Publications by authors named "Nicole Beauchemin"

64 Publications

Neutrophil Extracellular Trap-Associated CEACAM1 as a Putative Therapeutic Target to Prevent Metastatic Progression of Colon Carcinoma.

J Immunol 2020 04 13;204(8):2285-2294. Epub 2020 Mar 13.

Cancer Research Program and the LD MacLean Surgical Research Laboratories, Department of Surgery, Research Institute of the McGill University Health Center, Montreal, Quebec H4A 3J1, Canada;

Neutrophils promote tumor growth and metastasis at multiple stages of cancer progression. One mechanism through which this occurs is via release of neutrophil extracellular traps (NETs). We have previously shown that NETs trap tumor cells in both the liver and the lung, increasing their adhesion and metastasis following postoperative complications. Multiple studies have since shown that NETs play a role in tumor progression and metastasis. NETs are composed of nuclear DNA-derived web-like structures decorated with neutrophil-derived proteins. However, it is unknown which, if any, of these NET-affiliated proteins is responsible for inducing the metastatic phenotype. In this study, we identify the NET-associated carcinoembryonic Ag cell adhesion molecule 1 (CEACAM1) as an essential element for this interaction. Indeed, blocking CEACAM1 on NETs, or knocking it out in a murine model, leads to a significant decrease in colon carcinoma cell adhesion, migration and metastasis. Thus, this work identifies NET-associated CEACAM1 as a putative therapeutic target to prevent the metastatic progression of colon carcinoma.
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http://dx.doi.org/10.4049/jimmunol.1900240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534954PMC
April 2020

Inactivation of Interferon Regulatory Factor 1 Causes Susceptibility to Colitis-Associated Colorectal Cancer.

Sci Rep 2019 12 11;9(1):18897. Epub 2019 Dec 11.

Department of Biochemistry, McGill University, Montreal, QC, Canada.

The mechanisms linking chronic inflammation of the gut (IBD) and increased colorectal cancer susceptibility are poorly understood. IBD risk is influenced by genetic factors, including the IBD5 locus (human 5q31), that harbors the IRF1 gene. A cause-to-effect relationship between chronic inflammation and colorectal cancer, and a possible role of IRF1 were studied in Irf1 mice in a model of colitis-associated colorectal cancer (CA-CRC) induced by azoxymethane and dextran sulfate. Loss of Irf1 causes hyper-susceptibility to CA-CRC, with early onset and increased number of tumors leading to rapid lethality. Transcript profiling (RNA-seq) and immunostaining of colons shows heightened inflammation and enhanced enterocyte proliferation in Irf1 mutants, prior to appearance of tumors. Considerable infiltration of leukocytes is seen in Irf1 colons at this early stage, and is composed primarily of proinflammatory Gr1 Cd11b myeloid cells and other granulocytes, as well as CD4 lymphoid cells. Differential susceptibility to CA-CRC of Irf1 vs. B6 controls is fully transferable through hematopoietic cells as observed in bone marrow chimera studies. Transcript signatures seen in Irf1 mice in response to AOM/DSS are enriched in clinical specimens from patients with IBD and with colorectal cancer. In addition, IRF1 expression in the colon is significantly decreased in late stage colorectal cancer (stages 3, 4) and is associated with poorer prognosis. This suggests that partial or complete loss of IRF1 expression alters the type, number, and function of immune cells in situ during chronic inflammation, possibly via the creation of a tumor-promoting environment.
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http://dx.doi.org/10.1038/s41598-019-55378-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906452PMC
December 2019

Impact of the Microbiome on the Human Genome.

Trends Parasitol 2019 10 23;35(10):809-821. Epub 2019 Aug 23.

Department of Biochemistry, McGill University, Montreal, Canada; McGill Center for the Study of Complex Traits, McGill University, Montreal, Canada; Goodman Cancer Research Center, McGill University, Montreal, Canada. Electronic address:

Humans live in a microbial world that includes pathogenic bacteria, viruses, and fungi that cause lethal infections. In addition, a large number of microbial communities inhabit mucosal surfaces where they provide key metabolic activities, facilitating adaptation to changing environments. New genome technologies enable both sequencing of the human genome and sequence-based cataloging of microbial communities inhabiting human mucosal surfaces. These have revealed intricate two-way relationships between the microbiome and the genome, including strong effects of human genotypes on the composition and activity of the microbiome. Likewise, the microbiome plays an important role in training and regulating the immune system, and acts to modify expression of human genetic risk for debilitating chronic inflammatory and immune conditions. These studies are suggesting a new role of the microbiome in human health and disease.
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http://dx.doi.org/10.1016/j.pt.2019.07.015DOI Listing
October 2019

[Delivery in hypoxic tumor regions of a chemotherapeutic agent encapsulated in nanoliposomes carried by magnetoaerotactic bacteria].

Med Sci (Paris) 2018 Mar 16;34(3):197-199. Epub 2018 Mar 16.

Laboratoire de nanorobotique - département de génie informatique et génie logiciel, Institut de génie biomédical, Polytechnique Montréal, Montréal H3T 1J4, Canada.

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http://dx.doi.org/10.1051/medsci/20183403002DOI Listing
March 2018

EphA2 signaling is impacted by carcinoembryonic antigen cell adhesion molecule 1-L expression in colorectal cancer liver metastasis in a cell context-dependent manner.

