Epithelial‐mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients

Abstract

Epithelial-mesenchymal transition (EMT) is a reversible and dynamic process hypothesized to be co-opted by carcinoma during invasion and metastasis. Yet, there is still no quantitative measure to assess the interplay between EMT and cancer progression. Here, we derived a method for universal EMT scoring from cancer-specific transcriptomic EMT signatures of ovarian, breast, bladder, lung, colorectal and gastric cancers. We show that EMT scoring exhibits good correlation with previously published, cancer-specific EMT signatures. This universal and quantitative EMT scoring was used to establish an EMT spectrum across various cancers, with good correlation noted between cell lines and tumours. We show correlations between EMT and poorer disease-free survival in ovarian and colorectal, but not breast, carcinomas, despite previous notions. Importantly, we found distinct responses between epithelial- and mesenchymal-like ovarian cancers to therapeutic regimes administered with or without paclitaxelin vivo and demonstrated that mesenchymal-like tumours do not always show resistance to chemotherapy. EMT scoring is thus a promising, versatile tool for the objective and systematic investigation of EMT roles and dynamics in cancer progression, treatment response and survival.

Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome

“…Given the association between EMT and immune evasion and poor outcome and metastasis (23,24), we hypothesized that suppression of the immunoproteasome in mesenchymal cells is a mechanism of escape from immune surveillance. IHC analysis of PSMB8 and known EMT markers on tissue microarrays also supported a significant association between low immunoproteasome expression and a mesenchymal or intermediate phenotype, which may suggest that lower immunoproteasome expression occurs before cells become locked in a mesenchymal state (25)(26)(27). A better prognosis in NSCLC patients was significantly associated with increased immunoproteasome expression, potentially attributable to IFNγ secreted by T lymphocytes infiltrating the tumor.…”

EGF augments TGFβ-induced epithelial–mesenchymal transition by promoting SHP2 binding to GAB1

“…EMT is accompanied by shifts in transcription factor expression, cytoskeletal arrangement, RNA splicing, and cell signaling (Thiery, 2003;Massagué, 2008;Kalluri and Weinberg, 2009). Although EMT is required for normal development and wound healing, aberrant EMT has also been linked to metastasis (Chaffer and Weinberg, 2011;Rhim et al, 2012) and tumor resistance to therapy (Tan et al, 2014). In lung and pancreatic cancer cells, sensitivity to therapeutic agents can be increased by promoting an epithelial phenotype (Witta et al, 2006;Arumugam et al, 2009;Buonato and Lazzara, 2014).…”

Distinct Effects of Adipose-Derived Stem Cells and Adipocytes on Normal and Cancer Cell Hierarchy

“…ASC coculture increased the number of CD49f We recently reported that the EMT-associated gene SLUG increases MCF10A stemness (16). As EMT is linked to various aspects of cancer progression including drug resistance (28,29), we then examined whether ASCs can further alter the phenotype of MCF10A-SLUG cells. ASC CM increased the size of MCF10A-SLUG-derived mammospheres with corresponding elevation in number of cells with luminal progenitor phenotype (Fig.…”