Oncogenic roles of CEACAM6 in pancreatic ductal adenocarcinoma.

Abstract

e16744 Background: Carcinoembryonic cell adhesion molecule 6 (CEACAM6) is a cell adhesion receptor of the Ig-superfamily overexpressed in human Pancreatic Ductal Adenocarcinoma (PDA), enriching to the classical activated stroma subtype. CEACAM6 has multifaceted roles in PDA and is a poor prognostic maker (Pandey et al. Sci Rep 2019). We report functional correlative studies across PDA cell lines with high vs KO vs low of CEACAM6 and a PDX model with a therapeutic Mab. Methods: RNA-Seq and microarray expression data of PDA cell lines were downloaded from GEO using R (4.3), normalized and log transformed for analysis: CEACAM6 high vs. low were assessed for differential gene expression changes. Correlation of CEACAM6 levels with genes of interest was studied and compared with the CEACAM6 KO proteomic profile of HPAF-II cells. CEACAM6 WT vs. KO cells were profiled for protein kinase (PK) activity (PAMChip) and gene expression changes by RNA-Seq. NSG-CD34+ mice bearing PDX were evaluated with a humanized anti-CEACAM6 Mab for anti-tumor activity. Results: Differential expression analyses between PDA cell lines with low vs KO vs high CEACAM6 resulted in identifying similar markers changing in quantitative proteomics. KRT20, SYTL1, SKIL, CES1P1, MAN1A1 were down-regulated and HMOX1, CPNE2, ABCD1 were up-regulated in CEACAM6 low or KO cell lines. Specific PKs are upregulated in CEACAM6 KO enriching to the TK family (EPH A1, 3, 4, 8 and HCK), AGC family (e.g. AKT, PKA) and cellular apoptosis (e.g. BAD). RNA-Seq of CEACAM6 WT vs KO cells reconfirmed the up-regulation of MMP1, IL2RG, ATP6V0D2 and low expression of KRT20, AGK and MAN1A1 in CEACAM6 KO cells. Pharmacologic inhibition with a humanized anti-CEACAM6 scFv-Fc (IgG4) in PDA PDX of NSG CD34+ mice demonstrated ~55% tumor growth inhibition (TGI) with enhanced survival of > 14 days vs. control. Conclusions: CEACAM6 is expressed exclusively in primates and humans and plays multifaceted oncogenic roles in PDA pathogenesis. When CEACAM6 is disrupted, ECM proteins are altered reshaping the stroma, activating specific PKs and priming apoptosis. The therapeutic anti-CEACAM6 Mab possesses anti-tumor activity with associated cellular apoptosis and increased mouse survival.