies included were of Asian extraction. Most of the papers also did not test for E6/E7 RNA and therefore we are unsure of the amount of active E6/E7 RNA in NPC.

cancer biology↗

bioRxiv2018

Comparing the efficacy of cancer therapies between subgroups in basket trials

An increase in the number of targeted anti-cancer drugs and growing genomic stratification of patients has led to the development of basket clinical trials in which a single drug is tested simultaneously in multiple tumor subtypes under a master protocol. Basket trials typically involve few patients per type, making it difficult to rigorously compare responses across types. We describe the use of permutation testing to analyze tumor volume changes and Progression Free Survival across subtypes in basket trials for neratinib, larotrectinib, pembrolizumab, and imatinib. Permutation testing is a complement to the standard Simons two-stage binomial approach and can test for differences among subgroups using empirical null distributions while controlling for multiple hypothesis testing. This approach uncovers examples of therapeutic benefit missed by a binomial test; in the case of the SUMMIT trial, our analysis identifies an overlooked opportunity for use of neratinib in lung cancers carrying ERBB2 Exon 20 mutations.

cancer biology↗

bioRxiv2018

Aurora A inhibition limits centrosome clustering and promotes mitotic catastrophe in cells with supernumerary centrosomes

The presence of supernumerary centrosomes is prevalent in cancer, where they promote the formation of transient multipolar mitotic spindles. Active clustering of supernumerary centrosomes enables the formation of a functional bipolar spindle that is competent to complete a bipolar division. Disruption of spindle pole clustering in cancer cells promotes multipolar division and generation of non-proliferative daughter cells with compromised viability. Hence molecular pathways required for spindle pole clustering in cells with supernumerary centrosomes, but dispensable in normal cells, are promising therapeutic targets. Here we demonstrate that Aurora A kinase activity is required for spindle pole clustering in cells with extra centrosomes. While cells with two centrosomes are ultimately able to build a bipolar spindle and proceed through a normal cell division in the presence of Aurora A inhibition, cells with supernumerary centrosomes form multipolar and disorganized spindles that are not competent for chromosome segregation. Instead, following a prolonged mitosis, these cells experience catastrophic divisions that result in grossly aneuploid, and non-proliferative daughter cells. Aurora A inhibition in a panel of Acute Myeloid Leukemia cancer cells has a similarly disparate impact on cells with supernumerary centrosomes, suggesting that centrosome number and spindle polarity may serve as predictive biomarkers for response to therapeutic approaches that target Aurora A kinase function.

cancer biology↗

bioRxiv2018

Elevated pyrimidine dimer formation at distinct genomic bases underlie promoter mutation hotspots in UV-exposed cancers

Sequencing of whole cancer genomes has revealed an abundance of recurrent mutations in gene-regulatory promoter regions, in particular in melanoma where strong mutation hotspots are observed adjacent to ETS-family transcription factor (TF) binding sites. While sometimes interpreted as functional driver events, these mutations have also been suggested to be due to locally inhibited DNA repair or, alternatively, locally increased propensity for UV damage. Here, we provide evidence that base-specific elevations in the efficacy of UV lesion formation underlie these mutations. First, we find that low-dose UV light induces mutations preferably at a known ETS promoter hotspot in cultured cells even in the absence of global or transcription-coupled nucleotide excision repair (NER), ruling out inhibited repair. Further, by genome-wide mapping of cyclobutane pyrimidine dimers (CPDs) shortly after UV exposure and thus before DNA repair, we find that ETS-related mutation hotspots exhibit a strong base-specific increase in CPD formation frequency. Analysis of a large whole genome cohort illustrates the widespread contribution of this effect to recurrent mutations in melanoma. While inhibited NER underlies a general increase in somatic mutation burden in regulatory regions, we conclude that the most recurrently mutated individual DNA bases arise instead due to locally favorable conditions for UV damage formation, thus explaining a key phenomenon in whole-genome cancer analyses.

cancer biology↗

bioRxiv2018

Naked Mole-Rat Cells are Susceptible to Malignant Transformation by SV40LT and Oncogenic Ras

The Naked Mole-Rat, Hetercephalus glaber, is a mouse-sized subterranean rodent native to East Africa. Research on NMRs is intensifying in an effort to gain leverage from their unusual physiology, long-life span and cancer resistance. Few studies have attempted to explain the reasons behind NMRs cancer resistance, but most prominently Tian et al. reported that NMR cells produce high-molecular weight hyaluronan as a potential cause for the NMRs cancer resistance. Tian et al. have shown that NMR cells are resistant to transformation by SV40 Large T Antigen (SV40LT) and oncogenic HRAS (HRASG12V), a combination of oncogenes sufficient to transform mouse and rat fibroblasts. We have developed a single lentiviral vector to deliver both these oncogenes and generated multiple cell lines from five different tissues and nine different NMRs, and report here that contrary to Tian et al.s observation, NMR cells are susceptible to oncogenic transformation by SV40LT and HRAS. Our data thus point to a non-cell autonomous mechanism underlying the remarkable cancer resistance of NMRs. Identifying these non-cell autonomous mechanisms could have implications on our understanding of human cancer development.

cancer biology↗

bioRxiv2018

Clonotypic Heterogeneity In Cutaneous T-Cell Lymphoma Revealed By Comprehensive Whole Exome/Transcriptome Sequencing

Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, is believed to represent a clonal expansion of a transformed skin resident memory T-cell. T-cell receptor (TCR) clonality (i.e. identical sequences of rearranged TCR, {beta} and {gamma}), the key premise of this hypothesis, has been difficult to document conclusively because malignant cells are not readily distinguishable from the tumor infiltrating, reactive lymphocytes, which contribute to the TCR clonotypic repertoire of MF. Here we have successfully adopted the technique of targeted whole exome and whole transcriptome sequencing (WES/WTS) to identify the repertoire of rearranged TCR genes in tumor enriched samples from patients with MF. Although most of the investigated biopsies of MF had the expected monoclonal rearrangements of TCR{gamma} of the frequency corresponding to the frequency of tumor cells, in half of the samples we detected multiple (up to seven) TCR and -{beta} clonotypes by WES and WTS. Our findings are compatible with the model in which the initial malignant transformation in MF does not occur in mature, memory T-cells but rather at the level of T-lymphocyte progenitor after TCR{gamma} rearrangement but before TCR{beta} or TCR rearrangements. The WES/WTS method is potentially applicable to other types of T-cell lymphomas and enables comprehensive characterization of the TCR repertoire and mutational landscape in these malignancies.

cancer biology↗