L1CAM

Gene Summary

Gene:L1CAM; L1 cell adhesion molecule
Aliases: S10, HSAS, MASA, MIC5, SPG1, CAML1, CD171, HSAS1, N-CAML1, NCAM-L1, N-CAM-L1
Location:Xq28
Summary:The protein encoded by this gene is an axonal glycoprotein belonging to the immunoglobulin supergene family. The ectodomain, consisting of several immunoglobulin-like domains and fibronectin-like repeats (type III), is linked via a single transmembrane sequence to a conserved cytoplasmic domain. This cell adhesion molecule plays an important role in nervous system development, including neuronal migration and differentiation. Mutations in the gene cause X-linked neurological syndromes known as CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia and hydrocephalus). Alternative splicing of this gene results in multiple transcript variants, some of which include an alternate exon that is considered to be specific to neurons. [provided by RefSeq, May 2013]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:neural cell adhesion molecule L1
Source:NCBIAccessed: 29 August, 2019

Ontology:

What does this gene/protein do?
Show (25)
Pathways:What pathways are this gene/protein implicaed in?
Show (2)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: L1CAM (cancer-related)

Hu Q, Ye Y, Chan LC, et al.
Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression.
Nat Immunol. 2019; 20(7):835-851 [PubMed] Article available free on PMC after 03/12/2019 Related Publications
How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissue-specific expression of the human long noncoding RNA LINK-A in mouse mammary glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein-1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention.

Iwanishi M, Kusakabe T, Azuma C, et al.
Clinical characteristics in two patients with partial lipodystrophy and Type A insulin resistance syndrome due to a novel heterozygous missense mutation in the insulin receptor gene.
Diabetes Res Clin Pract. 2019; 152:79-87 [PubMed] Related Publications
AIMS: The present report aimed to clarify the clinical characteristics in a girl at the age of 12 and her mother with partial lipodystrophy and Type A insulin resistance syndrome.
METHODS: We examined fat distribution in the patients using dual-energy X-ray absorptiometry, magnetic resonance imaging, and computed tomography. We performed genetic analysis to examine the causal gene for lipodystrophy and insulin resistance.
RESULTS: Both patients had partial lipodystrophy and a novel heterozygous missense mutation (Asn
CONCLUSIONS: This case might help to understand the mechanisms insulin receptor dysfunction that cause lipodystrophy.

Ferreira MA, Gamazon ER, Al-Ejeh F, et al.
Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer.
Nat Commun. 2019; 10(1):1741 [PubMed] Article available free on PMC after 03/12/2019 Related Publications
Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

Tejero R, Huang Y, Katsyv I, et al.
Gene signatures of quiescent glioblastoma cells reveal mesenchymal shift and interactions with niche microenvironment.
EBioMedicine. 2019; 42:252-269 [PubMed] Article available free on PMC after 03/12/2019 Related Publications
BACKGROUND: Glioblastoma (GBM), a highly malignant brain tumor, invariably recurs after therapy. Quiescent GBM cells represent a potential source of tumor recurrence, but little is known about their molecular underpinnings.
METHODS: Patient-derived GBM cells were engineered by CRISPR/Cas9-assisted knock-in of an inducible histone2B-GFP (iH2B-GFP) reporter to track cell division history. We utilized an in vitro 3D GBM organoid approach to isolate live quiescent GBM (qGBM) cells and their proliferative counterparts (pGBM) to compare stem cell properties and therapy resistance. Gene expression programs of qGBM and pGBM cells were analyzed by RNA-Seq and NanoString platforms.
FINDINGS: H2B-GFP-retaining qGBM cells exhibited comparable self-renewal capacity but higher therapy resistance relative to pGBM. Quiescent GBM cells expressed distinct gene programs that affect cell cycle control, metabolic adaptation, and extracellular matrix (ECM) interactions. Transcriptome analysis also revealed a mesenchymal shift in qGBM cells of both proneural and mesenchymal GBM subtypes. Bioinformatic analyses and functional assays in GBM organoids established hypoxia and TGFβ signaling as potential niche factors that promote quiescence in GBM. Finally, network co-expression analysis of TCGA glioma patient data identified gene modules that are enriched for qGBM signatures and also associated with survival rate.
INTERPRETATION: Our in vitro study in 3D GBM organoids supports the presence of a quiescent cell population that displays self-renewal capacity, high therapy resistance, and mesenchymal gene signatures. It also sheds light on how GBM cells may acquire and maintain quiescence through ECM organization and interaction with niche factors such as TGFβ and hypoxia. Our findings provide a starting point for developing strategies to tackle the quiescent population of GBM. FUND: National Institutes of Health (NIH) and Deutsche Forschungsgemeinschaft (DFG).

