Biology subjects

Wiedenmann, B.

Publications and source records attributed to Wiedenmann, B..

6 recordsLinked to original sources

bioRxiv2025

Aberrant brain-type neuronal programs in large-cell pancreatic neuroendocrine carcinoma

High-grade pancreatic neuroendocrine carcinoma (panNEC) is a rare, aggressive cancer with limited tissue availability. Single-nucleus transcriptomics of five large-cell panNECs revealed two clinically relevant neuroendocrine cell states: one highly proliferative with an aberrant brain-specific neuronal differentiation program and another stress-responsive state enriched for heat stress, hypoxia, and glycolysis. Our findings suggest potentially new therapeutic vulnerabilities, highlighting the need to evaluate the efficacy of combination therapies.

cancer biology↗

bioRxiv2022

Patient-derived tumoroids of advanced high-grade neuroendocrine neoplasms mimic patient chemotherapy responses and guide the design of personalized combination therapies

There are no therapeutic predictive biomarkers or representative preclinical models for high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), a highly aggressive, fatal, and heterogeneous epithelial malignancy. We established patient-derived (PD) tumoroids from biobanked tissue samples of advanced high-grade GEP-NEN patients and applied this model for targeted rapid ex vivo pharmacotyping, next-generation sequencing, and perturbational profiling. We used tissue-matched PD tumoroids to profile individual patients, compared ex vivo drug response to patients clinical response to chemotherapy, and investigated treatment-induced adaptive stress responses. PD tumoroids recapitulated biological key features of high-grade GEP-NEN and mimicked clinical response to cisplatin and temozolomide ex vivo. When we investigated treatment-induced adaptive stress responses in PD tumoroids in silico, we discovered and functionally validated Lysine demethylase 5A and interferon-beta, which act synergistically in combination with cisplatin. Since ex vivo drug response in PD tumoroids matched clinical patient responses to standard-of-care chemotherapeutics for GEP-NEN, our rapid and functional precision oncology approach could expand personalized therapeutic options for patients with advanced high-grade GEP-NEN.

cancer biology↗

bioRxiv2022

Secretin receptor as a target in gastrointestinal cancer: expression analysis and ligand development

Secretin was originally discovered as a gastrointestinal peptide that stimulates fluid secretion from pancreas and liver and delays gastric emptying. In disease, secretin receptor (SCTR) was found to occur as a splice variant in gastrinoma and pancreatic adenocarcinoma. Overexpression of SCTR has been described for gastrinomas, carcinoid tumors of the lung and cholangiocarcinoma. SCTR therefore remains a candidate target for molecular tumor imaging as well as for peptide receptor radioligand therapy (PRRT) in a number of oncological indications. The aim of this study was to characterize SCTR expression in esophageal and pancreatic cancer. 65 of 70 PDAC tissues stained strongly positive for SCTR in immunohistochemistry, as were most of 151 esophageal cancer samples, with minor influence of grading in both entities. In addition, the aim of this study was to further delineate residues in human secretin that are critical for binding to and activation of the human SCTR. For a potential development of short and metabolically stable analogs for clinical use, it was intended to probe the peptide for its capacity to incorporate deletions and substitutions without losing its affinity to SCTR. A library of 146 secretin variants containing single amino acid substitutions as well as truncations on either end was tested using {beta}-arrestin2-GFP translocation and fluorescent ligand internalization high-content analysis and cAMP assays run in agonist and antagonist mode as well as a radioligand binding. The main structural determinants of SCTR binding and activation were localized to the N-terminus, with His1, Asp3 being among the most sensitive positions, followed by Phe6, Thr7 and Leu10. Aminoterminal truncation caused a rapid decline in receptor activity and most of these variants proved to be partial agonists showing antagonistic properties. In this study, the most potent antagonist showed an IC50 of 309 {+/-} 74 nM in the {beta}-arrestin2-GFP translocation assay on human SCTR while remaining a weak partial agonist. Future studies will have to demonstrate the utility of further enhanced secretin analogues as tracers for in vivo imaging and therapy.

cancer biology↗

bioRxiv2021

Spatial organisation and homeostasis of epithelial lineages at the gastroesophageal junction is regulated by the divergent Wnt mucosal microenvironment

