Universität zu Köln

Tishina, Sofya ORCID: 0000-0002-8232-496X (2025). Oncogenic KRAS-induces necroptotic priming of pancreatic neoplasia. Thesis Abstract, Universität zu Köln.

PDF (Thesis Abstract) 20230913_Thesis_EandG_Abstract_Sofya_Tishina.pdf Download (100kB)

Abstract

Caspase 8 regulates normal tissue homeostasis by executing apoptosis and protecting from necroptosis. Several aggressive cancers express high levels of caspase 8, yet its function in neoplastic disease remains poorly explored. Here, we find that oncogenic KRAS-driven neoplastic transformation induces upregulation of Ripk3 and MLKL – proteins which form part of the necroptosis machinery, but necroptosis itself is kept in check by co-upregulation of caspase 8. Mice in which caspase 8 is deleted in the pancreas manifested a drastic decrease in precursor lesion formation in a KRASG12D-driven model of pancreatic cancer. Co- deletion of the essential necroptosis effector MLKL reversed the protective effects of caspase 8 ablation and promoted metastasis. Mechanistically, oncogenic KRAS induced a STING-dependent type I interferon response, resulting in upregulation of components of the necroptosis pathway. High caspase 8 expression in precursor lesions was a result of co-selection to prevent necroptosis. Therefore, triggering necroptosis by blocking caspase 8 activity was therapeutically highly efficacious in models of genetically engineered PDAC in vivo. These results assign a tumour- protective function to caspase 8 in PDAC and show that overcoming caspase 8 activity has therapeutic benefit in this incurable malignancy. Thus, in this study, we have discovered an upregulation of necroptosis machinery, which we refer to as "necroptotic priming," in the context of mutated KRAS expression. This discovery indicates that upon oncogenic KRAS-driven necroptotic priming, cancer cells and not healthy cells become more susceptible to necroptosis induction. Given that KRAS is one of the most commonly occurring oncogenes in human cancers, we have uncovered a potential target for therapeutic intervention. Importantly, we have successfully demonstrated this vulnerability in pancreatic neoplasia, a cancer type that has historically posed significant treatment challenges.

Item Type:	Thesis Abstract
Creators:	Creators Email ORCID ORCID Put Code Tishina, Sofya sofilp94@gmail.com https://orcid.org/0000-0002-8232-496X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-722135
Date:	2025
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases
Subjects:	Natural sciences and mathematics
Uncontrolled Keywords:	Keywords Language cancer English cell death English pancreas English necroptosis English KRAS English
Date of oral exam:	19 January 2024
Referee:	Name Academic Title von Karstedt, Silvia Prof. Dr. Walczak, Henning Prof. Dr. Silke, John Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/72213