Sawant DV, Yano H, Chikina M, et al.
Adaptive plasticity of IL-10
Nat Immunol. 2019; 20(6):724-735 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Regulatory T cells (T

Sasaki A, Hirato J, Hirose T, et al.
Review of ependymomas: assessment of consensus in pathological diagnosis and correlations with genetic profiles and outcome.
Brain Tumor Pathol. 2019; 36(2):92-101 [PubMed] Related Publications
We focused on histological and immunohistochemical characteristics of ependymoma (EPN) with molecular profiles to develop more reproducible criteria of the diagnosis. Three expert neuropathologists reviewed the pathology of 130 samples from the Japan Pediatric Molecular Neuro-Oncology Group study. Confirmed cases were assessed for histology, surrogate markers, molecular subgrouping, and survival data. We reached a consensus regarding the diagnosis of EPNs in 100% of spinal cord tumors and 93% of posterior fossa (PF) tumors that had been diagnosed as EPNs by local pathologists, whereas we reached a consensus regarding only 77% of the local diagnosis of supratentorial (ST) EPNs. Among the PF-EPNs, most of anaplastic ependymomas (AEPNs) were defined as EPN-A by methylation profiling, which was significantly correlated with the subgroup assignment. Regarding prognosis, the overall survival of patients with PF-EPN was significantly better than that of patients with PF AEPN (p = 0.01). Histologically, all ependymoma, RELA fusion-positive (EPN-RELA) qualified as Grade III. Both L1 cell adhesion molecule and nuclear factor kappaB p65 antibodies showed good sensitivity for detecting EPN-RELA. This study indicated that the expert consensus pathological diagnosis could correlate well with the molecular classifications in EPNs. ST EPNs should be diagnosed more carefully by histological and molecular analyses.

Lawrenson K, Song F, Hazelett DJ, et al.
Genome-wide association studies identify susceptibility loci for epithelial ovarian cancer in east Asian women.
Gynecol Oncol. 2019; 153(2):343-355 [PubMed] Related Publications
OBJECTIVE: Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women.
METHODS: Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations.
RESULTS: At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10
CONCLUSION: While some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.

Palangat M, Anastasakis DG, Fei DL, et al.
The splicing factor U2AF1 contributes to cancer progression through a noncanonical role in translation regulation.
Genes Dev. 2019; 33(9-10):482-497 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Somatic mutations in the genes encoding components of the spliceosome occur frequently in human neoplasms, including myeloid dysplasias and leukemias, and less often in solid tumors. One of the affected factors, U2AF1, is involved in splice site selection, and the most common change, S34F, alters a conserved nucleic acid-binding domain, recognition of the 3' splice site, and alternative splicing of many mRNAs. However, the role that this mutation plays in oncogenesis is still unknown. Here, we uncovered a noncanonical function of U2AF1, showing that it directly binds mature mRNA in the cytoplasm and negatively regulates mRNA translation. This splicing-independent role of U2AF1 is altered by the S34F mutation, and polysome profiling indicates that the mutation affects translation of hundreds of mRNA. One functional consequence is increased synthesis of the secreted chemokine interleukin 8, which contributes to metastasis, inflammation, and cancer progression in mice and humans.

