Biology subjects

Mulaw, M.

Publications and source records attributed to Mulaw, M..

4 recordsLinked to original sources

bioRxiv2026

NIK stabilization reprograms the pancreas toward chronic pancreatitis and pancreatic lipomatosis

Pancreatic lipomatosis, characterized by progressive adipose replacement of the exocrine pancreas, is a known consequence of chronic pancreatitis. Despite its clinical relevance, the mechanisms driving lipomatosis remain poorly understood. Here, we used a pancreas-specific NF-{kappa}B-inducing kinase (NIK) stabilization mouse model to investigate how sustained non-canonical NF-{kappa}B signaling contributes to chronic pancreatitis and pancreatic lipomatosis. NIK stabilization initiated a rapid and fully penetrant pancreatic remodeling program, leading to acinar cell death already by the end of the first week of age. Deep learning on high-definition spatial transcriptomics revealed a progressive loss of acinar identity resulting in acinar-to-ductal metaplasia (ADM) formation and identified GPA33 as a novel surface marker of ADMs. Over time, ADM lesions underwent apoptosis, leading to progressive loss of pancreatic parenchyma, organ atrophy, and extensive adipose replacement. Mechanistically, Relb deletion fully rescued the NIK-induced pancreatic phenotype, demonstrating that chronic pancreatitis and lipomatosis require RelB-dependent non-canonical NF-{kappa}B signaling in this model. Together, these findings define a RelB-dependent pathway linking sustained NIK stabilization to chronic pancreatitis and pancreatic lipomatosis. Our study provides a model for studying the development of pancreatic lipomatosis and for exploring potential therapeutic approaches.

cancer biology↗

bioRxiv2025

Exploiting TGF-β-mediated Stromal Programming in Homologous Recombination-Deficient Pancreatic Cancer

The tumor microenvironment (TME) actively contributes to pancreatic ductal adenocarcinoma (PDAC) pathogenesis through dynamic bidirectional tumor-stroma interactions. Here, we demonstrate that homologous recombination-defective (HRD) tumor epithelium reprograms the TME in a genotype-specific manner to enhance cancer aggressiveness. Using genetically engineered mouse models, pancreatic stellate cell (PSC) and cancer-associated fibroblast (CAF) co-culture systems, single-nucleus multiomics, and human PDAC models, we show that tumoral loss of ATM serine/threonine kinase drives CAFs toward SMA+ myofibroblastic differentiation, independently of P53 status. These myCAFs, in turn, promote cancer aggressiveness and chemoresistance. Mechanistically, ATM deficiency increases reactive oxygen species and contractility signaling, enhancing TGF-{beta}1 secretion. Pharmacological TGF-{beta} inhibition reverses myCAF differentiation, sensitizes tumors to chemotherapy, and impairs tumor progression in both murine and human ATM-null models. Our findings reveal that ATM-deficient tumors shape a cancer-promoting niche via TGF-{beta} signaling and identify dual targeting of intrinsic and extrinsic vulnerabilities as a promising precision oncology strategy. SIGNIFICANCEHRD pancreatic cancers reprogram the tumor microenvironment in a genotype-specific manner through TGF-{beta}-driven myCAF-enrichment. Targeting this stromal axis alongside platinum-based chemotherapy improves therapeutic efficacy in ATM-deficient models. These findings highlight the need to integrate epithelial genotype and stromal context for truly personalized treatment strategies in PDAC.

cancer biology↗

bioRxiv2025

Monocyte Dysregulation Defines an MDD-Specific Transcriptional Signature Closely Linked to Clinical MDD Traits

ObjectiveMajor depressive disorder (MDD) is a highly heterogeneous psychiatric condition contributing significantly to the global disease burden. In a subset of MDD patients inflammatory processes accompany the disease and this has also been reported for other psychiatric conditions like schizophrenia (SZ). However, little is known regarding immune deregulation in relation to clinical symptoms. MethodsCellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) of peripheral blood mononuclear cells (PBMCs) from patients with MDD (n=22), SZ (n=10), and healthy controls (HCs, n=26) was performed, yielding 633,284 high-quality single-cell profiles. Differential gene expression, cell composition, pathway enrichment, and weighted gene co-expression network analyses were conducted. MDD symptom severity was assessed using the Beck Depression Inventory-II (BDI-II), enabling the correlation of gene expression with individual disease symptoms. ResultsWe identified disease-specific transcriptomic signatures for MDD as well as for SZ and shared gene expression changes between the two conditions. For MDD, monocyte numbers were elevated concomitant with a strong enrichment of interferon signaling. The MDD-specific signature involving all peripheral cell types correlated strongly with key symptoms of depression like sadness or pessimism. Reactome analysis identified nuclear factor kappa-light-chain-enhancer of activated B cells (NF-{kappa}B)-associated pathways among the genes positively correlating with disease symptoms and traits. ConclusionOur findings might help to stratify psychiatric patients and provide a multidimensional framework for investigating immune contributions to psychiatric disorders and highlight potential targets for therapeutic intervention. Clinical symptoms might be reflected on a molecular level paving the way for more targeted and effective interventions.

genomics↗

bioRxiv2021

Met/HGFR triggers detrimental reactive microglia in TBI

The complexity of the signaling events, cellular responses unfolding in neuronal, glial and immune cells upon Traumatic brain injury (TBI) constitutes an obstacle in elucidating pathophysiological links and targets for intervention. We used array phosphoproteomics in a murine mild blunt TBI to reconstruct the temporal dynamics of tyrosine-kinase signaling in TBI and then to scrutinize the large-scale effects of the perturbation of cMet/HGFR, VEGFR1 and Btk signaling by small molecules. cMet/HGFR emerged as a selective modifier of the early microglial response, and cMet/HGFR blockade prevented the induction of microglial inflammatory mediators, of reactive microglia morphology and of TBI-associated responses in neurons, vessels and brain extracellular matrix. Acute or prolonged cMet/HGFR inhibition ameliorated neuronal survival and motor recovery. Early elevation of HGF itself in the CSF of TBI patients suggest that this mechanism has translational value in human subjects. Our findings identify cMet/HGFR as a modulator of early neuroinflammation in TBI with translational potential and indicate several RTK families as possible additional targets for TBI treatment. SummaryControlling neuroinflammation in neurotrauma is an important but unachieved goal. This study exploits a moderate TBI model and array-based proteomics to identify cMet as a new inducer of reactive microglia. A small-molecule inhibitor of cMet contains microglial reactivity, reduces neuronal and vascular alterations, limits behavioural disturbances and accelerates recovery. HighlightsO_LIMet is activated in microglia upon TBI and drives microglial reactivity. C_LIO_LIA Met inhibitor reduces motor dysfunction upon TBI and promotes recovery. C_LIO_LIBlockade of MET prevents the appearance of a reactive microglia. C_LIO_LIThe cMET inhibitor reduces the sub-acute neuronal loss after TBI. C_LI

neuroscience↗