Biology subjects

Hanninen, S.

Publications and source records attributed to Hanninen, S..

3 recordsLinked to original sources

bioRxiv2026

Spatial transcriptomics reveals interferon pathway enrichment in early relapsing serous carcinoma

High-grade serous carcinoma (HGSC) is characterized by extensive inter and intra-patient heterogeneity, complicating the identification of reliable prognostic biomarkers and the prediction of treatment response. In clinical practice, the origin of diagnostic biopsies varies, from tubo-ovarian (adnexal) tissue to omental or peritoneal metastatic foci. Whether the different sites provide similar information for molecular characterization or treatment decisions remains unclear. Studies comparing site-specific molecular details and the spatial relationship of HGSC tissue from patients with different treatment outcomes could provide answers to the open questions. Here, we used spatial transcriptomics to profile matched treatment-naive adnexal and omental tumor samples from nine HGSC patients stratified by platinum-free interval (PFI). Pathway enrichment analysis revealed several differences between short and medium- and long PFI tumors, however most of these differences were site-agnostic. Most strikingly, tumor epithelium from short PFI patients showed an inflammatory phenotype driven by increased interferon response signaling, carried by effector interferon-stimulated gene expression at both tumor sites. Further, medium- and long PFI tumors were enriched for proliferative and cell cycle regulatory programs. Differential gene expression and copy-number analyses identified three genes, complement gene C3, and interferon-related genes IFI27 and BST2, consistently associated with short PFI across adnexal and omental sites. These were validated at the tissue level using RNA in-situ hybridization. A case study of copy-number-defined subclones further suggested that this phenotype can arise as a distinct subclonal population within a single tumor. Outcome analysis, using two publicly available ovarian cancer cohorts, showed that high C3 expression was significantly associated with shorter platinum-free survival. Together, these findings implicate complement and interferon signaling as concurrent features of treatment-naive HGSC tumors with early relapse in both adnexal and omental tissue, and nominate C3 as a candidate prognostic biomarker and potential therapeutic target.

cancer biology↗

bioRxiv2021

Single-cell RNA sequencing-based characterization of resident lung mesenchymal stromal cells in bronchopulmonary dysplasia

Late lung development is a period of alveolar and microvascular formation, which is pivotal in ensuring sufficient and effective gas exchange. Defects in late lung development manifest in premature infants as a chronic lung disease named bronchopulmonary dysplasia (BPD). Numerous studies demonstrated the therapeutic properties of exogenous bone marrow and umbilical cord-derived mesenchymal stromal cells (MSCs) in experimental BPD. However, very little is known regarding the regenerative capacity of resident lung MSCs (L-MSCs) during normal development and in BPD. In this study we aimed to characterize the L-MSC population in homeostasis and upon injury. We used single-cell RNA sequencing (scRNA-seq) to profile in situ Ly6a+ L-MSCs in the lungs of normal and O2-exposed neonatal mice (a well-established model to mimic BPD) at three developmental timepoints (postnatal days 3, 7 and 14). Hyperoxia exposure increased the number, and altered the expression profile of L-MSCs, particularly by increasing the expression of multiple pro-inflammatory, pro-fibrotic, and anti-angiogenic genes. In order to identify potential changes induced in the L-MSCs transcriptome by storage and culture, we profiled 15,000 Ly6a+ L-MSCs after in vitro culture. We observed great differences in expression profiles of in situ and cultured L-MSCs, particularly those derived from healthy lungs. Additionally, we have identified the location of L-MSCs in the developing lung and propose Serpinf1 as a novel, culture-stable marker of L-MSCs. Finally, cell communication analysis suggests inflammatory signals from immune and endothelial cells as main drivers of hyperoxia-induced changes in L-MSCs transcriptome.

cell biology↗

bioRxiv2021

Peripheral neuropathy linked mRNA export factor GANP reshapes gene regulation in human motor neurons

Loss-of-function of the mRNA export protein GANP (MCM3AP gene) cause early-onset sensorimotor neuropathy, characterised by axonal degeneration in long peripheral nerves. GANP functions as a scaffold at nuclear pore complexes, contributing to selective nuclear export of mRNAs. Here, we aimed to identify motor neuron specific transcripts that are regulated by GANP and may be limiting for local protein synthesis in motor neuron axons. We compared motor neurons with a gene edited mutation in the Sac3 mRNA binding domain of GANP to isogenic controls. We also examined patient-derived motor neurons. RNA sequencing of motor neurons as well as nuclear and axonal subcompartments showed that mutant GANP had a profound effect on motor neuron transcriptomes, with alterations in nearly 40 percent of all expressed genes and broad changes in splicing. Expression changes in multiple genes critical for neuronal functions, combined with compensatory upregulation of protein synthesis and early-stage metabolic stress genes, indicated that RNA metabolism was abnormal in GANP-deficient motor neurons. Surprisingly, limited evidence was found for large-scale nuclear retention of mRNA. This first study of neuropathy-linked GANP defects in human motor neurons shows that GANP has a wide gene regulatory role in a disease-relevant cell type that requires long-distance mRNA transport.

neuroscience↗