Yang Y, Ishak Gabra MB, Hanse EA, et al.
MiR-135 suppresses glycolysis and promotes pancreatic cancer cell adaptation to metabolic stress by targeting phosphofructokinase-1.
Nat Commun. 2019; 10(1):809 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. It thrives in a nutrient-poor environment; however, the mechanisms by which PDAC cells undergo metabolic reprogramming to adapt to metabolic stress are still poorly understood. Here, we show that microRNA-135 is significantly increased in PDAC patient samples compared to adjacent normal tissue. Mechanistically, miR-135 accumulates specifically in response to glutamine deprivation and requires ROS-dependent activation of mutant p53, which directly promotes miR-135 expression. Functionally, we found miR-135 targets phosphofructokinase-1 (PFK1) and inhibits aerobic glycolysis, thereby promoting the utilization of glucose to support the tricarboxylic acid (TCA) cycle. Consistently, miR-135 silencing sensitizes PDAC cells to glutamine deprivation and represses tumor growth in vivo. Together, these results identify a mechanism used by PDAC cells to survive the nutrient-poor tumor microenvironment, and also provide insight regarding the role of mutant p53 and miRNA in pancreatic cancer cell adaptation to metabolic stresses.

Gao Y, Yin J, Tu Y, Chen YC
Theaflavin-3,3'-Digallate Suppresses Human Ovarian Carcinoma OVCAR-3 Cells by Regulating the Checkpoint Kinase 2 and p27 kip1 Pathways.
Molecules. 2019; 24(4) [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Theaflavin-3,3'-digallate (TF3) is a unique polyphenol in black tea. Epidemiological studies have proved that black tea consumption decreases the incidence rate of ovarian cancer. Our former research demonstrated that TF3 inhibited human ovarian cancer cells. Nevertheless, the roles of checkpoint kinase 2 (Chk2) and p27 kip1 (p27) in TF3-mediated inhibition of human ovarian cancer cells have not yet been investigated. In the current study, TF3 enhanced the phosphorylation of Chk2 to modulate the ratio of pro/anti-apoptotic Bcl-2 family proteins to initiate intrinsic apoptosis in a p53-independent manner and increased the expression of death receptors to activate extrinsic apoptosis in OVCAR-3 human ovarian carcinoma cells. In addition, TF3 up-regulated the expression of p27 to induce G0/G1 cell cycle arrest in OVCAR-3 cells. Our study indicated that Chk2 and p27 were vital anticancer targets of TF3 and provided more evidence that TF3 might be a potent agent to be applied as adjuvant treatment for ovarian cancer.

Jiang X, Finucane HK, Schumacher FR, et al.
Shared heritability and functional enrichment across six solid cancers.
Nat Commun. 2019; 10(1):431 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r

Kovalski JR, Bhaduri A, Zehnder AM, et al.
The Functional Proximal Proteome of Oncogenic Ras Includes mTORC2.
Mol Cell. 2019; 73(4):830-844.e12 [PubMed] Article available free on PMC after 21/02/2020 Related Publications
Proximity-dependent biotin labeling (BioID) may identify new targets for cancers driven by difficult-to-drug oncogenes such as Ras. Therefore, BioID was used with wild-type (WT) and oncogenic mutant (MT) H-, K-, and N-Ras, identifying known interactors, including Raf and PI3K, as well as a common set of 130 novel proteins proximal to all Ras isoforms. A CRISPR screen of these proteins for Ras dependence identified mTOR, which was also found proximal to MT Ras in human tumors. Oncogenic Ras directly bound two mTOR complex 2 (mTORC2) components, mTOR and MAPKAP1, to promote mTORC2 kinase activity at the plasma membrane. mTORC2 enabled the Ras pro-proliferative cell cycle transcriptional program, and perturbing the Ras-mTORC2 interaction impaired Ras-dependent neoplasia in vivo. Combining proximity-dependent proteomics with CRISPR screening identified a new set of functional Ras-associated proteins, defined mTORC2 as a new direct Ras effector, and offers a strategy for finding new proteins that cooperate with dominant oncogenes.