Oncotarget 2017 Nov 1;8(61):104330-104346. Epub 2017 Nov 1.

Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.

We have shown that carcinoembryonic antigen cell adhesion molecule 1 long isoform (CEACAM1-L) expression in MC38 metastatic colorectal cancer (CRC) cells results in liver metastasis inhibition via CCL2 and STAT3 signaling. But other molecular mechanisms orchestrating CEACAM1-L-mediated metastasis inhibition remain to be defined. We screened a panel of mouse and human CRC cells and evaluated their metastatic outcome after CEACAM1 overexpression or downregulation. An unbiased transcript profiling and a phospho-receptor tyrosine kinase screen comparing MC38 CEACAM1-L-expressing and non-expressing (CT) CRC cells revealed reduced ephrin type-A receptor 2 (EPHA2) expression and activity. An EPHA2-specific inhibitor reduced EPHA2 downstream signaling in CT cells similar to that in CEACAM1-L cells with decreased proliferation and migration. Human CRC patients exhibiting high in combination with low expression benefited from longer time to first recurrence/metastasis compared to those with high expression. With the added interaction of , we denoted that high- and low-expressing patient samples with lower expression also exhibited a longer time to first recurrence/metastasis. In HT29 human CRC cells, down-regulation of CEACAM1 along with CEA and CEACAM6 up-regulation led to higher metastatic burden. Overall, CEACAM1-L expression in poorly differentiated CRC can inhibit liver metastasis through cell context-dependent EPHA2-mediated signaling. However, CEACAM1's role should be considered in the presence of other CEACAM family members.
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http://dx.doi.org/10.18632/oncotarget.22236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732810PMC
November 2017

CEACAM1 as a multi-purpose target for cancer immunotherapy.

Oncoimmunology 2017;6(7):e1328336. Epub 2017 May 16.

Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.

CEACAM1 is an extensively studied cell surface molecule with established functions in multiple cancer types, as well as in various compartments of the immune system. Due to its multi-faceted role as a recently appreciated immune checkpoint inhibitor and tumor marker, CEACAM1 is an attractive target for cancer immunotherapy. Herein, we highlight CEACAM1's function in various immune compartments and cancer types, including in the context of metastatic disease. This review outlines CEACAM1's role as a therapeutic target for cancer treatment in light of these properties.
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http://dx.doi.org/10.1080/2162402X.2017.1328336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543821PMC
May 2017

Next generation sequencing of progressive colorectal liver metastases after portal vein embolization.

Clin Exp Metastasis 2017 06 31;34(5):351-361. Epub 2017 Jul 31.

Department of Surgery, Section of HPB Surgery, McGill University Health Center, Montreal, Canada.

Portal vein embolization (PVE) can be required to stimulate liver regeneration before hepatectomy for colorectal liver metastasis (CRCLM), however PVE may also trigger CRCLM progression in patients initially exhibiting chemotherapy response. Using RNA-seq, we aimed to determine the molecular networks involved in metastatic progression in this context. A prospective study including all CRCLM patients undergoing PVE prior to hepatectomy was conducted. Paired biopsies of metastatic lesions were obtained prior to and after PVE and total RNA was isolated and used to prepare Illumina rRNA-depleted TruSeq stranded cDNA libraries for HiSeq 100 bp paired-end sequencing. Patients were classified with progression of disease (PD) or stable disease (SD) post-PVE using 3D-CT tumor volumetric analysis.

Results: Twenty patients were included, 13 (65.0%) in the PD group (median 58.0% (18.6-234.3) increase in tumor volume) and 7 (35.0%) in the SD group exhibiting continuous chemotherapy response (median -14.3% (-40.8 to -2.8) decrease in tumor volume) (p < 0.0001). Our results showed that progressive CRCLM after PVE undergo gene expression changes that indicate activation of core cancer pathways (IL-17 (p = 5.94 × 10), PI3K (p = 8.71 × 10), IL6 and IGF-1 signaling pathways), consistent with changes driven by cytokines and growth factors. Differential expression analysis in a paired model of progression (EdgeR, DeSeq) identified significantly dysregulated genes in the PD group (FOS, FOSB, RAB20, IRS2).

Conclusion: Differentially expressed genes and pathways with known links to cancer and metastasis were identified post-PVE in patients with disease progression. Highlighting these molecular changes is a crucial first step towards development of targeted therapeutic strategies that may mitigate the effects of PVE on tumor growth.
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http://dx.doi.org/10.1007/s10585-017-9855-9DOI Listing
June 2017

Murine MTHFD1-synthetase deficiency, a model for the human MTHFD1 R653Q polymorphism, decreases growth of colorectal tumors.

Mol Carcinog 2017 03 1;56(3):1030-1040. Epub 2016 Nov 1.

Departments of Human Genetics and Pediatrics, The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada.

