Biology subjects

Peset, I.

Publications and source records attributed to Peset, I..

5 recordsLinked to original sources

bioRxiv2026

NGFR-driven suppression of antigen presentation limits CD8+ T cell immunity and response to checkpoint blockade

Immune checkpoint blockade has revolutionized cancer therapy; however, numerous tumors remain resistant by adopting cellular states that impede immune recognition. In this study, we identify the nerve growth factor receptor (NGFR) as a regulator of immune evasion in head and neck squamous cell carcinoma (HNSCC). Genetic ablation of Ngfr resulted in impaired tumor growth in immunocompetent MOC2 HNSCC, while pharmacological inhibition with THX-B reduced primary tumor growth and spontaneous metastatic dissemination. Single-cell profiling of MOC2 tumors demonstrated that Ngfr loss redirected tumor cells away from invasive EMT-like states and enhanced antigen-processing and presentation programs. This was accompanied by increased presentation of tumor antigens and expansion of effector CD8+ T-cells in vivo. Functionally, CD8+ T-cell depletion, Batf3 deficiency, and JAK1/2 inhibition restored the growth of Ngfr-deficient tumors, indicating that NGFR loss exposes tumors to CD8+ T-cell-mediated control through a JAK-associated antigen-presentation program. Notably, NGFR blockade sensitized otherwise resistant MOC2 tumors to anti-PD1 therapy, and the combination of THX-B with anti-PD1 significantly improved tumor control and survival. In human HNSCC, spatial profiling revealed that NGFR+ tumor regions exhibited reduced HLA-DR expression and limited CD3+ T-cell infiltration. Notably, an NGFR-associated antigen-presentation signature stratified survival and response in HNSCC patients undergoing immune checkpoint blockade. Interestingly, this signature was also linked to improved outcomes in melanoma patients. We also observed a significant increase in the effector CD8+ T-cell fraction in melanoma NGFR KO tumors linked to a significant decrease in tumor growth. These findings position NGFR as a regulator of tumor immune visibility and support NGFR inhibition as a strategy to enhance immunotherapy response.

cancer biology↗

bioRxiv2026

Grading HER2 at the nanoscale in clinical tissue

To guide diagnosis and treatment, breast cancer biopsies are assessed for HER2 status and assigned one of four grades (0-3+). While current practices are sufficient for detection of HER2 overexpression (3+), there is a need for more sensitive methods capable of characterising lower HER2 expression in patients who may still benefit from HER2-targeted therapies. Super-resolution fluorescence microscopy techniques, such as single molecule localisation microscopy (SMLM), have reshaped the study of nanoscale molecular architecture by visualising single target molecules in a range of sample types. Here, we have developed a quantitative SMLM workflow to visualise HER2 nanoclustering in patient-derived xenografts (PDX) and clinical breast tumour tissue from eight patients spanning all disease grades. Analysis of HER2 cluster architecture revealed grade-dependent changes in size of cluster and HER2 abundance. We then applied a blinded data-driven approach to regroup samples based on this nanoscale HER2 clustering. This led to the reclassification of three samples into new groups, due to similarities in nanoscale signature. Together, these findings demonstrate that quantitative fluorescence nanoscopy can be used to identify clinical HER2 phenotypes across a range of expression levels due to its exquisite sensitivity, and this could be leveraged to stratify patients for targeted therapy.

cancer biology↗

bioRxiv2025

MIF-induced CD74+ microglia/macrophages are clinically relevant disease-associated subpopulations in brain metastasis and other CNS disorders

The upregulation of CD74, a chaperone involved in MHC-II antigen processing 1,2, has been broadly reported in virtually all brain disorders analyzed by single-cell RNA sequencing 3-6. However, its expression is usually interpreted as indicative of antigen presentation. In parallel, CD74 expression has also been described in cancer cells across multiple tumor types, but interestingly in glioma its expression has been mainly identified in the microenvironment. However, the functional contribution of CD74 to disease progression in the brain, and specifically in secondary brain tumors, has not been directly addressed. Here we described that, in contrast to what it has been assumed, the presence of CD74+ microglia/macrophages, which is induced by increased levels of interferon gamma in the brain affected by metastases, does not relate to its canonical pathway. Instead, CD74s alternative function as cytokine receptor is pivotal. Rewired by increasing levels of its ligand MIF, produced by proliferating cancer cells, the CD74 receptor, upon binding to this ligand, translocates to the nucleus activating a NF-{kappa}B-dependent program promoting metastasis progression. A brain metastasis-associated CD74 signature involves a more aggressive progression of the local disease in patients, while it has no clinical correlation with the matched primary tumor. Furthermore, we identified the CD74+ myeloid population in additional brain disorders including Alzheimers disease and multiple sclerosis, which shared a pan-disease non-canonical signature with clinical relevance. The brain-penetrant drug ibudilast, which prevents the binding of MIF to CD74, decreases brain metastases in experimental models in vivo and in patient-derived organotypic cultures ex vivo in a primary tumor-agnostic manner. Our findings suggest that MIF/CD74-induced reprogramming of myeloid cells in brain disorders is a novel vulnerability that could be exploited therapeutically against brain metastases, and possibly other brain disorders, guided by a non-invasive molecular strategy.