Dzimianski JV, Beldon BS, Daczkowski CM, et al.
Probing the impact of nairovirus genomic diversity on viral ovarian tumor domain protease (vOTU) structure and deubiquitinase activity.
PLoS Pathog. 2019; 15(1):e1007515 [PubMed] Article available free on PMC after 21/02/2020 Related Publications
Post-translational modification of host and viral proteins by ubiquitin (Ub) and Ub-like proteins, such as interferon stimulated gene product 15 (ISG15), plays a key role in response to infection. Viruses have been increasingly identified that contain proteases possessing deubiquitinase (DUB) and/or deISGylase functions. This includes viruses in the Nairoviridae family that encode a viral homologue of the ovarian tumor protease (vOTU). vOTU activity was recently demonstrated to be critical for replication of the often-fatal Crimean-Congo hemorrhagic fever virus, with DUB activity suppressing the type I interferon responses and deISGylase activity broadly removing ISG15 conjugated proteins. There are currently about 40 known nairoviruses classified into fourteen species. Recent genomic characterization has revealed a high degree of diversity, with vOTUs showing less than 25% amino acids identities within the family. Previous investigations have been limited to only a few closely related nairoviruses, leaving it unclear what impact this diversity has on vOTU function. To probe the effects of vOTU diversity on enzyme activity and specificity, we assessed representative vOTUs spanning the Nairoviridae family towards Ub and ISG15 fluorogenic substrates. This revealed great variation in enzymatic activity and specific substrate preferences. A subset of the vOTUs were further assayed against eight biologically relevant di-Ub substrates, uncovering both common trends and distinct preferences of poly-Ub linkages by vOTUs. Four novel X-ray crystal structures were obtained that provide a biochemical rationale for vOTU substrate preferences and elucidate structural features that distinguish the vOTUs, including a motif in the Hughes orthonairovirus species that has not been previously observed in OTU domains. Additionally, structure-informed mutagenesis provided the first direct evidence of a second site involved in di-Ub binding for vOTUs. These results provide new insight into nairovirus evolution and pathogenesis, and further enhances the development of tools for therapeutic purposes.

Tang H, Jiang L, Zhu C, et al.
Loss of cell adhesion molecule L1 like promotes tumor growth and metastasis in esophageal squamous cell carcinoma.
Oncogene. 2019; 38(17):3119-3133 [PubMed] Related Publications
Esophageal squamous cells carcinoma (ESCC) is a major common thoracic tumor characterized by distinctly high incidences and mortality rates. Despite advances in multimodality therapy, the mortality rate of ESCC remains high and understanding of molecular alterations leading to the development and progression of ESCC is still very limited. In this study, a new tumor suppressor candidate, cell adhesion molecule with homology to L1CAM (CHL1), located at 3p26 which was frequently deleted in ESCC was identified. Reduced expression of CHL1 correlated with poor differentiation, increased invasion, and lymph-node metastasis, advanced tumor stage, and decreased overall survival. Methylation-specific PCR and FISH assays revealed that down-regulation of CHL1 in both ESCC cell lines and clinical samples were associated with promoter hypermethylation and loss of heterozygosity. Functional studies using lentiviral-based overexpression and knockdown systems provided direct support of CHL1 to function as an important tumor suppressor with both anti-proliferation and anti-metastasis abilities, through Merlin and SEMA3B-Np1-mediated inhibition of AKT signaling pathway. Further characterization of CHL1 may provide a novel therapeutic target in ESCC treatment.

