Poster Presentation 37th Lorne Cancer Conference 2025

Establishment of a novel syngeneic mouse model to study the role of sphingolipid metabolism in prostate cancer (#221)

An Dieu Trang Nguyen 1 2 , Chui Yan Mah 1 2 , Madison Helm 1 2 , Adrienne R Hanson 3 , Ian G Mills 4 , Luke A Selth 3 , Lisa G Horvath 5 6 7 , Lisa M Butler 1 2
  1. South Australian Immunogenomics Cancer Institute and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, South Australia, Australia
  2. Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
  3. Flinders Health and Medical Research Institute and Freemasons Centre for Male Health and Wellbeing, Flinders University, Bedford Park, South Australia, Australia
  4. Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
  5. Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
  6. Chris O'Brien Lifehouse, Sydney, New South Wales, Australia
  7. University of Sydney, Sydney, New South Wales, Australia

Background and Aims: Aberrant sphingolipid metabolism, as indicated by elevated levels of circulating ceramide, is associated with poor patient prognosis across the natural history of prostate cancer (PC), spanning localised PC, metastatic hormone-sensitive, and metastatic castrate-resistant PC. This clinical observation raises the biological question of the functional significance of these prognostic ceramides in relation to broader sphingolipid metabolism in the tumour. To study the impact of circulating ceramides on tumour progression over time, we will employ an immunocompetent, syngeneic PC mouse model with the characteristics of primary, high-risk localised PC, coupled with dietary interventions to recapitulate the elevated circulating ceramide environment. As the first step, we aimed to establish the mouse model, using a mouse PC cell line termed ‘DVL3’ that is derived from prostate tumour tissue of a Pten-/-/trp53-/- genetically-modified mouse model of PC 

Methods:  DVL3 cells, transduced with a luciferase expression vector that enables non-invasive bioluminescence imaging of the tumours (DVL3-luc), were either surgically transplanted directly into the prostate gland (orthotopic) or injected into the flank (subcutaneous) of male C57BL/6 mice. Our aim was to determine the optimal inoculation route of DVL3-luc cells by assessing tumour growth and metastasis. 

Results: Both subcutaneous and orthotopic implantations of DVL3-luc in immunocompetent mice were able to develop into tumours within four weeks, and tumours gradually grew up to eight weeks. Some evidence of metastasis was detected for the orthotopic model. Notably, immunohistochemistry showed that tumours from both models actively retained intact androgen receptor (AR) expression, the main oncogenic driver of PC.

Conclusions and Significance: This is the first study that successfully established both subcutaneous and orthotopic models of DVL3 in immunocompetent mice using DVL3 cells transduced with luciferase vector. DVL3 mouse PC model is a very promising model for future work in PC research, given that it is one of a few immunocompetent, syngeneic models in PC research with fast tumour growth rate and primary PC characteristics of intact AR expression. We will leverage this model in our subsequent studies to study the biological significance of the prognostic ceramides in PC.