Poster Presentation 35th Lorne Cancer Conference 2023

A multi-omics approach to dissect the impact of the cancer secretome during pancreatic cancer progression. (#313)

Shona Ritchie 1 2 , Cecilia Chambers 1 2 , Ruth Pidsley 1 2 , Kendelle Murphy 1 2 , Victoria Lee 1 2 , Luke O'Regan 1 2 , Anna Howell 1 2 , Astrid Magenau 1 2 , Julia Yin 1 2 , Sai Vara Prasad Chitti 3 , Shalima Nair 1 2 , Jens Altvater 4 , Ben Crossett 4 , Alex Ward 5 , Thomas Grewal 6 , Australian Pancreatic Genome Initiative 1 , Australian Pancreatic Matrix Atlas 1 , Owen Sansom 7 8 , Jen Morton 7 8 , Lisa Horvarth 1 2 9 , Ben Parker 10 , Suresh Mathivanan 3 , Sue Clark 1 2 , David Herrmann 1 2 , Thomas Cox 1 2 , Marina Pajic 1 2 , Brooke Pereira 1 2 , Paul Timpson 1 2
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
  3. Biochemistry and Genetics, La Trobe University, Melbourne, VIC, Australia
  4. Schools of Life and Environmental Sciences, the Charles Perkin Centre, the University of Sydney, Sydney, NSw, Australia
  5. Victor Chang Cardiac Research Institute, Sydney, NSW , Australia
  6. Sydney Medical School, University of Sydney, Sydney, NSW, Australia
  7. Cancer Research UK Beatson Institute, Glasgow, Scotland, UK
  8. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland
  9. Chris O’Brien Lifehouse, Sydney, NSW, Australia
  10. School of Biomedical Sciences, University of Melbourne, Melbourne, VIC, Australia

Pancreatic cancer is a lethal malignancy (~9% 5-year survival), and is projected to become the second-leading cause of cancer death by 2030[1]. Most patients present with aggressive, metastatic disease where curative surgery is not possible. Current chemotherapies provide little benefit; thus, novel therapies are urgently required. The pancreas is a highly secretory organ, in which 74% of all human proteins are expressed[2], of which can become severely perturbed during cancer. Using a multi-omics screening pipeline, we have identified novel proteins that are abundantly secreted by highly metastatic pancreatic cancer cells. We will investigate if pharmacological and genetic inhibition of these proteins can reduce tumour burden and metastasis ± standard-of-care chemotherapies, Gemcitabine/Abraxane, as well as immunotherapies, anti-PD1/anti-CTLA4. 

We isolated pancreatic cancer cells  from the highly metastatic KPC (Pdx1-Cre; LSL-K-rasG12D/+; LSL-p53R172H/+) mouse, and the poorly-metastatic KPflC (Pdx1-Cre; LSL-K-rasG12D/+; LSL-p53fl/+)[ mouse[3], followed by RNA-Sequencing analysis to profile aberrant transcriptional differences. Label-Free Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) was also used to assess the secreted proteome of the cancer cells. 19 significant common differentially expressed genes (DEGs) and differentially abundant (DA) proteins were revealed when the two -omics results were integrated. Of these, four proteins are associated with significantly poor patient prognosis when interrogated in the PCAWG cohorts, of which will be discussed during presentation. These proteins were functionally validated by western blotting, qPCR and ELISA as being overexpressed in KPC cancer cells. IHC staining in KPC and KPflC tumours show increased expression of aberrant proteins in the KPC model. Therefore, this robust assessment across multiple platforms identifies significant aberrantly secreted proteins in metastatic pancreatic cancer cells, of which several are associated with two common features of PDAC pathological mechanisms: extracellular matrix remodelling and reprogrammed metabolism. Ongoing work involves in vivo inhibition by repurposing FDA-approved drugs ± chemotherapies to investigate the impact of the cancer secretome on tumour progression in PDAC.

References

  1. Siegel, R.L. et al. CA Cancer J Clin, 2020. 70(1): p. 7-30.
  2. Uhlén, M., et al. Science, 2015. 347(6220): p. 1260419.
  3. Morton, J.P., et al. Proc Natl Acad Sci U S A, 2010.