EMT Subtype Influences Epithelial Plasticity and Mode of Cell Migration

Abstract

Epithelial-mesenchymal transition (EMT) is strongly implicated in tumor cell invasion and metastasis. EMT is thought to be regulated primarily at the transcriptional level through the repressive activity of EMT transcription factors. However, these classical mechanisms have been parsed out almost exclusively in vitro, leaving questions about the programs driving EMT in physiological contexts. Here, using a lineage-labeled mouse model of pancreatic ductal adenocarcinoma to study EMT in vivo, we found that most tumors lose their epithelial phenotype through an alternative program involving protein internalization rather than transcriptional repression, resulting in a "partial EMT" phenotype. Carcinoma cells utilizing this program migrate as clusters, contrasting with the single-cell migration pattern associated with traditionally defined EMT mechanisms. Moreover, many breast and colorectal cancer cell lines utilize this alternative program to undergo EMT. Collectively, these results suggest that carcinoma cells have different ways of losing their epithelial program, resulting in distinct modes of invasion and dissemination.

Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state

“…Previous studies also employed established cultured cancer cell lines and experimental murine tumors, but not human clinical materials. 23,25,26 Herein, using various PDXs and their corresponding tumor cell organoids, we obtained previously unrecognized findings that the hybrid E/M state in human CRC cell clusters does indeed drive their metastatic seeding (Fig. 5e).…”

“…17,18,53 The partial EMT program also reportedly plays roles in regulating collective invasion and the dissemination of various carcinoma cell clusters. 23,25,26 Collectively, these series of observations indicate important associations between the E/M state in the tumor cell cluster and the early steps of the invasionmetastasis cascade, although the functional roles of E/M plasticity in the tumor cell cluster in metastatic colonization have yet to be fully investigated. Previous studies also employed established cultured cancer cell lines and experimental murine tumors, but not human clinical materials.…”

“…Collectively, these findings support the notion that the formation of tumor cell clusters, maintaining their cell‐to‐cell adhesions, contributes significantly to the seeding of metastasis. Moreover, partial EMT contributes to the formation of tumor cell clusters and thereby allows their collective invasion and dissemination …”

“…Moreover, partial EMT contributes to the formation of tumor cell clusters and thereby allows their collective invasion and dissemination. 9,[23][24][25][26][27] However, roles of EMT in the tumor cell clusters involved in metastasis formation remain unknown. Studies focusing on collective cancer cell migration have also depended mostly on specific cultured cell lines and experimental murine tumors, while investigations using human clinical materials are rare.…”

Differential RNA editing between epithelial and mesenchymal tumors impacts mRNA abundance in immune response pathways

“…EMT plasticity is thought to underlie cell dissemination and metastatic formation in many cancer types 18 . Supported by studies on primary tumors and various model systems, features of EMT have been associated with metastasis 16,18,63,64 . For instance, higher expression of mesenchymal markers, with preserved epithelial markers in the absence of nearly all canonical EMT transcription factors, was detected in cells located at the leading edge of primary human HNSC tumors 64 .…”