Biology subjects

Batardiere, M.

Publications and source records attributed to Batardiere, M..

4 recordsLinked to original sources

bioRxiv2026

Spatial multi-omics resolve epithelium-fibroblast gradients and highlight NESTIN-NOTCH1-expressing subepithelial fibroblasts during human pancreatic tumorigenesis

Intraductal papillary mucinous neoplasms (IPMNs) are cystic precursors of pancreatic ductal adenocarcinoma undergoing dynamic epithelial and stromal remodeling during progression. In this study, we integrated computational pathology, cyclic immunofluorescence, and Xenium spatial transcriptomics to define the spatial organization of the IPMN microenvironment. We queried cell-based histopathological features and identified stromal patterns strongly associated with epithelium proximity. Cyclic immunofluorescence and Xenium revealed a subepithelial gradient extending from myofibroblasts to inflammatory fibroblasts. Xenium further identified a distinct subepithelial NOTCH1-NESTIN-expressing fibroblast subset in myofibroblasts that expands with tumor progression. By recapitulating the spatial remodeling event using human pancreatic tumor cells and primary myofibroblast co-culture models, we demonstrated the capacity of pancreatic tumor cells to induce a NESTIN-expressing state in neighboring myofibroblasts. These findings reveal new dynamic epithelial-stromal interactions through subepithelial NESTIN+ fibroblasts associated with pancreatic tumorigenesis and immediate microenvironment remodeling by active tumor cells, highlighting the power of computational pathology integrated with spatial transcriptomics.

cancer biology↗

bioRxiv2026

Spatial analysis of Intraductal Papillary Mucinous Neoplasms reveals secretory cell-enriched neighborhoods

Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer-related deaths in the United States. Intraductal papillary mucinous neoplasms (IPMNs) are neoplastic lesions of ductal origin that seed 10-25% of PDAC. There are currently no markers that distinguish between IPMN that will remain benign and those that will progress to cancer. A heterogenous population of secretory cells, including chemosensory tuft cells and hormone-expressing enteroendocrine cells (EECs), form during metaplasia and neoplastic progression in the pancreas, but the relevance of these populations as it relates to IPMN progression is not well characterized. Here, we performed spatial transcriptomics as well as multiplex immunostaining and spatial statistics on surgically resected IPMN from 60 patients to characterize these populations in all subtypes (gastric foveolar, intestinal, pancreatobiliary) and grades (low-grade, high-grade, invasive). We found that POU2F3+ tuft-like cells, CHGA+ EECs, and a subset of pancreatic endocrine cells ([a] and {gamma} cells) were present in all types of IPMN. Further, serotonin-expressing enterochromaffin cells made up the bulk of EECs in low-grade disease. Enterochromaffin, tuft-like, and glucagon-expressing alpha cells were not evenly distributed and instead were significantly enriched in a spatial manner, which is overlooked using conventional whole tissue quantification approaches. Tuft-like cell clusters were enriched with monocytes and resident memory T cells and anti-correlated to activated fibroblasts (myCAFs, iCAFs). Overall, these secretory cell clusters may reflect clonal expansion resulting in formation of distinct stromal niches with unknown consequences for disease progression.

Cancer Biology↗

bioRxiv2024

Early IKKb-dependent anabolic signature governs vascular smooth muscle cells fate and abdominal aortic aneurysm development

BackgroundAbdominal aortic aneurysm (AAA) is a detrimental disease with no effective pharmacological therapy. While inflammation is recognized as one of the key regulators of AAA, targeting inflammatory pathways once the disease is established does not impact the outcomes. However, understanding the earliest molecular indicators could shed light on the precise biological targets and prognostic markers for AAA. MethodsUsing apolipoprotein E (ApoE)-deficient mice fed with a standard diet and infused with Angiotensin II (Ang II), we conducted bulk RNA-sequencing (RNA-Seq) analysis on suprarenal (SRA) regions obtained from both unchallenged and challenged WT mice, specifically examining responses 24 hours after Ang II infusion to capture the initial phases of aortic stress response. We further created a unique model of hyperlipidemic mice in which the expression of the inhibitor of nuclear factor kappa B kinase subunit beta (IKK{beta}) can be conditionally (via tamoxifen injection) suppressed in vascular smooth muscle cells (VSMC). The development of AAA was evaluated using in situ examination and quantified using RT-qPCR, immunohistochemistry and fluorescence microscopy. Cultured VSMC were exposed to the selective IKK{beta} inhibitor MLN120b and the expression levels of phenotypic markers kruppel like factor 4 (KLF4), {beta}-Catenin and cellular communication network factor 2 (CCN2) were addressed using cellular extracts and immunoblot analysis. ResultsRNA-Seq data support the presence of early anabolic events in SRA regions detailing activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, which paralleled cellular anabolic processes including mitochondria, ribosome and sterol biosynthesis, the Unfolded Protein Response (UPR) and fibrogenesis. Conditional deletion of the Ikbkb gene in VSMC significantly reduces the incidence of SRA lesions as well as the rate of aneurysm ruptures in mice exposed to Ang II. In situ analysis further demonstrated that the protection conferred by the lack of IKK{beta} expression in VSMC is associated with reduced inflammatory response, the preservation of the contractile over the degradative VSMC phenotypes, and the absence of an anabolic signature. ConclusionOur results not only reinforce the major roles played by VSMC in the rapid adaptation leading to the deleterious remodeling of the vascular wall and aortic lesions but also support a paradigm aiming at repositioning the efforts focusing on anabolic rather than inflammatory events.

molecular biology↗

bioRxiv2024

Oncogenic GNAS drives a gastric pylorus program in intraductal papillary mucinous neoplasms of the pancreas

BACKGROUND & AIMSIntraductal Papillary Mucinous Neoplasms (IPMNs) are cystic lesions and bona fide precursors for pancreatic ductal adenocarcinoma (PDAC). Recent studies have shown that pancreatic precancer is characterized by a transcriptomic program similar to gastric metaplasia. The aims of this study were to assay IPMN for pyloric markers, to identify molecular drivers, and to determine a functional role for this program in the pancreas. METHODSPyloric marker expression was evaluated by RNA-seq and multiplex immunostaining in patient samples. Cell lines and organoids expressing KrasG12D +/- GNASR201C underwent RNA sequencing. A PyScenic-based regulon analysis was performed to identify molecular drivers, and candidates were evaluated by RNA-seq, immunostaining, and small interfering RNA knockdown. Glycosylation profiling was performed to identify GNASR201C-driven changes. Glycan abundance was evaluated in patient samples. RESULTSPyloric markers were identified in human IPMN. GNASR201Cdrove expression of this program as well as an indolent phenotype characterized by distinct glycosyltransferase changes. Glycan profiling identified an increase in LacdiNAcs and loss of pro-tumorigenic Lewis antigens. Knockdown of transcription factors Spdef or Creb3l1 or chitinase treatment reduced LacdiNAc deposition and reversed the indolent phenotype. LacdiNAc and 3-sulfoLeA/C abundance discriminated low from high grade patient IPMN. CONCLUSIONGNASR201C drives an indolent phenotype in IPMN by amplifying a differentiated, pyloric phenotype through SPDEF/CREB3L1 which is characterized by distinct glycans. Acting as a glycan rheostat, mutant GNAS elevates LacdiNAcs at the expense of pro-tumorigenic acidic Lewis epitopes, inhibiting cancer cell invasion and disease progression. LacdiNAc and 3-Sulfo-LeA/C are mutually exclusive and may serve as markers of disease progression.

cancer biology↗