Abstract 699: Targeting radiation-driven invasion and metastasis in pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a dismal prognosis. Standard of care includes chemotherapy and radiotherapy (RT) for locally advanced, unresectable disease. Despite radiotherapy being an effective and sometimes curative option for many cancer types, radio-resistance is common, and pre-clinical research in recent years has found that RT can initiate a more aggressive, pro-invasive phenotype in the remaining cells post treatment (1,2). Little is known about the molecular mechanisms responsible for this phenomenon.There is accumulating evidence highlighting a role for the RhoGTPase family in mediating radioresistance and enhanced invasion (2, 3). Understanding their role in PDAC progression may aid the identification of novel chemotherapeutics that could be used alongside RT in the future. We present in vitro data that confirms the pro-migratory effect of RT and importantly indicates a significant increase in metastases formed in a clinically relevant model of PDAC (KPC Pdx1-Cre; KrasG12D/+; Trp53R172H/+) after treatment using a small animal radiation research platform (n=31, p<0.0001). In concurrence with previous literature, we found that PDAC cell motility was dependent on the RhoGTPase pathway, RhoA/ROCK1 (p=0.004). However, post-RT, this dependency was switched to an alternative pathway, CDC42/Rac1/MRCK, indicating a clear change in the balance of RhoGTPase signaling (p=0.002). This switch was confirmed via high-throughput immunofluorescence analysis. To widen this investigation further, we performed an siRNA screen targeting all members of the RhoGTPase family. Preliminary results indicate signaling dependency on Rac2, Rac3 and CDC42 post-RT. Additionally, we have performed RNAseq to investigate pro-invasive gene signatures arising from the acute irradiation of pancreatic cancer cells. This was done at sufficient depth to identify splice variants, with differential transcript expression (DTE) analysis identifying 236 differentially expressed transcripts and the differential transcript usage (DTU) analysis identifying 28 transcripts and 23 genes. Initial functional enrichment analysis found gene signatures relating to cell migration and adhesion, which may be indicative of an invasive phenotype. In conclusion, we present in vitro and in vivo data suggesting RT may promote a more invasive phenotype in PDAC at least in part due to a switch in RhoGTPase signaling. 1. Mueller, A.C., et al., Induction of ADAM10 by Radiation Therapy Drives Fibrosis, Resistance, and Epithelial-to-Mesenchyal Transition in Pancreatic Cancer. Cancer Res, 2021. 81(12): p. 3255-3269. 2. Birch, J.L., et al., A Novel Small-Molecule Inhibitor of MRCK Prevents Radiation-Driven Invasion in Glioblastoma. Cancer Res, 2018. 78(22): p. 6509-6522. Citation Format: Kathy Mclay, Mathias Tesson, Dion Gilmour, Jennifer P. Morton, Joanna L. Birch. Targeting radiation-driven invasion and metastasis in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 699.