Poster Presentation 36th Lorne Cancer Conference 2024

Investigating a novel matrisomal target in PC to reduce fibrosis and improve standard-of-care chemotherapy (#244)

Jessie Zhu 1 2 , Cecilia R Chambers 1 2 , Shona Ritchie 1 2 , Morghan Lucas 1 2 , Daniel A Reed 1 2 , Alice Tran 1 2 , Kendelle J Murphy 1 2 , Diego Chacon-Fajardo 1 2 , Benjamin L Parker 3 , Marina Pajic 1 2 , Owen Sansom 4 , Jennifer P Morton 4 , Thomas R Cox 1 2 , Brooke A Pereira 1 2 , David Herrmann 1 2 , Paul Timpson 1 2
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW , Australia
  3. Department of Anatomy & Physiology, The University of Melbourne, Melbourne, Victoria, Australia
  4. Cancer Research UK , Beatson Institute, Glasglow, G61 1BD, United Kingdom

Pancreatic cancer (PC) is a highly fatal cancer with a dismal 5-year survival rate of 11% (1). A key driver of this poor prognosis is the highly fibrotic response of the PC tumour microenvironment which forms a stiff, impenetrable barrier that shields tumours from therapeutic intervention whilst promoting metastatic progression (2). It is therefore of significant importance to explore novel therapies to reduce this fibrotic response in PC. Here, we aim to investigate previously under-explored, clinically relevant matrisomal proteins and target them in conjunction with standard-of-care chemotherapy as a novel therapeutic strategy to improve treatment outcomes for PC patients.

We have employed a proteomic approach to specifically interrogate the matrisomal changes in well-established genetically engineered PC mouse models: the KPflC (Pdx1-Cre; KrasG12D/+; p53fl/+) and KPC (Pdx1-Cre; KrasG12D/+; p53R172H/+) mouse models. Pancreatic tissues from early, mid and late-stage disease were isolated from KPflC, KPC and age-matched wildtype mice and de-cellularised, prior to quantification of protein abundance via liquid chromatography tandem mass spectrometry.

Here, we identified the enzyme, PLOD1, to be significantly enriched in PC compared to normal pancreas, which was validated via expression analysis in murine and patient tissue libraries. We have generated PLOD1 knockdown cancer cells and matched cancer-associated fibroblasts to further assess whether PLOD1 inhibition (i) has anti-fibrotic efficacy and (ii) can improve chemotherapy performance using 3D in vitro assays (cell-derived matrices, organotypic assay) and in vivo PC models.

The fibrotic tumour microenvironment in PC is a known driver of disease progression and drug resistance. Proteomic characterisation has helped us map the PC matrisome over disease progression and will assist in the assessment of novel anti-fibrotic therapies in combination with standard-of-care chemotherapy in PC.

  1. Siegel, R.L., Miller, K. D., Wagle, N.K & Jemal, A. Cancer Statistics, 2023. CA. Cancer J. Clin. 73, 17-48 (2023).
  2. Jacobetz, M. A. et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62, 112–120 (2013).