Role of DPPA3 in hypoxia and tumour dormancy in cancer
[eng] Colorectal cancer (CRC) is a leading cause of death worldwide and tumour recurrence is a frequent complication that arises from minimal residual disease and shows up after a period of clinical dormancy. Slow-cycling cancer cells (SCCC), also called dormant tumour cells, have been shown to be r...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/147963 |
| Acceso en línea: | https://hdl.handle.net/2445/147963 http://hdl.handle.net/10803/668282 |
| Access Level: | acceso abierto |
| Palabra clave: | Càncer Anoxèmia Proteïnes Cancer Anoxemia Proteins |
| Sumario: | [eng] Colorectal cancer (CRC) is a leading cause of death worldwide and tumour recurrence is a frequent complication that arises from minimal residual disease and shows up after a period of clinical dormancy. Slow-cycling cancer cells (SCCC), also called dormant tumour cells, have been shown to be responsible for tumour relapse due to their enhanced chemoresistance and tumour-initiating capacity. Although the recent efforts invested in the characterization of SCCC, our knowledge about the mechanisms underlying tumour dormancy is still limited. Thanks to the identification, isolation and molecular characterization of SCCC in our laboratory, we identified a set of pluripotency factors overexpressed in these cells, among them, DPPA3. In the present work, we characterized for the first time the role of DPPA3 in the biology of tumour dormancy. DPPA3 is an epigenetic factor essential for early development and predominantly expressed in embryonic stem cells (ESCs) and primordial germ cells (PGCs). Its function is linked to the protection of imprinted loci and transposable elements in the genome from active demethylation processes. Besides maintaining a repressive state in specific loci, DPPA3 is also related to the passive demethylation phenomenon observed in cells at these developmental stages. By the use of genetically modified CRC cell lines we revealed a central role of DPPA3 promoting cell dormancy. We unmasked its capacity controlling the response to hypoxia as a key mechanism to govern cancer cell phenotype. DPPA3 overexpression stimulated the hypoxia program by increasing hypoxia inducible factor 1 subunit alpha (HIF1α) protein levels and enhancing its transcriptional activity. Besides, overexpression of DPPA3 alone was sufficient to induce a G2/M-phase cell cycle arrest and reduce tumour growth. Interestingly, DPPA3 enhanced chemoresistance to CRC standard of care adjuvant chemotherapies. Finally, a cohort of CRC patients with high expression of DPPA3 or enriched in a DPPA3 signature showed a shorter disease-free survival. Altogether, these results pioneer the importance of DPPA3 in cancer and contribute to the understanding of tumour malignancy associated to hypoxia, chemoresistance and dormancy, the unravelling of which is of foremost importance to progress in the battle against the disease |
|---|