Implications of epithelial-mesenchymal plasticity for heterogeneity in colorectal cancer

Abstract

Colorectal cancer (CRC) is a genetically heterogeneous disease that develops and progresses through several distinct pathways characterized by genomic instability. In recent years, it has emerged that inherent plasticity in some populations of CRC cells can contribute to heterogeneity in differentiation state, metastatic potential, therapeutic response, and disease relapse. Such plasticity is thought to arise through interactions between aberrant signaling events, including persistent activation of the APC/β-catenin and KRAS/BRAF/ERK pathways, and the tumor microenvironment. Here, we highlight key concepts and evidence relating to the role of epithelial-mesenchymal plasticity as a driver of CRC progression and stratification of the disease into distinct molecular and clinicopathological subsets.

Keywords: CRC; cancer stem cell; epithelial–mesenchymal transition; serrated; subtypes; tumor progression.

Figure 1

Molecular phenotypes, genetic alterations, and major signaling pathways associated with CRC progression.

Figure 2

Overview of suggested contemporary subtype classification of CRC. Genomic and expression analyses involving large patient cohorts (highlighted in red) combined with existing mutational, clinical, and pathological classifiers (highlighted in blue) have identified several distinct molecularly defined CRC subtypes as indicated by the various studies. Each of these subtypes is driven by unique and/or overlapping signaling pathways (see Figure 1) and exhibit different prognostic and therapeutic responses. A unifying feature is a CRC subtype enriched for genes associated with a poorly differentiated, mesenchymal/invasive phenotype, and often co-enriched for genes indicative of a stem-like state (highlighted in green). A more detailed description of these subtypes and their clinical/therapeutic response can be found within the text (, –17, 41, 74).