Role of TGFβ-induced hyaluronan-CD44 signaling in cancer progression

Hyaluronan, a prevalent glycosaminoglycan of the extracellular space often accumulates in pathological conditions, such as chronic inflammation, infection, and cancer. Hyaluronan synthase HAS2 has been responsible for the synthesis and deposition of hyaluronan in a variety of tumors. We have shown that HAS2 was required for efficient transforming growth factor β (TGFβ)-induced epithelial to mesenchymal transition (EMT), a developmental program which is commandeered by cancer cells to increase their migratory and invasive capacity. In study I, our findings show that long non-coding RNA Has2as has a key role in TGFβ- and Has2-induced breast cancer EMT, migration and acquisition of stemness. Hyaluronan conveys its signaling properties via binding to its cell surface receptor CD44, a well-established stem cell marker in a plethora of tumors. CD44 exerts its signaling properties by interacting with components of the actin cytoskeleton machinery, and by acting as a co-receptor for other receptor tyrosine or threonine kinases impacting their signaling properties. Furthermore, CD44 is subjected to proteolytic cleavage, which eventually liberates the cytoplasmic tail (CD44-ICD). CD44-ICD translocates to the nucleus and alters gene expression. In study II, our findings support that TRAF4/6 mediates pro-tumorigenic effects of CD44, and suggests that inhibitors of CD44 signaling via TRAF4/6 and RAC1 may be beneficial in the treatment of tumor patients. Glioblastoma (GBM) multiforme remains one of the most aggressive and lethal types of brain tumors worldwide with a poor prognosis. In study III, we have initiated studies to elucidate the CD44-dependent molecular mechanisms in GBM progression by knocking out (KO) CD44 by employing CRISPR/Cas9 gene editing in glioma U251MG cells. Aberrant hyaluronan levels are also found during infectious diseases. In study V, we show that in a cohort study of dengue patients, high levels of circulating Dengue Nonstructural Protein 1 (NS1) correlate with high levels of serum hyaluronan. Moreover, we propose that hyaluronan can serve as a prognostic marker for the onset of warning signs during the course of dengue viral infection. Mechanistically, NS1 treatment-induced hyaluronan production contributing to increased vascular permeability. In study IV, we have identified a bifurcating loop during TGFβ signaling, whereby transcriptional induction of NUAK1 serves as a negative checkpoint and NUAK2 induction positively contributes to signaling and terminal differentiation responses to TGFβ activity. In summary, the current thesis provides mechanistic insights into the roles of TGFβ-induced hyaluronan-CD44 interactions in cancer progression.