Poster Presentation 35th Lorne Cancer Conference 2023

Investigating novel matrisomal targets in PC to reduce fibrosis and improve standard-of-care chemotherapy (#373)

Jessie Zhu 1 2 , Cecilia R Chambers 1 2 , Shona Ritchie 1 2 , Morghan Lucas 1 2 , Kendelle J Murphy 1 2 , Diego C Fajardo 1 2 , Benjamin L Parker 3 , Marina Pajic 1 2 , 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

Background: Pancreatic cancer (PC) is a highly fatal cancer with a dismal 5-year survival rate of 11%. 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. It is therefore of significant importance to explore novel therapies to reduce this fibrotic response in PC.

Aim: We aim to assess novel therapeutic strategies for the treatment of PC by investigating previously under-explored, clinically relevant proteins within the tumour microenvironment to improve outcomes for patients diagnosed with this highly aggressive disease. The targets are selected from an atlas of matrisomal proteins derived from the de-cellularised tissues of well-established PC genetically engineered mouse models (GEMMs).

Methods: We have employed a proteomic approach to specifically interrogate the matrisomal changes in commonly used PC GEMMs: 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 (LC-MS/MS). Significantly upregulated targets in PC are currently being validated using Immunohistochemistry, Western Blot, Quantitative Real-Time PCR and via expression analysis in established murine and patient tissue libraries. Anti-fibrotic efficacy and improvement of standard-of-care chemotherapy will then be assessed using 3D in vitro assays and in vivo PC models combined with intravital imaging of treatment response in live PC tissue.

Results: We have generated an atlas of matrisomal proteins comparing two PC GEMMs (KPC and KPflC) to age-matched wildtype. Now, we have selected two candidate targets for further validation and characterisation.

Conclusions: 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.