Unraveling the mechanisms behind testicular germ cell tumour using an organoid model

Background

Testicular cancer is the most common form of cancer in young men in the Western world¹. Approximately 95% of malignant tumours in the testis are testicular germ cell tumours (TGCTs), which are the focus of this project. There has been an increasing incidence rate globally in the last decades, with Norway and Denmark being among the countries with highest incidence².

The causes of the increase in incidence and regional differences are unknown. TGCT originates in the foetal life, and environmental exposure, lifestyle factors and prenatal characteristics play a role in TGCT^3,4. Importantly, genetic effects account for 25% of TGCT susceptibility⁶. There is a fourfold increased risk if the father has had TGCT and an eightfold increased risk if brothers have developed TGCT. Genome wide association studies (GWAS) have revealed 78 single nucleotide polymorphisms (SNPs) associated with the risk of developing TGCT (termed susceptibility genes).

Since there have not been appropriate model systems to study TGCT development, the function and significance of these gene variants has not been validated. Up until now, our understanding of TGCT has primarily been based on epidemiologic and genetic studies. Recent advancements in three-dimensional culture technology include organoids, which are a 3D representation of an organ or tissue grown outside the body. These can be grown from human biopsies, pluripotent stem cells or from induced pluripotent stem cells as well as cancer cells⁷. This technology has been successful in the field of cancer research (Figure 1), but no studies of TGCT organoids have been published as far as we know.

Figure 1. Organoids cultured from small intestine and analysed by Airy Scan microscopy⁵

Aims and Methods

The Master project will consist of establishing testicular organoids from induced pluripotent stem cells (iPSCs) initially, and from TGCT biopsies. Gene-editing of susceptibility genes will be performed to recreate the SNPs identified by GWAS. The student will learn cell culture, organoid technology, imaging techniques as well as CRISPR-Cas9 technology.

Contact persons

Viola Lobert viola.lobert@oslomet.no will be the main supervisor (OsloMet). She is located at the Department for Mechanical, Electronic and Chemical Engineering at OsloMet and has supervised several Master students from IBV in the past. She has expertise in organoid technology and CRISPR. Co-supervisor: Trine B. Haugen (OsloMet, TGCT expertise). Internal supervisor: P?l Falnes (pal.falnes@ibv.uio.no IBV, UiO).

References

1. Znaor A, Skakkebaek NE, Rajpert-De Meyts E, et al. Testicular cancer incidence predictions in Europe 2010-2035: A rising burden despite population ageing. Int J Cancer. Aug 1 2020;147(3):820-828.
2. Gurney JK, Florio AA, Znaor A, et al. International Trends in the Incidence of Testicular Cancer: Lessons from 35 Years and 41 Countries. Eur Urol. Nov 2019;76(5):615-623.
3. Aschim EL, Grotmol T, Tretli S, Haugen TB. Is there an association between maternal weight and the risk of testicular cancer? An epidemiologic study of Norwegian data with emphasis on World War II. Int J Cancer. Aug 20 2005;116(2):327-330.
4. Cargnelutti F, Di Nisio A, Pallotti F, et al. Effects of endocrine disruptors on fetal testis development, male puberty, and transition age. Endocrine. May 2021;72(2):358-374.
5. Lobert VH. Organoids: the good, the bad and the beautiful. Medisinbloggen 2020; https://www.med.uio.no/om/aktuelt/blogg/2020/organoids-the-good-the-bad-and-the-beautiful-.html. Accessed 28.06, 2024.
6. Czene K, Lichtenstein P, Hemminki K. Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish Family-Cancer Database. Int J Cancer. May 10 2002;99(2):260-266.
7. Xu H, Lyu X, Yi M, Zhao W, Song Y, Wu K. Organoid technology and applications in cancer research. J Hematol Oncol. Sep 15 2018;11(1):116.