Stubendorff B, Wilhelm K, Posselt K, et al.
A three-gene methylation marker panel for the nodal metastatic risk assessment of muscle-invasive bladder cancer.
J Cancer Res Clin Oncol. 2019; 145(4):811-820 [PubMed] Related Publications
PURPOSE: In this study, we aimed to identify a DNA methylation pattern suitable for prognosis assessment of muscle-invasive bladder cancer and to investigate metastasis-associated processes regulated by DNA methylation.
METHODS: Genome-wide methylation analysis was performed on 23 muscle-invasive bladder tumors by microarray analysis. Validation was performed by the qAMP technique in two different patient cohorts (n = 32 and n = 100). mRNA expression was analyzed in 12 samples. Protein expression was determined using tissue microarrays of 291 patients. Bladder cancer cell lines T24 and 253JB-V were used for functional analyses.
RESULTS: Microarray analyses revealed KISS1R, SEPT9 and CSAD as putative biomarkers with hypermethylation in node-positive tumors. The combination of the three genes predicted the metastatic risk with sensitivity of 73% and specificity of 71% in cohort 1, and sensitivity of 82% and specificity of 54% in cohort 2. mRNA expression differences were detected for KISS1R (p = 0.04). Protein expression of KISS1R was significantly reduced (p < 0.001). Knockdown of SEPT9v3 resulted in increased cell migration by 28% (p = 0.04) and increased invasion by 22% (p = 0.004). KISS1R overexpression resulted in decreased cell migration (25%, p = 0.1).
CONCLUSIONS: We identified a methylation marker panel suitable to differentiate between patients with positive and negative lymph nodes at time of cystectomy. This enables a risk assessment for patients who potentially benefit from extended lymph node resection as well as from neoadjuvant chemotherapy and could improve the survival rates. Furthermore, we examined the impact of putative markers on tumor behavior. Hence, KISS1R and SEPT9 could represent a starting point for the development of novel therapy approaches.

Lin J, Hu Y, Zhao JJ
Repression of Multiple Myeloma Cell Growth In Vivo by Single-wall Carbon Nanotube (SWCNT)-delivered MALAT1 Antisense Oligos.
J Vis Exp. 2018; (142) [PubMed] Article available free on PMC after 21/02/2020 Related Publications
The single-wall carbon nanotube (SWCNT) is a new type of nanoparticle, which has been used to deliver multiple kinds of drugs into cells, such as proteins, oligonucleotides, and synthetic small-molecule drugs. The SWCNT has customizable dimensions, a large superficial area, and can flexibly bind with drugs through different modifications on its surface; therefore, it is an ideal system to transport drugs into cells. Long noncoding RNAs (lncRNAs) are a cluster of noncoding RNA longer than 200 nt, which cannot be translated to protein but play an important role in biological and pathophysiological processes. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a highly conserved lncRNA. It was demonstrated that higher MALAT1 levels are related to the poor prognosis of various cancers, including multiple myeloma (MM). We have revealed that MALAT1 regulates DNA repair and cell death in MM; thus, MALAT1 can be considered as a therapeutic target for MM. However, the efficient delivery of the antisense oligo to inhibit/knockdown MALAT1 in vivo is still a problem. In this study, we modify the SWCNT with PEG-2000 and conjugate an anti-MALAT1 oligo to it, test the delivery of this compound in vitro, inject it intravenously into a disseminated MM mouse model, and observe a significant inhibition of MM progression, which indicates that SWCNT is an ideal delivery shuttle for anti-MALAT1 gapmer DNA.

Klat J, Mladenka A, Dvorackova J, et al.
L1CAM as a Negative Prognostic Factor in Endometrioid Endometrial Adenocarcinoma FIGO Stage IA-IB.
Anticancer Res. 2019; 39(1):421-424 [PubMed] Related Publications
AIMS: In this study, we aimed to investigate how positivity for L1 cell adhesion molecule (L1CAM) was associated with outcome and relapse pattern in patients with Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage IA-IB endometrial cancer.
MATERIALS AND METHODS: This retrospective study included 358 patients who underwent surgical treatment for endometrial carcinoma. Tumor samples from 312 patients (87.2%) were available for L1CAM analysis by immunohistochemistry.
RESULTS: Of the 312 tumor samples analyzed, 93 (29.8%) were L1CAM-positive. L1CAM positivity was significantly more common in grade 3 compared to grade 1-2 carcinomas (p=0.02). Patients with L1CAM positivity more commonly experienced disease progression. Distant metastasis was significantly associated with L1CAM positivity (p=0.01). Progression-free interval and overall survival did not significantly differ between L1CAM-positive and L1CAM-negative cases.
CONCLUSION: L1CAM is a promising independent prognostic marker associated with aggressive tumor behavior and recurrence risk, but not with overall survival.

