Biology subjects

Perren, A.

Publications and source records attributed to Perren, A..

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↗

bioRxiv2025

Mapping 3D Heterogeneity of Thyroid Tumors Using Micro-CTbased Radiomics

Tumor heterogeneity plays a central role in treatment resistance, disease progression, and diagnostic uncertainty. However, it may be overlooked by traditional 2D histology. Accurate 3D assessment of tumor microarchitecture is therefore essential for capturing its spatial complexity. Micro-CT, an emerging imaging modality that offers high-resolution 3D virtual histology of soft tissues, provides a promising alternative. Combined with radiomics--a computational approach for interpretable quantification of tissue phenotypes--this technique enables a deeper understanding of tumor biology beyond visual inspection. In this study, we analyzed a large cohort of thyroid tumors (418 patients) using micro-CT imaging of next-generation tissue microarrays, from which we extracted radiomics features. We achieved robust classification of (i) neoplastic versus non-neoplastic thyroid tissues, (ii) papillary versus follicular thyroid carcinoma, and (iii) BRAF V600E mutation status. Feature interpretation using Shapley additive explanations revealed key visual traits driving these classification decisions. Preliminary results also indicated radiomic patterns associated with TERT promoter mutations, suggesting the existence of potential surrogate imaging biomarkers. Overall, micro-CT radiomics shows strong potential as a complementary tool for improving diagnostic and prognostic accuracy in thyroid cancer and offers a novel platform for quantitative pathology into the 3D spatial complexity of neoplastic tissues.

pathology↗

bioRxiv2025

Dual inhibition of lactate transporters MCT1 and MCT4 in pancreatic neuroendocrine tumors targets metabolic heterogeneity and functional redundancy

Our current understanding of the metabolic landscape of pancreatic neuroendocrine tumors (PanNETs) is very limited. Such knowledge could lead the development of novel therapeutic strategies for subgroups of PanNET patients based on the metabolic profile of their tumor. Here, we investigated the expression of lactate transporters MCT1 and MCT4 in two independent PanNET cohorts (n=93; n=70) and analyzed their association with tumor aggressiveness and therapeutic vulnerability in cell lines, spheroids and patient-derived tumoroids of PanNET. Immunohistochemistry revealed four expressor types: MCT1/4-negative, MCT1-positive, MCT4-positive, and MCT1/4-double positive with frequent regional co-expression. Both homogenous and heterogenous expression patterns were observed, indicating metabolic heterogeneity within the latter subset of PanNETs. MCT4 expression correlated with the hypoxia marker CA9, suggesting a hypoxic and acidic tumor microenvironment. Mechanistic studies revealed that MCT1 and MCT4 operate both as lactate efflux systems in PanNET cell lines, providing functional redundancy to their glycolytic roles. Inhibition of lactate efflux in normoxia and hypoxia using the dual MCT1/4 inhibitor syrosingopine significantly impaired lactate secretion, glycolysis, and proliferation across PanNET cell lines and 3D spheroid and patient-derived tumoroid models. In contrast, selective MCT1 or MCT4 inhibitors showed limited efficacy, underscoring the therapeutic need for co-targeting MCT1 and MCT4 due to functional redundancy and heterogenous expression. This work demonstrates MCT1 and MCT4 as metabolic markers and promising therapeutic targets of a subset of PanNETs with clinical features of aggressiveness.

cancer biology↗

bioRxiv2024

Mapping the Molecular Landscape of Thyroid Neoplasms: A Comprehensive Proteomic and Phosphoproteomic Analysis Across Tumors of Follicular Origin

Thyroid nodules are a widespread phenomenon, with follicular cell-derived thyroid tumors being the most prevalent type of endocrine tumor, spanning from benign through low grade malignant to aggressive neoplasms with dismal prognosis. In clinical practice, histopathological criteria are primarily used to determine malignancy and aggressiveness. Therefore, accurate classification may result in surgical procedures for diagnostic reasons, associated with an imbalanced risk/benefit ratio. In recent years, the use of integrated proteomic approaches has proven valuable in expanding the molecular understanding of thyroid neoplasms, with implications in classification, yet remains understudied in divergent thyroid nodules. Here we show the delineation of subtype-specific and malignancy-dependent molecular characteristics through integrative proteomic and phosphoproteomic analysis of 53 human thyroid tissues, encompassing five frequent benign and malignant tumors. We found that the (phospho)-proteomic profiles enable a clear stratification of malignant and benign thyroid tissues. The method also performs well in delineating follicular adenoma (FA) and follicular thyroid carcinoma (FTC) samples. Beside the dysregulation of cell cycle control, apoptosis, and metabolic reprogramming associated with tumor development and malignancy, we further report increased alterations within the well-established oncogenic RAS/BRAF/MAPK and AKT/MTOR signaling pathways, which, contrary to the prevailing paradigm, did not clearly differentiate between FTC and papillary thyroid carcinoma (PTC). In addition, activities of ATM, PLK2-3, and GRK5-6 kinases were predicted to be strongly upregulated in malignant subtypes. Together, this study provides an in-depth insight into molecular changes in different thyroid tumor subtypes. These findings highlight the potential of integrated proteomic approaches to refine our understanding of complex diseases like cancer. As such, they offer a pathway to more precise diagnostic and personalized treatment strategies.

bioinformatics↗

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↗

bioRxiv2020

Epigenetic landscape of pancreatic neuroendocrine tumours reveals distinct cells of origin and means of tumour progression

Recent data suggest that Pancreatic Neuroendocrine Tumours (PanNETs) originate from - or {beta}-cells of the islets of Langerhans. The majority of PanNETs are non-functional and do not express cell-type specific hormones. We examined whether tumour DNA methylation (DNAme) profiling combined with genomic data could identify cell of origin and reveal pathways involved in PanNET progression. We analysed genome-wide DNAme data of 125 PanNETs and sorted - and {beta}-cells. To confirm cell identity, we investigated ARX and PDX1 expression. Based on epigenetic similarities, PanNETs clustered in -like, {beta}-like and intermediate tumours. The epigenetic similarity to -cells progressively decreased in the intermediate tumours, which presented unclear differentiation. Specific transcription factor methylation and expression varied in the respective /{beta}-tumour groups. Depending on DNAme similarity to /{beta}-cells, PanNETs have different mutational spectra, stage of the disease and prognosis, indicating potential means of PanNET progression.

cancer biology↗