Quiescence and epithelial-mesenchymal transition in HNSCC

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The majority of head and neck squamous cell carcinoma (HNSCC) patients will die of metastases that develop from disseminated tumor cells (DTCs), months, years or even decades after treatment and removal of the primary tumor. Within years after primary tumor resection, approximately 50% of patients develop distant organ or loco regional recurrences, even if the surgical margins were free of cancer. This latency suggests that DTCs survive in a dormant, non-proliferative state at the site of future metastases. This state is known as quiescence, an uncommitted and reversible growth arrest that can be brought about by different, mostly stress associated, signals. The factors leading to induction and upkeep of this quiescence, and thus to the formation of metastases later on, have not been toughly investigated, yet. Most HNSCC patients suffer from lung and lymph node metastases, while bone metastases are very rare. Yet in >30% of HNSCC patients, DTCs are detectable in the bone marrow. In order to reach these distant sites in the first place, these epithelial cells have to acquire mobility. They achieve this through an epithelial mesenchymal transition (EMT), a highly conserved embryonic cellular program which allows epithelial cells to acquire mesenchymal traits like mobility and invasiveness. At the same time, cells undergo a cell-cycle arrest, limiting their proliferation.The stress activated protein kinase p38 cells was recently shown to regulate the induction of a program of prolonged quiescence in HNSCC in vivo. In a different study, the pharmacological inhibition of p38 led to a reduced gene expression of the EMT transcription factors (TF) Snail, Slug and ZEB. This research demonstrates a possible connection between the induction of dormancy and regulation of transcription factors crucial in EMT.The aim of this research is to identify the mechanisms regulating entry and exit of quiescence in DTCs and elucidate the possible connection with factors leading to or maintaining an EMT in HNSCC. I will test in an already established HNSCC mouse model, whether proposed dormancy regulators are linked to quiescence in bone marrow DTCs vs. growth of DTCs in lungs and lymphnodes. I will further test if the upregulation of the cytokine TGFbeta2 plays a part in HNSCC quiescence induction, since it has been identified as part of a dormancy gene signature in human breast cancer and is required to maintain bone marrow stem cells in quiescence. As TGFbeta signaling is also a known inducer of EMT, I will elucidate if there is crosstalk between known EMT and quiescence inducing transcription factors.It is of utmost importance to understand the quiescence of these DTCs. This way we may one day be able to devise a treatment that (I) either keeps the DTCs in permanent quiescence, thus keeping the patient in chronic yet asymptomatic minimal residual disease, or (II) selectively targets the survival mechanisms deployed by these quiescent DTCs to eradicate them.