Tumorbiological behaviour and metastatic spread in lower gastrointestinal (GI) tract malignancies – correlation with gene expression patterns

Introduction Epithelial-mesenchymal transition (EMT), angiogenesis, cell adhesion and extracellular matrix (ECM) interaction are essential for colorectal cancer (CRC) metastasis. Low grade mucinous neoplasia of the appendix (LAMN) and its advanced state low grade pseudomyxoma peritonei (lgPMP) show local aggressiveness with very limited metastatic potential as opposed to CRC. To better understand processes that foster or impede metastatic spread, we compared LAMN, lgPMP and CRC with respect to their molecular profile.

Material & Methods LAMN, lgPMP and (mucinous) CRC cases were subjected to transcriptomic analysis utilizing Poly(A) RNA sequencing. Successfully sequenced cases (LAMN n=10, 77%, lgPMP n=13, 100% and CRC n=8, 100%) were investigated using bioinformatic and statistical tests including differential expression analysis (DEseq2), hierarchical clustering, principal component analysis (PCA) and gene set enrichment analysis.

Results We identified a gene signature of 28 genes distinguishing LAMN, lgPMP and CRC. Ontology analyses revealed that multiple pathways including EMT, ECM interaction and angiogenesis are differentially regulated. Fifty-three significantly differentially regulated gene sets were identified between lgPMP and CRC followed by CRC vs. LAMN (n=21) and lgPMP vs. LAMN (n=16). Unexpectedly, a substantial enrichment of the EMT gene set was observed in lgPMP compared to LAMN (FDR=0.011) and CRC (FDR=0.004). Typical EMT markers were significantly upregulated (Vimentin, TWIST1, N-Cadherin) or downregulated (E-Cadherin) in lgPMP. However, MMP1 and MMP3 levels, associated with EMT and metastasis, were considerably higher in CRC.

Conclusion We show that different tumorbiological behaviours and metastatic patterns of lower GI tract malignancies are reflected in different gene expression profiles. We found a strong activation of EMT in locally aggressive, non-metastasizing lgPMP vs. CRC. In this respect, although EMT is considered a key step in hematogenous spread, successful EMT does not necessarily lead to hematogenous dissemination. This emphasizes the need for further pathway analyses and forms the basis for mechanistic and therapy-targeting research.

Publication History

Article published online:
28 August 2023