Biology subjects

Launhardt, L.

Publications and source records attributed to Launhardt, L..

3 recordsLinked to original sources

bioRxiv2026

Tumor Cell Death Drives Tumor-Promoting IL-6+ iCAF formation via P2X7-activation

Chemotherapy resistance in pancreatic ductal adenocarcinoma is commonly attributed to tumor cell-intrinsic mechanisms, yet how cytotoxic therapy reshapes the tumor microenvironment remains incompletely understood. Here we show that PDAC cells exposed to cytotoxic agents reprogram pancreatic stellate cells toward an inflammatory cancer-associated fibroblast phenotype. Mechanistically, chemotherapy triggers the release of ATP from dying PDAC cells, which activates P2X7 signaling in PSCs in a paracrine manner, leading ERK activation and inflammatory polarization. In turn, therapy-educated PSCs promote tumor cell proliferation, induce resistance-associated transcriptional programs and impair CD8 T cell-mediated cytotoxicity in an IL-6-dependent manner. Pharmacological inhibition of P2X7 suppressed stromal IL-6 induction and enhanced gemcitabine efficacy in vivo. These findings identify a therapy-induced ATP-P2X7-IL-6 axis that links tumor cell death to stromal reprogramming and adaptive resistance in PDAC.

cancer biology↗

bioRxiv2025

Loss of CD44 re-educates pancreatic cancer-associated fibroblasts modulating their fibrotic and immunosuppressive functions

Pancreatic tumors are characterized by a prominent stroma that makes up to 90% of the tumor. Due to the significant upregulation of CD44, a family of transmembrane glycoproteins, in pancreatic cancer-associated fibroblasts (CAFs), we investigated its role in myofibroblastic and inflammatory CAF subsets. Conditional deletion of Cd44 in CAFs in Cd44fl/fl;Pdgfr{beta}CreERT2 mice, significantly decreased the tumor volume. In human CAFs CRIPSR/Cas9-edited to delete CD44, the morphology of the fibroblasts changed drastically: CAFs lost their elongated phenotype and adopted a round shape, reflecting their inactivation. This was accompanied by a significant downregulation of activation markers, unresponsiveness to exogenous stimuli and reduced contractile activity. CD44 absence not only downregulated extracellular matrix proteins in CAFs, thus influencing fibrosis, but also changed the immunomodulatory cytokine secretion. Finally, this inactivation of CAFs upon CD44 deletion influenced their immunosuppressive effect on dendritic cells (DCs) and on cytotoxic T cells (CTLs), resulting in decreased expression of immunosuppressive cytokines in DCs and enhanced tumor-cell-killing by CTLs.

cancer biology↗

bioRxiv2023

Inter-Organellar Effects of Defective ER-localized Linolenic Acid Formation on Thylakoid Lipid Composition and Xanthophyll-Cycle Pigment De-epoxidation in the Arabidopsis fad3 mutant

Monogalactosyldiacylglycerol (MGDG) is the main lipid constituent of thylakoids and a structural component of photosystems and photosynthesis-related proteo-lipid complexes in green tissues. Previously reported changes in MGDG abundance upon stress-treatments are hypothesized to reflect mobilization of MGDG-based polyunsaturated lipid intermediates to maintain extraplastidial membrane integrity. While exchange of lipid intermediates between compartmental membranes is well documented, physiological consequences of mobilizing an essential thylakoid lipid, such as MGDG, for an alternative purpose are not well understood.Arabidopsis seedlings exposed to mild (50 mM) salt-treatment displayed significantly increased abundance of both MGDG and the extraplastidial lipid, phosphatidylcholine (PC). Interestingly, similar increases in MGDG and PC were observed in Arabidopsis fad3 mutant seedlings defective in ER-localized linolenic acid formation, in which compensatory plastid-to-ER-directed mobilization of linolenic acid-containing intermediates takes place. The postulated (salt) or evident (fad3) plastid-ER-exchange of intermediates concurred with altered thylakoid function according to parameters of photosynthetic performance. While salt-treatment of wild type seedlings inhibited photosynthetic parameters in a dose-dependent manner, interestingly the fad3 mutant did not show overall reduced photosynthetic quantum yield. By contrast, we observed a reduction specifically of non-photochemical quenching (NPQ) under high light, representing only part of observed salt effects. The decreased NPQ in the fad3 mutant was accompanied by reduced activity of the xanthophyll cycle, leading to a reduced concentration of the NPQ-effective pigment zeaxanthin. The findings suggest that altered ER-located fatty acid unsaturation and ensuing inter-organellar compensation impacts on aspects of thylakoids related to the function of specific enzymes, rather than globally affecting thylakoid function. Subject Areas(2) Environmental and stress responses (7) Membrane and transport

plant biology↗