The common R653Q variant (∼20% homozygosity in Caucasians) in the synthetase domain of the folate-metabolizing enzyme MTHFD1 reduces purine synthesis. Although this variant does not appear to affect risk for colorectal cancer, we questioned whether it would affect growth of colorectal tumors. We induced tumor formation in a mouse model for MTHFD1-synthetase deficiency (Mthfd1S ) using combined administration of azoxymethane (AOM) and dextran sodium sulfate (DSS) in male and female wild-type and Mthfd1S mice. Tumor size was significantly smaller in MthfdS mice, particularly in males. A reduction in the proliferation of MthfdS mouse embryonic fibroblast cell lines, compared with wild-type lines, was also observed. Tumor number was not influenced by genotype. The amount of inflammation observed within tumors from male Mthfd1S mice was lower than that in wild-type mice. Gene expression analysis in tumor adjacent normal (pre-neoplastic) tissue identified several genes involved in proliferation (Fosb, Fos, Ptk6, Esr2, Atf3) and inflammation (Atf3, Saa1, TNF-α) that were downregulated in MthfdS males. In females, MthfdS genotype was not associated with these gene expression changes, or with differences in tumor inflammation. These findings suggest that the mechanisms directing tumor growth differ significantly between males and females. We suggest that restriction of purine synthesis, reduced expression of genes involved in proliferation, and/or reduced inflammation lead to slower tumor growth in MTHFD1-synthetase deficiency. These findings may have implications for CRC tumor growth and prognosis in individuals with the R653Q variant. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/mc.22568DOI Listing
March 2017

Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions.

Nat Nanotechnol 2016 11 15;11(11):941-947. Epub 2016 Aug 15.

NanoRobotics Laboratory, Department of Computer and Software Engineering, Institute of Biomedical Engingeering, Polytechnique Montréal, Montréal H3T 1J4, Canada.

Oxygen-depleted hypoxic regions in the tumour are generally resistant to therapies. Although nanocarriers have been used to deliver drugs, the targeting ratios have been very low. Here, we show that the magneto-aerotactic migration behaviour of magnetotactic bacteria, Magnetococcus marinus strain MC-1 (ref. 4), can be used to transport drug-loaded nanoliposomes into hypoxic regions of the tumour. In their natural environment, MC-1 cells, each containing a chain of magnetic iron-oxide nanocrystals, tend to swim along local magnetic field lines and towards low oxygen concentrations based on a two-state aerotactic sensing system. We show that when MC-1 cells bearing covalently bound drug-containing nanoliposomes were injected near the tumour in severe combined immunodeficient beige mice and magnetically guided, up to 55% of MC-1 cells penetrated into hypoxic regions of HCT116 colorectal xenografts. Approximately 70 drug-loaded nanoliposomes were attached to each MC-1 cell. Our results suggest that harnessing swarms of microorganisms exhibiting magneto-aerotactic behaviour can significantly improve the therapeutic index of various nanocarriers in tumour hypoxic regions.
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http://dx.doi.org/10.1038/nnano.2016.137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094936PMC
November 2016

The p53 status can influence the role of Sam68 in tumorigenesis.

Oncotarget 2016 Nov;7(44):71651-71659

Terry Fox Molecular Oncology Group and the Bloomfield Center for Research on Aging, Sir Mortimer B Davis Jewish General Hospital, Lady Davis Institute for Medical Research, Montréal, Québec H3T 1E2, Canada.

The expression and activities of RNA binding proteins are frequently dysregulated in human cancer. Their roles, however, appears to be complex, with reports indicating both pro-tumorigenic and tumor suppressive functions. Here we show, using two classical mouse cancer models, that the role of KH-type RNA binding protein, Sam68, in tumor development can be influenced by the status of the p53 tumor suppressor. We demonstrate that in mice expressing wild type p53, Sam68-deficiency resulted in a higher incidence and malignancy of carcinogen-induced tumors, suggesting a tumor suppressive role for Sam68. In marked contrast, Sam68-haploinsufficiency significantly delayed the onset of tumors in mice lacking p53 and prolonged their survival, indicating that Sam68 accelerates the development of p53-deficient tumors. These findings provide considerable insight into a previously unknown relationship between Sam68 and the p53 tumor suppressor in tumorigenesis.
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http://dx.doi.org/10.18632/oncotarget.12305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342108PMC
November 2016

CEACAM1 controls the EMT switch in murine mammary carcinoma in vitro and in vivo.

Oncotarget 2016 Sep;7(39):63730-63746

Institute for Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, D-20251 Hamburg, Germany.

We analyzed the molecular basis for carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1)-controlled inhibition of epithelial-mesenchymal transition (EMT) in a mouse model for mammary adenocarcinoma (WAP-T mice). We demonstrate that silencing of CEACAM1 in WAP-T tumor-derived G-2 cells induces epithelial-mesenchymal plasticity (EMP), as evidenced by typical changes of gene expression, morphology and increased invasion. In contrast, reintroduction of CEACAM1 into G-2 cells reversed up-regulation of genes imposing mesenchymal transition, as well as cellular invasion. We identified the Wnt-pathway as target for CEACAM1-mediated repression of EMT. Importantly, β-catenin phosphorylation status and transcriptional activity strongly depend on CEACAM1 expression: CEACAM1high G-2 cells displayed enhanced phosphorylation of β-catenin at S33/S37/T41 and decreased phosphorylation at Y86, thereby inhibiting canonical Wnt/β-catenin signaling. We identified Src-homology 2 domain-containing phosphatase 2 (SHP-2) as a critical binding partner of CEACAM1 that could modulate β-catenin Y86 phosphorylation. Hence, CEACAM1 serves as a scaffold that controls membrane proximal β-catenin signaling. In vivo, mammary tumors of WAP-T/CEACAM1null mice displayed increased nuclear translocation of β-catenin and a dramatically enhanced metastasis rate compared to WAP-T mice. Hence, CEACAM1 controls EMT in vitro and in vivo by site-specific regulation of β-catenin phosphorylation. Survival analyses of human mammary carcinoma patients corroborated these data, indicating that CEACAM1 is a prognostic marker for breast cancer survival.
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http://dx.doi.org/10.18632/oncotarget.11650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325399PMC
September 2016

Mutational Profiles Reveal an Aberrant TGF-β-CEA Regulated Pathway in Colon Adenomas.