cancer biology↗

bioRxiv2024

A common CTRB misfolding variant associated with pancreatic cancer risk causes ER stress and inflammation in mice

ObjectiveGenome wide association studies have identified an exon 6 CTRB2 deletion variant that associates with increased risk of pancreatic cancer. To acquire evidence on its causal role, we developed a new mouse strain carrying an equivalent variant in Ctrb1, the mouse orthologue of CTRB2. DesignWe used CRISPR/Cas9 to introduce a 707bp deletion in Ctrb1 encompassing exon 6 (Ctrb1{Delta}exon6). This mutation closely mimics the human deletion variant. Mice carrying the mutant allele were extensively profiled at 3 months to assess their phenotype. ResultsCtrb1{Delta}exon6 mutant mice express a truncated CTRB1 that accumulates in the ER. The pancreas of homozygous mutant mice displays reduced chymotrypsin activity and total protein synthesis. The histological aspect of the pancreas is inconspicuous but ultrastructural analysis shows evidence of dramatic ER stress and cytoplasmic and nuclear inclusions. Transcriptomic analyses of the pancreas of mutant mice reveals acinar program down-regulation and increased activity of ER stress-related and inflammatory pathways. Heterozygous mice have an intermediate phenotype. Agr2 is one of the most up-regulated genes in mutant pancreata. Ctrb1{Delta}exon6 mice exhibit impaired recovery from acute caerulein-induced pancreatitis. Administration of TUDCA or sulindac partially alleviates the phenotype. A transcriptomic signature derived from the mutant pancreata is significantly enriched in normal human pancreas of CTRB2 exon 6 deletion variant carriers from the GTEx cohort. ConclusionsThis mouse strain provides formal evidence that the Ctrb1{Delta}exon6 variant causes ER stress and inflammation in vivo, providing an excellent model to understand its contribution to pancreatic ductal adenocarcinoma development and to identify preventive strategies. SUMMARY BOX What is already known about this subject?- CTRB2 is one of the most abundant proteins produced by human pancreatic acinar cells. - A common exon 6 deletion variant in CTRB2 has been associated with an increased risk of pancreatic ductal adenocarcinoma. - Misfolding of digestive enzymes is associated with pancreatic pathology. What are the new findings?- We developed a novel genetic model that recapitulates the human CTRB2 deletion variant in the mouse orthologue, Ctrb1. - Truncated CTRB1 misfolds and accumulates in the ER; yet, mutant mice display a histologically normal pancreas at 3 months age. - CTRB1 and associated chaperones colocalize in the ER, the cytoplasm, and the nucleus of acinar cells. - Transcriptomics analysis reveals reduced activity of the acinar program and increased activity of pathways involved in ER stress, unfolded protein response, and inflammation. - Mutant mice are sensitized to pancreatic damage and do not recover properly from a mild caerulein-induced pancreatitis. - TUDCA administration partially relieves the ER stress in mutant mice. How might it impact on clinical practice in the foreseeable future?- The new mouse model provides a tool to identify the mechanisms leading to increased pancreatic cancer risk in CTRB2 exon 6 carriers. - The findings suggest that drugs that cause ER stress relief and/or reduce inflammation might provide preventive opportunities.

cancer biology↗

bioRxiv2024

Essential conserved neuronal motors kinesin-1 and kinesin-3 regulate Abeta42 toxicity in vivo

Alzheimers Disease is the leading cause of dementia and the most common neurodegenerative disorder. Understanding the molecular pathology of Alzheimers Disease may help identify new ways to reduce neuronal damage. In the past decades Drosophila has become a powerful tool in modelling mechanisms underlying human diseases. Here we investigate how the expression of the human 42-residue {beta}-amyloid (A{beta}) carrying the E22G pathogenic "Arctic" mutation (A{beta}42Arc) affects axonal health and behaviour of Drosophila. We find that A{beta}42Arc flies present aberrant neurons, with altered axonal transport of mitochondrial and an increased number of terminal boutons at neuromuscular junctions. We demonstrate that the major axonal motor proteins kinesin-1 and kinesin-3 are essential for the correct development of neurons in Drosophila larvae and similar findings are replicated in human iPSC-derived cortical neurons. We then show that the over-expression of kinesin-1 or kinesin-3 restores the correct number of terminal boutons in A{beta}42Arc expressing neurons and that this is associated with a rescue of the overall neuronal function, measured by negative geotaxis locomotor behavioural assay. We therefore provide new evidence in understanding the mechanisms of axonal transport defects in Alzheimers Disease, and our results indicate that kinesins should be considered as potential drug targets to help reduce dementia-associated disorders.

cell biology↗