Bhoyar S, Godet I, DiGiacomo JW, Gilkes DM
A software tool for the quantification of metastatic colony growth dynamics and size distributions in vitro and in vivo.
PLoS One. 2018; 13(12):e0209591 [PubMed] Article available free on PMC after 21/02/2020 Related Publications
The majority of cancer-related deaths are due to metastasis, hence improved methods to biologically and computationally model metastasis are required. Computational models rely on robust data that is machine-readable. The current methods used to model metastasis in mice involve generating primary tumors by injecting human cells into immune-compromised mice, or by examining genetically engineered mice that are pre-disposed to tumor development and that eventually metastasize. The degree of metastasis can be measured using flow cytometry, bioluminescence imaging, quantitative PCR, and/or by manually counting individual lesions from metastatic tissue sections. The aforementioned methods are time-consuming and do not provide information on size distribution or spatial localization of individual metastatic lesions. In this work, we describe and provide a MATLAB script for an image-processing based method designed to obtain quantitative data from tissue sections comprised of multiple subpopulations of disseminated cells localized at metastatic sites in vivo. We further show that this method can be easily adapted for high throughput imaging of live or fixed cells in vitro under a multitude of conditions in order to assess clonal fitness and evolution. The inherent variation in mouse studies, increasing complexity in experimental design which incorporate fate-mapping of individual cells, result in the need for a large cohort of mice to generate a robust dataset. High-throughput imaging techniques such as the one that we describe will enhance the data that can be used as input for the development of computational models aimed at modeling the metastatic process.

Paroni G, Bolis M, Zanetti A, et al.
HER2-positive breast-cancer cell lines are sensitive to KDM5 inhibition: definition of a gene-expression model for the selection of sensitive cases.
Oncogene. 2019; 38(15):2675-2689 [PubMed] Related Publications
Targeting of histone methylation has therapeutic potential in oncology. Here, we provide proof-of-principle that pharmacological inhibition of KDM5 histone-demethylases is a new strategy for the personalized treatment of HER2

Camolotto SA, Pattabiraman S, Mosbruger TL, et al.
FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer.
Elife. 2018; 7 [PubMed] Article available free on PMC after 21/02/2020 Related Publications
Changes in cancer cell identity can alter malignant potential and therapeutic response. Loss of the pulmonary lineage specifier NKX2-1 augments the growth of KRAS-driven lung adenocarcinoma and causes pulmonary to gastric transdifferentiation. Here, we show that the transcription factors FoxA1 and FoxA2 are required for initiation of mucinous NKX2-1-negative lung adenocarcinomas in the mouse and for activation of their gastric differentiation program.

Song W, Gregory DA, Al-Janabi H, et al.
Magnetic-silk/polyethyleneimine core-shell nanoparticles for targeted gene delivery into human breast cancer cells.
Int J Pharm. 2019; 555:322-336 [PubMed] Related Publications
The lack of efficient and cost-effective methods for gene delivery has significantly hindered the applications of gene therapy. In this paper, a simple one step and cost effective salting-out method has been explored to fabricate silk-PEI nanoparticles (SPPs) and magnetic-silk/PEI core-shell nanoparticles (MSPPs) for targeted delivery of c-myc antisense oligodeoxynucleotides (ODNs) into MDA-MB-231 breast cancer cells. The size and zeta potential of the particles were controlled by adjusting the amount of silk fibroin in particle synthesis. Lower surface charges and reduced cytotoxicity were achieved for MSPPs compared with PEI coated magnetic nanoparticles (MPPs). Both SPPs and MSPPs were capable of delivering the ODNs into MDA-MB-231 cells and significantly inhibited the cell growth. Through magnetofection, high ODN uptake efficiencies (over 70%) were achieved within 20 min using MSPPs as carriers, exhibiting a significantly enhanced uptake effect compared to the same carriers via non-magnetofection. Both SPPs and MSPPs exhibited a significantly higher inhibition effect against MDA-MB-231 breast cancer cells compared to human dermal fibroblast (HDF) cells. Targeted ODN delivery was achieved using MSPPs with the help of a magnet, making them promising candidates for targeted gene therapy applications.

