Cellular Plasticity And Heterogeneity: Implications In Tumor Cell Invasion And Metastasis
The existence of heterogenous subpopulations of cells in cancer has been shown to arise via natural evolution or through movement between cellular states collectively known as “cellular plasticity.” This heterogeneity and plasticity are critical drivers of phenotypic diversity culminating in many facets of disease progression, such as metastasis. While the existence of heterogeneity and cellular plasticity are well accepted, the molecular underpinnings and functional outcomes, such as metastasis, of these populations remains limited. Here, we first investigated a form of cellular plasticity known as epithelial-to-mesenchymal transition (EMT) and dissect the molecular mechanisms of a recently described partial EMT (P-EMT) state operating in vivo in a mouse model of pancreatic ductal adenocarcinoma (PDAC), whereby tumor cells lose their epithelial state through a post-translational mechanism. This is distinct from complete EMT (C-EMT), which achieves the transition transcriptionally, through regulation of a complex hierarchy of EMT transcription factors (EMT-TFs). We report that prolonged calcium signaling in carcinoma cells induces a P-EMT phenotype characterized by the internalization of membranous E-cadherin (ECAD) and an increase in cellular migration and invasion. These effects can be recapitulated by signaling through Gaq-associated G-protein coupled receptors (GPCRs) and are mediated through the downstream activation of calmodulin. These results implicate calcium signaling as a potent driver of epithelial-mesenchymal plasticity in cancer cells that may be important for the metastatic cascade. We subsequently investigated other potential mechanisms of metastasis that may occur as tumors evolve de novo. Specifically, we analyzed paired primary tumors and metastases using a multi-fluorescent lineage-labeled mouse model of PDAC. Genomic and transcriptomic analysis revealed, for the first time, an association between metastatic burden and amplification of MYC. Mechanistically, we found that MYC promotes metastasis by recruiting tumor associated macrophages (TAMs), leading to greater bloodstream intravasation. Consistent with these findings, metastatic progression in human PDAC was associated with activation of MYC signaling pathways and enrichment for MYC amplifications specifically in metastatic patients. These results implicate MYC activity as a major determinant of metastatic burden in advanced PDAC. Thus, using novel mouse models of PDAC, we identified key pathways, genetic and non-genetic, that regulate cellular plasticity and lead to increased invasion and metastatic spread. The identification of these pathways and regulators represent an avenue for combating the most lethal aspects of tumor progression, metastasis and therapy resistance.
Sandra W. Ryeom