Background: Cancer is the second leading cause of death worldwide and was responsible for 8.9 million deaths in 2016. Cancer arises from the transformation of normal cells into tumour cells in a multistage process that generally progresses from a pre-cancerous lesion to a malignant tumour. These changes are the result of the interplay between a person's genetic factors, age and environmental factors (carcinogens). Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Global changes in the epigenetic landscape is a hallmark of cancer.
Sarcomas are rare soft tissue cancers comprising of 1% of newly diagnosed cancers. Liposarcoma (LPS) is the second most common sarcoma, consisting of over 50 different malignancies of mesenchymal origin (1). The diagnosis and treatment of soft tissue sarcomas are difficult. Surgical resection followed by chemotherapy/radiation is the standard treatment for localized disease. However, many LPS progress to advanced disease that is either unresectable, metastatic or both. The mortality rate is very high for advanced LPS (2, 3). To establish knowledge about the drivers that cause global changes in the epigenetic landscape in the cancer it is essential to improve the treatment options for these patients. Lack of information is a major challenge for diagnosis and patient centered treatment of LPS.
Somatic copy-number alterations are among the most common genomic alterations observed in cancer and affects the classical hallmarks of cancer such as proliferation and evasion of cell death (4; 5). Excessive copy-number amplification are characteristic of well-differentiated and dedifferentiated LPS (34, 35, 36, 37). The vulnerability characteristics for the amplifications remain largely unknown, although high accumulation of oncogenes is observed. Knowledge of the mechanisms of genomic amplification in LPS can pave the way to refine molecular diagnostic and prognostic patient markers.
Project:
This master project will be a part of a project working on the characterization of genomic amplifications in liposarcoma. The master student will work together with a researcher (Marie Rogne) and use various cancer cell line models and healthy mesenchymal stem cells to unravel the molecular mechanisms of cancer genomic amplification. We will perform genome-wide epigenetic analysis of LPS cell lines (+/-) auxin induced knockdown (AID) of important epigenetic regulators to decipher the molecular dynamics of the identified complexes.
Methods: The student will learn mammalian tissue- and mesenchymal stem cell- culture and differentiation, various molecular and immunological methods such as transfection, CRISPR, AID-knockdown of proteins, ImmunoFISH, western blotting, chromatin immunoprecipitation, immunofluorescence, confocal imaging, RNA extraction, RT-PCR and bioinformatic interpretation of data.
We have access to the NorSarc sarcoma database and collaborate with and bioinformatician Sigve Nakken, Dr Leonardo Meza-Zepeda and professors Eivind Hovig and Jørgen Wesche, at the Radium hospital in this project.
During this master project you will work in our group at IMB. To learn more about our lab see our recent movie.
You will learn to make good scientific presentations, have good creative discussions and will be able to attend national scientific retreats as a part of a young active ambitious research group.
We can also train you in scientific writing (https://www.med.uio.no/cancell/english/news-and-events/news/2020/crispr-cas9-article-from-eskeland-lab-in-aftenpost.html)
Reference list:
American Cancer Society (ACS), January 2018. https://www.cancer.org/soft-tissue-sarcoma
(1) Gimble et al, 2007. Circ Res. 100(9):1249-60; (2) Heitzer E., et al., 2016. Mol Oncol, 10(3), 494-502; (3) Zack T.I., et al., 2013. Nature Genetics, 45, 1134–1140; (4) Heitzer E., et al., 2016. Mol Oncol, 10(3), 494-502; (5) Hanahan D., et al., 2011. Cell, 144(5), 646-674; (6) Dahlback H.S., et al., 2009. Genes Chromosomes Cancer, 48, 908–924; (7) Sanborn J.Z., et al., 2013. Cancer Res, 73, 6036–6045; (8) Garsed D.W., et al., 2009. BioEssays, 31, 1191–1200; (9) Garsed D.W., et al., 2014. Cancer Cell, 26(5), 653-667.
Other relevant literature:
AID: Yesbolatova et al., 2019, Methods, 164–165, 73-80.
3D chromatin structure: van Steensel and Furlong, 2019. Nature Reviews Molecular Cell Biology, pp 1-11.