PLoS One 2016 21;11(4):e0153933. Epub 2016 Apr 21.

Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.

Mutational processes and signatures that drive early tumorigenesis are centrally important for early cancer prevention. Yet, to date, biomarkers and risk factors for polyps (adenomas) that inordinately and rapidly develop into colon cancer remain poorly defined. Here, we describe surprisingly high mutational profiles through whole-genome sequence (WGS) analysis in 2 of 4 pairs of benign colorectal adenoma tissue samples. Unsupervised hierarchical clustered transcriptomic analysis of a further 7 pairs of adenomas reveals distinct mutational signatures regardless of adenoma size. Transitional single nucleotide substitutions of C:G>T:A predominate in the adenoma mutational spectrum. Strikingly, we observe mutations in the TGF-β pathway and CEA-associated genes in 4 out of 11 adenomas, overlapping with the Wnt pathway. Immunohistochemical labeling reveals a nearly 5-fold increase in CEA levels in 23% of adenoma samples with a concomitant loss of TGF-β signaling. We also define a functional role by which the CEA B3 domain interacts with TGFBR1, potentially inactivating the tumor suppressor function of TGF-β signaling. Our study uncovers diverse mutational processes underlying the transition from early adenoma to cancer. This has broad implications for biomarker-driven targeting of CEA/TGF-β in high-risk adenomas and may lead to early detection of aggressive adenoma to CRC progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0153933PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839765PMC
September 2016

Mapping hyper-susceptibility to colitis-associated colorectal cancer in FVB/NJ mice.

Mamm Genome 2016 06 15;27(5-6):213-24. Epub 2016 Mar 15.

Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada.

Inbred strains of mice differ in susceptibility to colitis-associated colorectal cancer (CA-CRC). We tested 10 inbred strains of mice for their response to azoxymethane/dextran sulfate sodium-induced CA-CRC and identified a bimodal inter-strain distribution pattern when tumor multiplicity was used as a phenotypic marker of susceptibility. The FVB/NJ strain was particularly susceptible showing a higher tumor burden than any other susceptible strains (12.5-week post-treatment initiation). FVB/NJ hyper-susceptibility was detected as early as 8-week post-treatment initiation with FVB/NJ mice developing 5.5-fold more tumors than susceptible A/J or resistant B6 control mice. Linkage analysis by whole genome scan in informative (FVB/NJ×C3H/HeJ)F2 mice identified a novel susceptibility locus designated as C olon c ancer s usceptibility 6 (Ccs6) on proximal mouse chromosome 6. When gender was used as a covariate, a LOD score of 5.4 was computed with the peak marker being positioned at rs13478727, 43.8 Mbp. Mice homozygous for FVB/NJ alleles at this locus had increased tumor multiplicity compared to homozygous C3H/HeJ mice. Positional candidates in this region of chromosome 6 were analyzed with respect to a possible role in carcinogenesis and a role in inflammatory response using a new epigenetic gene scoring tool (Myeloid Inflammation Score).
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http://dx.doi.org/10.1007/s00335-016-9625-zDOI Listing
June 2016

Colitis-associated colon cancer: Is it in your genes?

World J Gastroenterol 2015 Nov;21(41):11688-99

Lauren Van Der Kraak, Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montréal, QC H3G 1Y6, Canada.

Colitis-associated colorectal cancer (CA-CRC) is the cause of death in 10%-15% of inflammatory bowel disease (IBD) patients. CA-CRC results from the accumulation of mutations in intestinal epithelial cells and progresses through a well-characterized inflammation to dysplasia to carcinoma sequence. Quantitative estimates of overall CA-CRC risks are highly variable ranging from 2% to 40% depending on IBD severity, duration and location, with IBD duration being the most significant risk factor associated with CA-CRC development. Recently, studies have identified IBD patients with similar patterns of colonic inflammation, but that differ with respect to CA-CRC development, suggesting a role for additional non-inflammatory risk factors in CA-CRC development. One suggestion is that select IBD patients carry polymorphisms in various low penetrance disease susceptibility genes, which pre-dispose them to CA-CRC development, although these loci have proven difficult to identify in human genome-wide association studies. Mouse models of CA-CRC have provided a viable alternative for the discovery, validation and study of individual genes in CA-CRC pathology. In this review, we summarize the current CA-CRC literature with a strong focus on genetic pre-disposition and highlight an emerging role for mouse models in the search for CA-CRC risk alleles.
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http://dx.doi.org/10.3748/wjg.v21.i41.11688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631970PMC
November 2015

The Nlrp3 Inflammasome Suppresses Colorectal Cancer Metastatic Growth in the Liver by Promoting Natural Killer Cell Tumoricidal Activity.

Immunity 2015 Oct 15;43(4):751-63. Epub 2015 Sep 15.

Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; The Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada; Department of Medicine, McGill University, Montréal, QC H3G 0B1, Canada. Electronic address:

The crosstalk between inflammation and tumorigenesis is now clearly established. However, how inflammation is elicited in the metastatic environment and the corresponding contribution of innate immunity pathways in suppressing tumor growth at secondary sites are poorly understood. Here, we show that mice deficient in Nlrp3 inflammasome components had exacerbated liver colorectal cancer metastatic growth, which was mediated by impaired interleukin-18 (IL-18) signaling. Control of tumor growth was independent of differential cancer cell colonization or proliferation, intestinal microbiota effects, or tumoricidal activity by the adaptive immune system. Instead, the inflammasome-IL-18 pathway impacted maturation of hepatic NK cells, surface expression of the death ligand FasL, and capacity to kill FasL-sensitive tumors. Our results define a regulatory signaling circuit within the innate immune system linking inflammasome activation to effective NK-cell-mediated tumor attack required to suppress colorectal cancer growth in the liver.
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http://dx.doi.org/10.1016/j.immuni.2015.08.013DOI Listing
October 2015

CEACAM1 regulates integrin αIIbβ3-mediated functions in platelets.

Platelets 2016 21;27(2):168-77. Epub 2015 Jul 21.

a Health Innovations Research Institute, RMIT University , Melbourne , Victoria , Australia and.

Previous studies have implicated that the Ig-ITIM superfamily member, CEACAM1 may regulate integrin function. While CEACAM1 has been demonstrated to play a role as an inhibitory co-receptor of ITAM-associated GPVI/FcR γ-chain signaling pathways in platelets, its physiologic role in integrin αIIbβ3-mediated platelet function is unclear. In this study, we investigate the functional importance of Ceacam1 in murine platelets. We show that CEACAM1 is constitutively associated with integrin αIIbβ3 in resting human and mouse platelets as demonstrated by co-immunoprecipitation studies. Using Ceacam1-deficient mice, we show that they have prolonged tail bleeding times and volume of blood lost that is corrected by reconstitution with platelet Ceacam1. Ceacam1(-/-) platelets have moderate integrin αIIbβ3 mediated functional defects with impaired kinetics of platelet spreading on fibrinogen and failure to retract fibrin clots in vitro. This functional integrin αIIbβ3 defect could not be attributed to altered integrin αIIbβ3 expression. Ceacam1(-/-) platelets displayed normal "inside-out" signaling properties as demonstrated by normal agonist-induced binding of soluble (fluorescein isothiocyanate) FITC-fibrinogen, JON/A antibody binding, and increases in cytosolic free calcium levels. This study provides direct evidence that Ceacam1 is essential for normal integrin αIIbβ3-mediated platelet function and that disruption of mouse Ceacam1 induced moderate integrin αIIbβ3-mediated functional defects.
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http://dx.doi.org/10.3109/09537104.2015.1064102DOI Listing
November 2016

CEACAM1 induces B-cell survival and is essential for protective antiviral antibody production.

Nat Commun 2015 Feb 18;6:6217. Epub 2015 Feb 18.

1] Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Hufelandstrasse 55, Essen 45147, Germany [2] Clinic of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, Düsseldorf 40225, Germany.

B cells are essential for antiviral immune defence because they produce neutralizing antibodies, present antigen and maintain the lymphoid architecture. Here we show that intrinsic signalling of CEACAM1 is essential for generating efficient B-cell responses. Although CEACAM1 exerts limited influence on the proliferation of B cells, expression of CEACAM1 induces survival of proliferating B cells via the BTK/Syk/NF-κB-axis. The absence of this signalling cascade in naive Ceacam1(-/-) mice limits the survival of B cells. During systemic infection with cytopathic vesicular stomatitis virus, Ceacam1(-/-) mice can barely induce neutralizing antibody responses and die early after infection. We find, therefore, that CEACAM1 is a crucial regulator of B-cell survival, influencing B-cell numbers and protective antiviral antibody responses.
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http://dx.doi.org/10.1038/ncomms7217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346637PMC
February 2015

Carcinoembryonic Antigen Cell Adhesion Molecule 1 long isoform modulates malignancy of poorly differentiated colon cancer cells.

Gut 2016 May 9;65(5):821-9. Epub 2015 Feb 9.

Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.

Objective: Nearly 20%-29% of patients with colorectal cancer (CRC) succumb to liver or lung metastasis and there is a dire need for novel targets to improve the survival of patients with metastasis. The long isoform of the Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1-L or CC1-L) is a key regulator of immune surveillance in primary CRC, but its role in metastasis remains largely unexplored. We have examined how CC1-L expression impacts on colon cancer liver metastasis.

Design: Murine MC38 transfected with CC1-L were evaluated in vitro for proliferation, migration and invasion, and for in vivo experimental liver metastasis. Using shRNA silencing or pharmacological inhibition, we delineated the role in liver metastasis of Chemokine (C-C motif) Ligand 2 (CCL2) and Signal Transducer and Activator of Transcription 3 (STAT3) downstream of CC1-L. We further assessed the clinical relevance of these findings in a cohort of patients with CRC.

Results: MC38-CC1-L-expressing cells exhibited significantly reduced in vivo liver metastasis and displayed decreased CCL2 chemokine secretion and reduced STAT3 activity. Down-modulation of CCL2 expression and pharmacological inhibition of STAT3 activity in MC38 cells led to reduced cell invasion capacity and decreased liver metastasis. The clinical relevance of our findings is illustrated by the fact that high CC1 expression in patients with CRC combined with some inflammation-regulated and STAT3-regulated genes correlate with improved 10-year survival.

