Advanced colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) are highly aggressive and heterogeneous diseases which urgently require the development of more effective treatment strategies. Novel membrane proteins overexpressed in CRC and PDAC, could have the potential to represent attractive molecular targets for development of antibody-based targeted therapeutics. Candidate molecular targets were identified by Bioinformatic, transcriptomic analysis of publicly available colon cancer gene microarray datasets. Lists were generated of genes overexpressed in colon adenoma and adenocarcinoma vs. normal colon with predicted membrane localisation. Seven novel candidate targets (LY6G6F, IL1RAPL1, IL20RA, BACE2, NTM, LRRC8E and EPHX4) were selected for protein validation in normal and colon cancer tissue sections. Two targets, LY6G6F and IL1RAPL1, both previously unexploited in cancer were found to be minimally expressed in normal colon and show strong expression in CRC, warranting further investigation and functional characterisation. LY6G6F is a type 1 transmembrane protein, first identified as a novel platelet plasma membrane protein, linking to downstream signal transduction pathways upon platelet activation. However, a ligand for LY6G6F remains unknown. LY6G6F was found in this study to be significantly overexpressed in colon adenocarcinoma, PDAC and gastric adenocarcinoma, with minimal expression observed in normal proliferating cells and tissues. IHC analysis of a 57 PDAC patient cohort revealed that 78.9% showed strong LY6G6F immunoreactivity; using Kaplan-Meier survival analysis, a clear trend was observed between high LY6G6F expression and decreased survival in this cohort, however this failed to reach significance (p-value: 0.182). High LY6G6F mRNA expression is significantly associated with decreased survival in gastric cancer using KM plotter survival analysis (logrank-p: 4.3e-05). Transient protein knockdown of LY6G6F in the colon cancer cell line HCT116 and the PDAC cell line MIA PaCa-2 significantly inhibits proliferation, 2D colony formation, migration and invasion of these cells in vitro. These effects were found to be potentially mediated by a decrease in FAK activation and an increase in apoptosis. Thus, taken together these results implicate LY6G6F in the proliferation and survival of these cancers. IL1RAPL1 is a type 1 transmembrane protein highly expressed in brain neurons, with a reported role in synapse formation. Deletions and mutations in IL1RAPL1 have been associated with X-linked intellectual disability. IL1RAPL1 was found to be significantly overexpressed in all CRC subtypes vs. normal colon and showed limited expression in a range of other normal tissues and highly proliferating cells. Furthermore, IL1RAPL1 expression was associated with oesophageal squamous cell carcinoma (OSCC), with significant overexpression compared to normal oesophagus and also other oesophageal cancer subtypes. The potential functional role of IL1RAPL1 in the colon cancer cell phenotype could not be determined. LY6G6F and IL1RAPL1 both represent novel candidate proteins overexpressed in these cancer types with restricted expression in normal tissues and should be investigated further as potential molecular targets for antibody-based therapeutic targeting.