The gastroesophageal junction (GEJ), where squamous and columnar epithelia meet, is a hotspot for Barretts metaplasia development, dysbiosis and carcinogenesis. However, the mechanisms regulating GEJ homeostasis remain unclear. Here, by employing organoids, bulk and single-cell transcriptomics, single-molecule RNA in situ hybridisations and lineage tracing, we identified the spatial organisation of the epithelial, stromal compartment and the regulators that maintain the normal GEJ homeostasis. During development, common KRT8 progenitors generate committed unilineage p63/KRT5-squamous and KRT8-columnar stem cells responsible for the regeneration of postnatal esophagus and gastric epithelium that meet at GEJ. A unique spatial distribution of Wnt regulators in the underlying stromal compartment of these stem cells creates diverging Wnt microenvironments at GEJ and supports their differential regeneration. Further, we show that these tissue-resident stem cells do not possess the plasticity to transdifferentiate to the other lineage with the altered Wnt signals. Our study provides invaluable insights into the fundamental process of GEJ homeostasis and is crucial for understanding disease development.

developmental biology↗

bioRxiv2021

SPECT/CT imaging, biodistribution and radiation dosimetry of a 177Lu-DOTA-integrin αvβ6 cystine knot peptide in a pancreatic cancer xenograft model

IntroductionPancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant neoplasms, as many cases go undetected until they reach an advanced stage. Integrin v{beta}6 is a cell surface receptor overexpressed in PDAC. Consequently, it may serve as a target for the development of probes for imaging diagnosis and radioligand therapy. Engineered cystine knottin peptides specific for integrin v{beta}6 have recently been developed showing high affinity and stability. This study aimed to evaluate an integrin v{beta}6-specific knottin molecular probe containing the therapeutic radionuclide 177Lu for targeting of PDAC. MethodsThe expression of integrin v{beta}6 in PDAC cell lines BxPC3 and Capan2 was analyzed using RT-qPCR and immunofluorescence. In vitro competition and saturation radioligand binding assays were performed to calculate the binding affinity of the DOTA-coupled tracer loaded with and without lutetium to BxPC3 and Capan2 cell lines. To evaluate tracer accumulation in the tumor and organs, SPECT/CT, biodistribution and dosimetry projections were carried out using a Capan2 xenograft tumor mouse model. ResultsRT-qPCR and immunofluorescence results showed high expression of integrin v{beta}6 in BxPC3 and Capan2 cells. A competition binding assay revealed high affinity of the tracer with IC50 values of 1.69 nM and 9.46 nM for BxPC3 and Capan2, respectively. SPECT/CT and biodistribution analysis of the conjugate 177Lu-DOTA-integrin v{beta}6 knottin demonstrated accumulation in Capan2 xenograft tumors (3.13 {+/-} 0.63 %IA/g at day 1 post injection) with kidney uptake at 19.2 {+/-} 2.5 %IA/g, declining much more rapidly than in tumors. Conclusion177Lu-DOTA-integrin v{beta}6 knottin was found to be a high-affinity tracer for PDAC tumors with considerable tumor accumulation and moderate, rapidly declining kidney uptake. These promising results warrant a preclinical treatment study to establish therapeutic efficacy.

cancer biology↗

bioRxiv2019

AGTR1 is overexpressed in neuroendocrine neoplasms, regulates secretion and may serve as a target for molecular imaging and therapy

Peptide receptor targeting has proven to be a pivotal tool for diagnostic imaging and radioligand therapy of neuroendocrine neoplasms (NENs), which frequently express somatostatin receptors (SSTRs) on their cell surface. However, up to 30 % of NEN patients do not benefit from SSTR-based approaches, others develop a resistance. Consequently, alternative cell surface targets need to be identified. In this study, cell-based dynamic mass redistribution and calcium mobilization screening using a 998-compound library identified and confirmed angiotensin II (ATII) as a strong activator of cellular signaling in NEN cells. Expression analyses of the ATII receptor type 1 (AGTR1) revealed an upregulation of both mRNA levels (RT-qPCR) and radioligand binding (autoradiography) in pancreatic (n=42) and small-intestinal (n=71) NEN tissues compared to healthy controls (n=25). The two NEN cell lines BON (pancreas) and H727 (lung) with elevated AGTR1 expression exhibited concentration-dependent calcium mobilization and chromogranin A secretion upon stimulation with ATII, blocked by AGTR1 antagonism and Gq inhibition. To assess the applicability of AGTR1 for optical in vivo imaging, the receptor ligand saralasin was coupled to the near-infrared dye indotricarbocyanine and tested for its biodistribution in a NMRI Foxn1nu/Foxn1nu mouse model bearing AGTR1-positive BON and negative QGP-1 xenograft tumors. Near-infrared fluorescent imaging showed a significantly higher uptake in BON tumors 3-6 hours after injection. This successful targeting in an NEN model establishes AGTR1 as an interesting target in this tumor entity, paving the way for the development of translational chelator-based probes for diagnostic PET imaging and peptide receptor radioligand therapy.

cancer biology↗