Conclusions: CC1-L regulates inflammation and STAT3 signalling and contributes to the maintenance of a less-invasive CRC metastatic phenotype of poorly differentiated carcinomas.
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http://dx.doi.org/10.1136/gutjnl-2014-308781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826327PMC
May 2016

Inflammation-induced tumorigenesis in mouse colon is caspase-6 independent.

PLoS One 2014 3;9(12):e114270. Epub 2014 Dec 3.

Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada; Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, QC, Canada.

Caspases play an important role in maintaining tissue homeostasis. Active Caspase-6 (Casp6) is considered a novel therapeutic target against Alzheimer disease (AD) since it is present in AD pathological brain lesions, associated with age-dependent cognitive decline, and causes age-dependent cognitive impairment in the mouse brain. However, active Casp6 is highly expressed and activated in normal human colon epithelial cells raising concerns that inhibiting Casp6 in AD may promote colon carcinogenesis. Furthermore, others have reported rare mutations of Casp6 in human colorectal cancers and an effect of Casp6 on apoptosis and metastasis of colon cancer cell lines. Here, we investigated the role of Casp6 in inflammation-associated azoxymethane/dextran sulfate sodium (AOM/DSS) colon cancer in Casp6-overexpressing and -deficient mice. In wild-type mice, AOM/DSS-induced tumors had significantly higher Casp6 mRNA, protein and activity levels compared to normal adjacent colon tissues. Increased human Casp6 or absence of Casp6 expression in mice colon epithelial cells did not change colonic tumor multiplicity, burden or distribution. Nevertheless, the incidence of hyperplasia was slightly reduced in human Casp6-overexpressing colons and increased in Casp6 null colons. Overexpression of Casp6 did not affect the grade of the tumors while all tumors in heterozygous or homozygous Casp6 null colons were high grade compared to only 50% high grade in wild-type mice. Casp6 levels did not alter cellular proliferation and apoptosis. These results suggest that Casp6 is unlikely to be involved in colitis-associated tumors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0114270PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255002PMC
December 2015

CEACAM1 regulates TIM-3-mediated tolerance and exhaustion.

Nature 2015 01 26;517(7534):386-90. Epub 2014 Oct 26.

Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.

T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is an activation-induced inhibitory molecule involved in tolerance and shown to induce T-cell exhaustion in chronic viral infection and cancers. Under some conditions, TIM-3 expression has also been shown to be stimulatory. Considering that TIM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), is being targeted for cancer immunotherapy, it is important to identify the circumstances under which TIM-3 can inhibit and activate T-cell responses. Here we show that TIM-3 is co-expressed and forms a heterodimer with carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on activated T cells and involved in T-cell inhibition. Biochemical, biophysical and X-ray crystallography studies show that the membrane-distal immunoglobulin-variable (IgV)-like amino-terminal domain of each is crucial to these interactions. The presence of CEACAM1 endows TIM-3 with inhibitory function. CEACAM1 facilitates the maturation and cell surface expression of TIM-3 by forming a heterodimeric interaction in cis through the highly related membrane-distal N-terminal domains of each molecule. CEACAM1 and TIM-3 also bind in trans through their N-terminal domains. Both cis and trans interactions between CEACAM1 and TIM-3 determine the tolerance-inducing function of TIM-3. In a mouse adoptive transfer colitis model, CEACAM1-deficient T cells are hyper-inflammatory with reduced cell surface expression of TIM-3 and regulatory cytokines, and this is restored by T-cell-specific CEACAM1 expression. During chronic viral infection and in a tumour environment, CEACAM1 and TIM-3 mark exhausted T cells. Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses with improved elimination of tumours in mouse colorectal cancer models. Thus, CEACAM1 serves as a heterophilic ligand for TIM-3 that is required for its ability to mediate T-cell inhibition, and this interaction has a crucial role in regulating autoimmunity and anti-tumour immunity.
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http://dx.doi.org/10.1038/nature13848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297519PMC
January 2015

p66ShcA promotes breast cancer plasticity by inducing an epithelial-to-mesenchymal transition.

Mol Cell Biol 2014 Oct 28;34(19):3689-701. Epub 2014 Jul 28.

Lady Davis Institute for Medical Research, Montreal, Quebec, Canada Department of Oncology, McGill University, Montreal, Quebec, Canada

Breast cancers are stratified into distinct subtypes, which influence therapeutic responsiveness and patient outcome. Patients with luminal breast cancers are often associated with a better prognosis relative to that with other subtypes. However, subsets of patients with luminal disease remain at increased risk of cancer-related death. A critical process that increases the malignant potential of breast cancers is the epithelial-to-mesenchymal transition (EMT). The p66ShcA adaptor protein stimulates the formation of reactive oxygen species in response to stress stimuli. In this paper, we report a novel role for p66ShcA in inducing an EMT in HER2(+) luminal breast cancers. p66ShcA increases the migratory properties of breast cancer cells and enhances signaling downstream of the Met receptor tyrosine kinase in these tumors. Moreover, Met activation is required for a p66ShcA-induced EMT in luminal breast cancer cells. Finally, elevated p66ShcA levels are associated with the acquisition of an EMT in primary breast cancers spanning all molecular subtypes, including luminal tumors. This is of high clinical relevance, as the luminal and HER2 subtypes together comprise 80% of all newly diagnosed breast cancers. This study identifies p66ShcA as one of the first prognostic biomarkers for the identification of more aggressive tumors with mesenchymal properties, regardless of molecular subtype.
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http://dx.doi.org/10.1128/MCB.00341-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4187732PMC
October 2014

Hepatocyte-specific Ptpn6 deletion promotes hepatic lipid accretion, but reduces NAFLD in diet-induced obesity: potential role of PPARγ.