Chun KA, Kocarnik JM, Hardikar SS, et al.
Leptin gene variants and colorectal cancer risk: Sex-specific associations.
PLoS One. 2018; 13(10):e0206519 [PubMed] Article available free on PMC after 21/02/2020 Related Publications
BACKGROUND: High levels of serum leptin and low levels of serum adiponectin are strongly correlated with obesity, a well-established risk factor for colorectal cancer (CRC). Growing evidence suggests that dysregulation of leptin and adiponectin levels may play an etiological role in colorectal carcinogenesis. We evaluated 20 candidate variants in 4 genes previously shown to alter serum leptin and adiponectin levels for associations with obesity (BMI>30 kg/m2) and CRC risk.
METHODS: We analyzed 6,246 CRC cases and 7,714 population-based controls from 11 studies within the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations of each variant with obesity or CRC were evaluated using multivariate logistic regression models stratified by sex and adjusted for age, a study variable, and the first three principal components of genetic ancestry. Gene-specific False Discovery Rate (FDR)-adjusted p-values <0.05 denoted statistical significance.
RESULTS: Two variants in the leptin gene showed statistically significant associations with CRC among women: LEP rs2167270 (OR = 1.13, 95% CI: 1.06-1.21) and LEP rs4731426 (OR = 1.09, 95% CI: 1.02-1.17). These associations remained significant after adjustment for obesity, suggesting that leptin SNPs may influence CRC risk independent of obesity. We observed statistically significant interactions of the leptin variants with hormone replacement therapy (HRT) for CRC risk; these variant associations were strengthened when analyses were restricted to post-menopausal women with low estrogen exposure, as estimated by 'never use' of HRT and/or non-obese BMI. No variants were associated with CRC among men.
CONCLUSIONS: Leptin gene variants may exhibit sex-specific associations with CRC risk. Endogenous and exogenous estrogen exposure may modify the association between these variants, leptin levels, and CRC risk.

Quayle LA, Ottewell PD, Holen I
Chemotherapy resistance and stemness in mitotically quiescent human breast cancer cells identified by fluorescent dye retention.
Clin Exp Metastasis. 2018; 35(8):831-846 [PubMed] Article available free on PMC after 21/02/2020 Related Publications
Metastatic recurrence in breast cancer is a major cause of mortality and often occurs many years after removal of the primary tumour. This process is driven by the reactivation of disseminated tumour cells that are characterised by mitotic quiescence and chemotherapeutic resistance. The ability to reliably isolate and characterise this cancer cell population is critical to enable development of novel therapeutic strategies for prevention of breast cancer recurrence. Here we describe the identification and characterisation of a sub-population of slow-cycling tumour cells in the MCF-7 and MDA-MB-231 human breast cancer cell lines based on their ability to retain the lipophilic fluorescent dye Vybrant

Probert C, Dottorini T, Speakman A, et al.
Communication of prostate cancer cells with bone cells via extracellular vesicle RNA; a potential mechanism of metastasis.
Oncogene. 2019; 38(10):1751-1763 [PubMed] Article available free on PMC after 21/02/2020 Related Publications
The role of extracellular vesicles (EVs) as vehicles for cell-to-cell communication between a tumour and its environment is a relatively new concept. The hypothesis that EVs may be critical in co-opting tissues by tumours to generate distant metastatic niches is particularly pertinent to prostate cancer (PCa), where metastatic-tropism to bone predominates over other tissue types. The potential role of EVs as a means of communication between PCa cells and cells of the bone stroma such as osteoblasts, is yet to be fully explored. In this study, we demonstrate that PCa cell EVs both enhance osteoblast viability and produce a significantly more supportive growth environment for PCa cells when grown in co-culture with EV-treated osteoblasts (p < 0.005). Characterisation of the RNA cargo of EVs produced by the bone-metastatic PCa cell line PC3, highlights the EV-RNA cargo is significantly enriched in genes relating to cell surface signalling, cell-cell interaction, and protein translation (p < 0.01). Using novel techniques to track RNA, we demonstrate the delivery of a set of PCa-RNAs to osteoblast via PCa-EVs and show the effect on osteoblast endogenous transcript abundance. Taken together, by using proof-of-concept studies we demonstrate for the first time the contribution of the RNA element of the PCa EV cargo, providing evidence to support PCa EV communication via RNA molecules as a potential novel route to mediate bone metastasis. We propose targeting PCa EVs could offer a potentially important preventative therapy for men at risk of metastatic PCa.

