Data from: Long-term severe hypoxia adaptation induces non-canonical EMT and a novel Wilms Tumor 1 (WT1) isoform

The majority of cancer deaths are caused by solid tumors, where the four
most prevalent cancers (breast, lung, colorectal and prostate) account for
more than 60% of all cases (1). Tumor cell heterogeneity driven by
variable cancer microenvironments, such as hypoxia, is a key determinant
of therapeutic outcome. We developed a novel culture protocol, termed the
Long-Term Hypoxia (LTHY) time course, to recapitulate the gradual
development of severe hypoxia seen in vivo to mimic conditions observed in
primary tumors. Cells subjected to LTHY underwent a non-canonical
epithelial to mesenchymal transition (EMT) based on miRNA and mRNA
signatures as well as displayed EMT-like morphological changes.
Concomitant to this, we report production of a novel truncated isoform of
WT1 transcription factor (tWt1), a non-canonical EMT driver, with
expression driven by a yet undescribed intronic promoter through
hypoxia-responsive elements (HREs). We further demonstrated that tWt1
initiates translation from an intron-derived start codon, retains proper
subcellular localization and DNA binding. A similar tWt1 is also expressed
in LTHY-cultured human cancer cell lines as well as primary cancers and
predicts long-term patient survival. Our study not only demonstrates the
importance of culture conditions that better mimic those observed in
primary cancers, especially with regards to hypoxia, but also identifies a
novel isoform of WT1 which correlates with poor long-term survival in
ovarian cancer.