Hepatology 2014 May 1;59(5):1803-15. Epub 2014 Apr 1.

Department of Medicine, Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Ste-Foy, Québec, Canada.

Unlabelled: Hepatocyte-specific Shp1 knockout mice (Ptpn6(H-KO)) are protected from hepatic insulin resistance evoked by high-fat diet (HFD) feeding for 8 weeks. Unexpectedly, we report herein that Ptpn6(H-KO) mice fed an HFD for up to 16 weeks are still protected from insulin resistance, but are more prone to hepatic steatosis, as compared with their HFD-fed Ptpn6(f/f) counterparts. The livers from HFD-fed Ptpn6(H-KO) mice displayed 1) augmented lipogenesis, marked by increased expression of several hepatic genes involved in fatty acid biosynthesis, 2) elevated postprandial fatty acid uptake, and 3) significantly reduced lipid export with enhanced degradation of apolipoprotein B (ApoB). Despite more extensive hepatic steatosis, the inflammatory profile of the HFD-fed Ptpn6(H-KO) liver was similar (8 weeks) or even improved (16 weeks) as compared to their HFD-fed Ptpn6(f/f) littermates, along with reduced hepatocellular damage as revealed by serum levels of hepatic enzymes. Interestingly, comparative microarray analysis revealed a significant up-regulation of peroxisome proliferator-activated receptor gamma (PPARγ) gene expression, confirmed by quantitative polymerase chain reaction. Elevated PPARγ nuclear activity also was observed and found to be directly regulated by Shp1 in a cell-autonomous manner.

Conclusion: These findings highlight a novel role for hepatocyte Shp1 in the regulation of PPARγ and hepatic lipid metabolism. Shp1 deficiency prevents the development of severe hepatic inflammation and hepatocellular damage in steatotic livers, presenting hepatocyte Shp1 as a potential novel mediator of nonalcoholic fatty liver diseases in obesity.
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http://dx.doi.org/10.1002/hep.26957DOI Listing
May 2014

Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis.

Cancer Metastasis Rev 2013 Dec;32(3-4):643-71

Goodman Cancer Research Centre, McGill University, Montreal, Canada,

The discovery of the carcinoembryonic antigen (CEA) as a tumor marker for colorectal cancer some 50 years ago became the first step in the identification of a much larger family of 12 carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) with surprisingly diverse functions in cell adhesion, in intracellular and intercellular signaling, and during complex biological processes such as cancer progression, inflammation, angiogenesis, and metastasis. The development of proper molecular and biochemical tools and mouse models has enabled bidirectional translation of the CEACAM network biology. Indeed, CEACAM1, CEACAM5, and CEACAM6 are now considered valid clinical biomarkers and promising therapeutic targets in melanoma, lung, colorectal, and pancreatic cancers. These fascinating proteins illustrate how a better understanding of the CEACAM family of cell adhesion molecules reveals their functional link to the underlying disease and lead to new monitoring and targeting opportunities.
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http://dx.doi.org/10.1007/s10555-013-9444-6DOI Listing
December 2013

Ceacam1 deletion causes vascular alterations in large vessels.

Am J Physiol Endocrinol Metab 2013 Aug 25;305(4):E519-29. Epub 2013 Jun 25.

Center for Diabetes and Endocrine Research, College of Medicine and life Sciences, University of Toledo, Health Science Campus, Toledo, Ohio;

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes hepatic insulin clearance and endothelial survival. However, its role in the morphology of macrovessels remains unknown. Mice lacking Ceacam1 (Cc1-/-) exhibit hyperinsulinemia, which causes insulin resistance and fatty liver. With increasing evidence of an association among hyperinsulinemia, fatty liver disease, and atherosclerosis, we investigated whether Cc1-/- exhibited vascular lesions in atherogenic-prone aortae. Histological analysis revealed impaired endothelial integrity with restricted fat deposition and aortic plaque-like lesions in Cc1-/- aortae, likely owing to their limited lipidemia. Immunohistochemical analysis indicated macrophage deposition, and in vitro studies showed increased leukocyte adhesion to aortic wall, mediated in part by elevation in vascular cell adhesion molecule 1 levels. Basal aortic eNOS protein and NO content were reduced, in parallel with reduced Akt/eNOS and Akt/Foxo1 phosphorylation. Ligand-induced vasorelaxation was compromised in aortic rings. Increased NADPH oxidase activity and plasma 8-isoprostane levels revealed oxidative stress and lipid peroxidation in Cc1-/- aortae. siRNA-mediated CEACAM1 knockdown in bovine aortic endothelial cells adversely affected insulin's stimulation of IRS-1/PI 3-kinase/Akt/eNOS activation by increasing IRS-1 binding to SHP2 phosphatase. This demonstrates that CEACAM1 regulates both endothelial cell autonomous and nonautonomous mechanisms involved in vascular morphology and NO production in aortae. Systemic factors such as hyperinsulinemia could contribute to the pathogenesis of these vascular abnormalities. Cc1-/- mice provide a first in vivo demonstration of distinct CEACAM1-dependent hepatic insulin clearance linking hepatic to macrovascular abnormalities.
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http://dx.doi.org/10.1152/ajpendo.00266.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3891225PMC
August 2013

CEACAM1 on activated NK cells inhibits NKG2D-mediated cytolytic function and signaling.

