Poster Presentation 37th Lorne Cancer Conference 2025

Understanding Clonal Evolution of Pancreatic Cancer Metastasis to Identify Novel Therapeutic Targets (#212)

Deanna C Miller 1 2 , Renina G Navarro 1 , Aji Istadi 1 2 , Silvia Lombardi 1 , Yasir Mahmood 1 , Henry Barraclough-Franks 1 , Emer Cahill 1 , Beatrice M Zema 1 , Diego Chacon-Fajardo 1 2 , Dannielle Upton 1 2 , Esmaeel Azadian 3 , Diana Schuhmacher 1 2 , Johana Luhur 1 2 , Sofia Omari 1 2 , Michael Samuel 4 , Delphine Merino 5 , Shalin Naik 3 , Marina Pajic 1 2
  1. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
  3. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  4. Centre for Cancer Biology, Adelaide, SA, Australia
  5. Olivia Newton-John Cancer Wellness & Research Centre, Heidelberg, VIC, Australia

Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate of only 12% and despite chemotherapy marginally improving outcome for patients, metastatic PDAC is the leading cause of death due to late diagnosis. Therefore, to better treat metastatic PDAC we need a more comprehensive understanding of the mechanisms that govern metastasis. Primary and metastatic tumors are frequently genetically heterogenous. The potentially diverse clonality within tumors can variably affect adaption to the different tumour microenvironments, immune evasion, and therapy resistance. Understanding the clonal composition and their dynamics within primary and secondary tumours may enable more specific targeting of malignant hallmarks and thus prevent further cancer spread.  To study this, we are utilizing cellular barcoding which efficiently labels individual cancer cells to support tracking of metastatic clones after dissemination from the primary tumour. By cellular barcoding of murine PDAC KC (KrasG12D), KPC (KrasG12D, p53R172H) and KPflC (KrasG12D, p53KO) cells, we are tracking in vivo cancer cell metastasis to distant sites (liver and lungs) and have isolated these metastatic cancer clones for sequencing analysis. Within the primary tumour we have established diverse clonal composition and have identified clonal dominance that governs primary tumour growth.  We show dissemination of specific malignant clones to secondary sites, are present within the primary tumour, while also observing further clonal evolution of metastatic clones. We are correlating the transcriptomic profile of malignant clones to the parental cells and are identifying hallmark characteristics of metastatic-capable clones. This study highlights PDAC cell dissemination to secondary sites is driven by malignant hallmarks present within the primary tumour, with new, potential avenues for therapeutic intervention.

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