Abstract
We investigated biomarker CEACAM6, a highly abundant cell surface adhesion receptor that modulates the extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDA). The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) RNA-Seq data from PDA patients were analyzed for CEACAM6 expression and evaluated for overall survival, association, enrichment and correlations. A CRISPR/Cas9 Knockout (KO) of CEACAM6 in PDA cell line for quantitative proteomics, mitochondrial bioenergetics and tumor growth in mice were conducted. We found CEACAM6 is over-expressed in primary and metastatic basal and classical PDA subtypes. Highest levels are in classical activated stroma subtype. CEACAM6 over-expression is universally a poor prognostic marker in KRAS mutant and wild type PDA. High CEACAM6 expression is associated with low cytolytic T-cell activity in both basal and classical PDA subtypes and correlates with low levels of T-REG markers. In HPAF-II cells knockout of CEACAM6 alters ECM-cell adhesion, catabolism, immune environment, transmembrane transport and autophagy. CEACAM6 loss increases mitochondrial basal and maximal respiratory capacity. HPAF-II CEACAM6−/− cells are growth suppressed by >65% vs. wild type in mice bearing tumors. CEACAM6, a key regulator affects several hallmarks of PDA including the fibrotic reaction, immune regulation, energy metabolism and is a novel therapeutic target in PDA.
Highlights
Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) is a cell adhesion receptor of the immunoglobulin-like superfamily (3 Ig-like domains), known to interact with other CEACAMs1–4 through cis and trans forming dimers via their N-terminal IgG V-domain[1]
Recent studies[11,12,13], have classified pancreatic ductal adenocarcinoma (PDA) into subtypes based on gene expression profiling and CEACAM6 is one of the most significant genes changing in these studies
We demonstrated that CEACAM6 levels are significantly low in normal pancreas and normal other organs compared to either from primary and/or at metastatic PDA
Summary
Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) is a cell adhesion receptor of the immunoglobulin-like superfamily (3 Ig-like domains), known to interact with other CEACAMs1–4 through cis and trans forming dimers via their N-terminal IgG V-domain[1]. CEACAM6 over-expression leads to anoikis, a regulated cell death mechanism induced by inadequate or inappropriate cell-matrix interactions via an ECM interaction, promoting invasion[8]. In PDA, CEACAM6 over-expression plays a role in reshaping the ECM-cell adhesion processes that promote anoikis resistance[10]. Recent analyses of PDA datasets using bioinformatics methods have made it possible to classify tumor and stromal cell types using molecular stratification based on distinct features[11,12,13]. These studies have provided multiple subtypes with different classifications but with overlapping molecular-cellular characteristics for PDA. We conducted a detailed analysis by expression profiling of CEACAM6 in several PDA types, tumor-stromal cells, and PDA cell lines to elucidate expression across PDA tumor types, effect on survival, association with the stroma, immune environment, relevance to KRAS mutations, proteomics and tumor growth potential of CECACAM6 knockout in PDA cells
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