Personalised targeting of the substance P/NK1R axis in pancreatic ductal adenocarcinoma

Ittermann, Iris (2025): Personalised targeting of the substance P/NK1R axis in pancreatic ductal adenocarcinoma: a molecular and sex-specific stratification approach. Dissertation, LMU München: Faculty of Medicine

Abstract

Background: The Neurokinin-1 receptor (NK1R) represents a promising target for pancreatic ductal adenocarcinoma (PDAC) therapy. Yet its complex ex-pression patterns and functional implications remain incompletely understood. Methods: A comprehensive multi-method approach was employed to investi-gate NK1R biology in PDAC, including transcriptomic analysis of multiple da-tasets, RT-qPCR analysis for isoform-specific expression profiling, Western blot analysis, functional assays with NK1R antagonist aprepitant (AP), as well as its ligand Substance P (SP), and bioinformatic analysis of sex-specific ex-pression patterns. Results: Differential expression of NK1R isoforms, encoded by TACR1, was demonstrated across PDAC cell lines with predominant expression of the trun-cated variant (NK1R-tr). Lower NK1R gene expression correlated with ad-vanced tumour stage and poorer prognosis, while inversely correlating with EMT marker ZEB1. Treatment with the NK1R antagonist aprepitant demon-strated significant antiproliferative effects in PDAC cells, particularly in cancer stem cell-like populations, with the highest sensitivity in cell lines expressing elevated NK1R-tr. Mechanistically, aprepitant induced cell cycle arrest rather than apoptosis, modulating ERK1/2 signalling. Bioinformatic analyses revealed distinct transcriptomic signatures associated with high versus low TACR1 ex-pression, with TACR1-high samples exhibiting enrichment of immune-related pathways. Unexpectedly, TACR1 expression demonstrated strong sex-specific patterns, with substantially higher expression in female PDAC samples com-pared to male samples, accompanied by differential XIST expression, suggest-ing potential X-chromosome-linked regulatory mechanisms. Conclusion: The SP/NK1R system exhibits complex expression patterns in PDAC with significant therapeutic and prognostic implications. NK1R inhibition represents a promising approach for targeted therapy, particularly in TACR1-high tumours. The pronounced sex-specific differences in TACR1 expression highlight potential for personalised therapeutic strategies and suggest im-portant biological differences in PDAC between males and females.

• Item Type: Theses (Dissertation, LMU Munich)
• Subjects: 600 Technology, Medicine; 600 Technology, Medicine > 610 Medical sciences and medicine
• Faculties: Faculty of Medicine
• Language: English
• Date of oral examination: 23. September 2025
• 1. Referee: Bazhin, Alexandr
• Signature of the printed copy: 0700/UMD 22463