Magnuson AM, Kiner E, Ergun A, et al.
Identification and validation of a tumor-infiltrating Treg transcriptional signature conserved across species and tumor types.
Proc Natl Acad Sci U S A. 2018; 115(45):E10672-E10681 [PubMed] Article available free on PMC after 21/02/2020 Related Publications
FoxP3

Koutsioumpa M, Hatziapostolou M, Polytarchou C, et al.
Lysine methyltransferase 2D regulates pancreatic carcinogenesis through metabolic reprogramming.
Gut. 2019; 68(7):1271-1286 [PubMed] Article available free on PMC after 21/02/2020 Related Publications
OBJECTIVE: Despite advances in the identification of epigenetic alterations in pancreatic cancer, their biological roles in the pathobiology of this dismal neoplasm remain elusive. Here, we aimed to characterise the functional significance of histone lysine methyltransferases (KMTs) and demethylases (KDMs) in pancreatic tumourigenesis.
DESIGN: DNA methylation sequencing and gene expression microarrays were employed to investigate CpG methylation and expression patterns of KMTs and KDMs in pancreatic cancer tissues versus normal tissues. Gene expression was assessed in five cohorts of patients by reverse transcription quantitative-PCR. Molecular analysis and functional assays were conducted in genetically modified cell lines. Cellular metabolic rates were measured using an XF24-3 Analyzer, while quantitative evaluation of lipids was performed by liquid chromatography-mass spectrometry (LC-MS) analysis. Subcutaneous xenograft mouse models were used to evaluate pancreatic tumour growth in vivo.
RESULTS: We define a new antitumorous function of the histone lysine (K)-specific methyltransferase 2D (KMT2D) in pancreatic cancer.
CONCLUSION: Together our findings define a new tumour suppressor function of KMT2D through the regulation of glucose/fatty acid metabolism in pancreatic cancer.

Luo J, Chimge NO, Zhou B, et al.
CLDN18.1 attenuates malignancy and related signaling pathways of lung adenocarcinoma in vivo and in vitro.
Int J Cancer. 2018; 143(12):3169-3180 [PubMed] Article available free on PMC after 15/12/2019 Related Publications
Claudins are a family of transmembrane proteins integral to the structure and function of tight junctions (TJ). Disruption of TJ and alterations in claudin expression are important features of invasive and metastatic cancer cells. Expression of CLDN18.1, the lung-specific isoform of CLDN18, is markedly decreased in lung adenocarcinoma (LuAd). Furthermore, we recently observed that aged Cldn18

Fei DL, Zhen T, Durham B, et al.
Impaired hematopoiesis and leukemia development in mice with a conditional knock-in allele of a mutant splicing factor gene
Proc Natl Acad Sci U S A. 2018; 115(44):E10437-E10446 [PubMed] Article available free on PMC after 15/12/2019 Related Publications
Mutations affecting the spliceosomal protein U2AF1 are commonly found in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML). We have generated mice that carry Cre-dependent knock-in alleles of

Chan CS, Laddha SV, Lewis PW, et al.
ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup.
Nat Commun. 2018; 9(1):4158 [PubMed] Article available free on PMC after 15/12/2019 Related Publications
The commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are ATRX, DAXX, and MEN1. We genotyped 64 PanNETs and found 58% carry ATRX, DAXX, and MEN1 mutations (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing and DNA-methylation analysis to reveal two distinct subgroups with one consisting entirely of A-D-M mutant PanNETs. Two genes differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature related to that of alpha-cells (FDR q-value < 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells.

Song M, Sandoval TA, Chae CS, et al.
IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity.
Nature. 2018; 562(7727):423-428 [PubMed] Article available free on PMC after 15/12/2019 Related Publications
Tumours evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. L1CAM, Cancer Genetics Web: http://www.cancer-genetics.org/L1CAM.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 29 August, 2019     Cancer Genetics Web, Established 1999