Eur J Immunol 2013 Sep 18;43(9):2473-83. Epub 2013 Jun 18.

Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed on activated natural killer (NK) cells wherein it inhibits lysis of CEACAM1-bearing tumor cell lines. The mechanism for this is unknown. Here, we show that interleukin-2-induced expression of CEACAM1 on both mouse and primary human NK cells impairs the ability of NK gene complex group 2 member D (NKG2D) to stimulate cytolysis of CEACAM1-bearing cells. This process requires the expression of CEACAM1 on the NK cells and on the tumor cells, which is consistent with the involvement of trans-homophilic interactions between CEACAM1. Mechanistically, co-engagement of NKG2D and CEACAM1 results in a biochemical association between these two surface receptors and the recruitment of Src homology phosphatase 1 by CEACAM1 that leads to dephosphorylation of the guanine nucleotide exchange factor Vav1 and blockade of downstream signaling that is associated with the initiation of cytolysis. Thus, CEACAM1 on activated NK cells functions as an inhibitory receptor for NKG2D-mediated cytolysis, which has important implications for understanding the means by which CEACAM1 expression adversely affects tumor immunity.
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http://dx.doi.org/10.1002/eji.201242676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775953PMC
September 2013

Positional mapping and candidate gene analysis of the mouse Ccs3 locus that regulates differential susceptibility to carcinogen-induced colorectal cancer.

PLoS One 2013 14;8(3):e58733. Epub 2013 Mar 14.

Department of Biochemistry, McGill University, Montreal, Quebec, Canada.

The Ccs3 locus on mouse chromosome 3 regulates differential susceptibility of A/J (A, susceptible) and C57BL/6J (B6, resistant) mouse strains to chemically-induced colorectal cancer (CRC). Here, we report the high-resolution positional mapping of the gene underlying the Ccs3 effect. Using phenotype/genotype correlation in a series of 33 AcB/BcA recombinant congenic mouse strains, as well as in groups of backcross populations bearing unique recombinant chromosomes for the interval, and in subcongenic strains, we have delineated the maximum size of the Ccs3 physical interval to a ∼2.15 Mb segment. This interval contains 12 annotated transcripts. Sequencing of positional candidates in A and B6 identified many either low-priority coding changes or non-protein coding variants. We found a unique copy number variant (CNV) in intron 15 of the Nfkb1 gene. The CNV consists of two copies of a 54 bp sequence immediately adjacent to the exon 15 splice site, while only one copy is found in CRC-susceptible A. The Nfkb1 protein (p105/p50) expression is much reduced in A tumors compared to normal A colonic epithelium as analyzed by immunohistochemistry. Studies in primary macrophages from A and B6 mice demonstrate a marked differential activation of the NfκB pathway by lipopolysaccharide (kinetics of stimulation and maximum levels of phosphorylated IκBα), with a more robust activation being associated with resistance to CRC. NfκB has been previously implicated in regulating homeostasis and inflammatory response in the intestinal mucosa. The interval contains another positional candidate Slc39a8 that is differentially expressed in A vs B6 colons, and that has recently been associated in CRC tumor aggressiveness in humans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058733PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597735PMC
September 2013

Stromal CEACAM1 expression regulates colorectal cancer metastasis.

Oncoimmunology 2012 Oct;1(7):1205-1207

Goodman Cancer Research Centre; McGill University; Montreal, QC Canada.

Colorectal cancer metastasis to Ceacam1-/- livers is significantly impaired, compared with wild type livers, due to decreased endothelial cell survival, reduced tumor cell proliferation, diminished immune infiltration and altered chemokine expression. Ceacam1-/- myeloid-derived suppressor cells diminish metastatic burden, as confirmed by bone marrow transplantation and adoptive transfer experiments.
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http://dx.doi.org/10.4161/onci.20735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494647PMC
October 2012

The short isoform of the CEACAM1 receptor in intestinal T cells regulates mucosal immunity and homeostasis via Tfh cell induction.

Immunity 2012 Nov 1;37(5):930-46. Epub 2012 Nov 1.

Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Carcinoembryonic antigen cell adhesion molecule like I (CEACAM1) is expressed on activated T cells and signals through either a long (L) cytoplasmic tail containing immune receptor tyrosine based inhibitory motifs, which provide inhibitory function, or a short (S) cytoplasmic tail with an unknown role. Previous studies on peripheral T cells show that CEACAM1-L isoforms predominate with little to no detectable CEACAM1-S isoforms in mouse and human. We show here that this was not the case in tissue resident T cells of intestines and gut associated lymphoid tissues, which demonstrated predominant expression of CEACAM1-S isoforms relative to CEACAM1-L isoforms in human and mouse. This tissue resident predominance of CEACAM1-S expression was determined by the intestinal environment where it served a stimulatory function leading to the regulation of T cell subsets associated with the generation of secretory IgA immunity, the regulation of mucosal commensalism, and defense of the barrier against enteropathogens.
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http://dx.doi.org/10.1016/j.immuni.2012.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516394PMC
November 2012