Characteristics of ABCC4 and ABCG2 High Expression Subpopulations in CRC-A New Opportunity to Predict Therapy Response

Simple Summary Colorectal cancer (CRC) is one of the most common malignancies worldwide, causing thousands to die each year. Its complex molecular nature leads to significant heterogeneity and variable responses to therapy. ABC proteins, which for many years were regarded as the pillar of the resistance to chemotherapy because they export anticancer drugs from cancer cells, have recently been identified as interesting molecular markers associated with many other physiological functions. We previously reported that during the phenotypic transition, CRC differentially regulates the expression of two transporters, ABCC4 and ABCG2. In cells with a mesenchymal and invasive phenotype, ABCC4 is upregulated, and ABCG2 is downregulated. We have therefore decided to explore this phenomenon by analysing samples from CRC patients with high expression of either ABCC4 or ABCG2 to determine their potential use as markers of therapeutic outcome.Abstract Background: Our previous findings proved that ABCC4 and ABCG2 proteins present much more complex roles in colorectal cancer (CRC) than typically cancer-associated functions as drug exporters. Our objective was to evaluate their predictive/diagnostic potential. Methods: CRC patients' transcriptomic data from the Gene Expression Omnibus database (GSE18105, GSE21510 and GSE41568) were discriminated into two subpopulations presenting either high expression levels of ABCC4 (ABCC4 High) or ABCG2 (ABCG2 High). Subpopulations were analysed using various bioinformatical tools and platforms (KEEG, Gene Ontology, FunRich v3.1.3, TIMER2.0 and STRING 12.0). Results: The analysed subpopulations present different gene expression patterns. The protein-protein interaction network of subpopulation-specific genes revealed the top hub proteins in ABCC4 High: RPS27A, SRSF1, DDX3X, BPTF, RBBP7, POLR1B, HNRNPA2B1, PSMD14, NOP58 and EIF2S3 and in ABCG2 High: MAPK3, HIST2H2BE, LMNA, HIST1H2BD, HIST1H2BK, HIST1H2AC, FYN, TLR4, FLNA and HIST1H2AJ. Additionally, our multi-omics analysis proved that the ABCC4 expression correlates with substantially increased tumour-associated macrophage infiltration and sensitivity to FOLFOX treatment. Conclusions: ABCC4 and ABCG2 may be used to distinguish CRC subpopulations that present different molecular and physiological functions. The ABCC4 High subpopulation demonstrates significant EMT reprogramming, RNA metabolism and high response to DNA damage stimuli. The ABCG2 High subpopulation may resist the anti-EGFR therapy, presenting higher proteolytical activity.

Automated summary

ABCC4 and ABCG2 may have predictive/diagnostic potential in colorectal cancer (CRC) beyond their known functions as drug exporters. By analyzing transcriptomic data of CRC patients, this study identified two subpopulations with high expression levels of ABCC4 or ABCG2, which exhibit distinct gene expression patterns and potential molecular functions.