Abstract A060: Copper homeostasis and stress adaptation in pancreatic ductal adenocarcinoma
Rejina Shrestha, Ahmad Hegazi, Deep Patel, Shi-He Liu, Charles Thodeti, Andrea Kalinoski, Kuo-Hui SuAbstract
Background:
Pancreatic ductal adenocarcinoma (PDAC) mitochondria rely on copper as an essential enzymatic cofactor, and elevated tumor copper content has been associated with poor patient outcomes. Excess copper is known to destabilize iron–sulfur (Fe-S) cluster proteins required for mitochondrial electron transport, creating a potential conflict between copper-dependent metabolism and Fe-S cofactor integrity. The mechanisms by which PDAC cells tolerate elevated copper while preserving mitochondrial function are still not fully understood.
Methods:
Using PDAC cell line (MIA PaCa-2, PANC-1, and PDCL5) models with genetic or pharmacologic modulation of heat shock factor 1 (HSF1), a transcription factor regulating proteostasis, we examined the relationship between HSF1 activity, copper handling, and mitochondrial function under copper stress. Copper stress was induced by copper ionophore (Elesclomol-copper and Disulfiram-copper). Oxygen consumption rate was measured using Seahorse XF analysis. Cell viability was measured by CCK-8 assay kit, copper content was measured by fluorescent probe Coppersensor-1, protein expression of copper transporters was assessed by immunoblotting following copper ionophore exposure in the presence or absence of HSF1 inhibition.
Results:
Copper exposure altered HSF1 activity in PDAC cells, and pharmacologic or genetic suppression of HSF1 increased sensitivity to copper-induced toxicity. HSF1 overexpression reversed the copper ionophore-induced reduction in ATP7B expression in PDAC cells. Knockdown of HSF1 further decreased the excess copper-reduced oxygen consumption rate in PDAC cells.
Conclusion:
These observations suggest that HSF1 may contribute to a cellular adaptation that limits copper-associated mitochondrial stress in PDAC.
Citation Format:
Rejina Shrestha, Ahmad Hegazi, Deep Patel, Shi-He Liu, Charles Thodeti, Andrea Kalinoski, Kuo-Hui Su. Copper homeostasis and stress adaptation in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A060.