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INTRODUCTION
Epithelial-mesenchymal transition in tumor progression and metastasis
Metastasis represents a critical step in tumor progression and accounts for more than 90% of cancer-induced
[1]
mortality . Despite the tremendous efforts made by the scientific community over recent decades, the
cellular and molecular events that control tumor cell plasticity remain incompletely elucidated.

It has been shown that the epithelial-mesenchymal transition (EMT) is essential in embryonic development
and in tumor metastasis and is among the mechanisms deemed critical in tumor cell plasticity. EMT
consists of a fine-tuned phenotypic switch, characterized by the loss of apical-basal polarity and cellular
[2,3]
adhesion in epithelial cells . Cells undergoing transition gradually express mesenchymal features, such as
enhanced cytoskeletal rearrangement and extracellular matrix (ECM) degradation, both essential for cell
motility [Figure 1].

EMT is not a unidirectional mechanism. The transition is a fine-tuned, reversible mechanism that allows
cells to switch between epithelial and mesenchymal phenotypes while manifesting all intermediate
[2,4]
phenotypic shades . The reverse mechanism, known as mesenchymal-epithelial transition (MET), allows
reversion to the differentiated phenotype. Reversion is important for the potential formation of metastases
that can occur as tumor cells attempt to relocate to distant organs to develop secondary tumors. Due to
its transience, its presence in multiple-states, and its reversible nature, EMT is technically challenging to
[4]
observe throughout tumor progression in vivo . Nevertheless, it is clearly demonstrated that transitioned
[5-7]
cells harbor higher invasive capacities . In the early steps of metastasis, epithelial cancer cells must acquire
[4,8]
the ability to separate from the primary tumor . Such departure may occur as single cells or as clusters of
[9]
cells, and always requires the loss or the alteration of cell-to-cell and cell-to-matrix interactions .
In the current model, EMT-positive tumor cells displaying newly-acquired mesenchymal features invade
their surrounding environment and intravasate into the circulatory system. Cancer dissemination in this
model results from ECM degradation and increased motility [10,11] . It was also proposed that the survival
of circulating tumor cells (CTCs) in the blood stream was enhanced by the phenotypic plasticity observed
during EMT [12-15] . Following dissemination into the circulation, CTCs extravasate and colonize distant
organs to ultimately form secondary tumors. The ultimate metastatic colonization occurs through the re-
epithelialization of cells by MET and is followed either by a proliferative cycle with subsequent drug resistant
secondary tumor growth, or by a dormant cycle with latency of tumor relapse. Although there are countless
reports demonstrating that genetic mutations are recurrently arising in many types of primary tumors, the
attempts to identify genes that are recurrently mutated in the genomes of metastasized cells have consistently
failed until now. Such observations are advocating for the prime role of cell plasticity in tumor cells
dissemination. However, the experimental evidences of the casual function of EMT in metastasis formation
remain to be clearly demonstrated. The explicit role of EMT in tumor progression remains actively debated
but its implication in the increased resistance seen in both conventional and targeted antitumor therapies is
currently well-accepted by the scientific community [12,14,16-21] . I seems now clear that the controversy around
the role of EMT in tumor dissemination might be attributed to its non-linear and multi-modal nature and
that these many intermediate stages of EMT may occupy different regions on such a multi-dimensional
[22]
landscape . Many groups are still investigating the role of EMT in tumor cells dissemination, and at
this point, multiple hypotheses are still emerging to underline the mechanisms involved in the successful
[23]
dissemination of tumor cells beyond the current EMT/MET view .
Heterogeneous nuclear ribonucleoprotein E1
Heterogeneous nuclear ribonucleoproteins (hnRNPs) encompass a large family of RNA-binding proteins
(RBPs) that contribute to multiple aspects of nucleic acid metabolism. These aspects include alternative
splicing, mRNA stabilization, transcriptional control, and translation regulation. The coding sequences