Quiescence and epithelial-mesenchymal transition in HNSCC
Otolaryngology, Phoniatrics and Audiology
Hematology, Oncology
Final Report Abstract
Even though 90% of cancer patients die from metastatic disease and not the primary tumor, we still know very little about the underlying biology of cancer dissemination. It is generally accepted that metastases arise from tumor cells that leave the primary tumor even before the tumor is clinically diagnosed. These cells can sometimes survive years in secondary organs in a state called dormancy, in which they do not proliferate, yet remain viable and retain the ability to from metastases. As such, it was my aim to further elucidate what constitutes this biology so we might be able to identify treatable dormancy mechanisms in the future. Whether primary tumor microenvironments might influence the fate of disseminating tumor cells (DTC) has never been explored in situ. Previously, a gene signature of dormancy was described in primary breast cancer and was associated with longer metastasis-free periods. Key genes in this signature induce quiescence and are also regulated by hypoxia. Interestingly, a main response of tumor cells to hypoxia is growth arrest, while clinical evidence links hypoxic tumors to increased therapy resistance and a worse outcome. We hypothesized that hypoxic primary tumor microenvironments may spawn a subpopulation of DTCs that, by virtue of becoming dormant, might escape therapies and eventually fuel incurable metastasis. Our results show how hypoxia in primary tumor microenvironments can have long-lasting effects that determine the fate of DTCs after dissemination and in different anatomical locations. In HNSCC tumors, while hypoxia was associated with a dormant or slow-cycling population in primary sites, it was also associated with both dormancy and enhanced aggressiveness of DTCs in the lungs. Our work shows how hypoxia can activate a core dormancy program that can similarly be naturally induced by specific microenvironments, like in the bone marrow. These data also argue that phenotypic heterogeneity in patients may influence response to therapy. This suggests that therapies that target such dormancy mechanisms might be useful to target quiescent tumor cells during minimal residual disease, or in combination with anti-proliferative therapies, to concomitantly target proliferative and quiescent or slow-cycling cells and thus therapeutically address the full spectrum of disseminated disease. The experiences and techniques the applicant learned through this work have been fundamental to the applicant in securing a research grant to start an independent research group after his return to Germany.
Publications
- Hypoxic primary tumor stress microenvironments prime DTCs in lungs for dormancy. ASCB Annual Meeting 2015, Philadelphia, December 12-16, 2015
G. Fluegen
- Phenotypic heterogeneity of disseminated tumor cells is predetermined by primary tumor hypoxic microenvironments. AACR Annual Meeting 2015, Philadelphia, April 18-22, 2015
G. Fluegen
- Phenotypic heterogeneity of disseminated tumor cells is predetermined by primary tumor hypoxic microenvironments. AACR Tumor Metastasis Meeting, Austin, November 30 – December 3, 2015
G. Fluegen
- Phenotypic heterogeneity of disseminated tumour cells is preset by primary tumour hypoxic microenvironments. Nature Cell Biology 19, pages 120–132 (2017)
Georg Fluegen & Alvaro Avivar-Valderas, Ana Rita Nobre, Yarong Wang, Michael R. Padgen, James K. Williams, Vladislav Verkhusha, Julie F. Cheung, Veronica Calvo, David Entenberg, James Castracane, Patricia J. Keely, John S. Condeelis and Julio A. Aguirre-G
(See online at https://doi.org/10.1038/ncb3465)
