Biology subjects

Tuckermann, J.

Publications and source records attributed to Tuckermann, J..

3 recordsLinked to original sources

bioRxiv2026

Multi-omic and spatial analysis reveals tumour-derived paracrine signals drive suppressive macrophage polarisation via activation of the cAMP-CREB axis in glioblastoma

Tumor-associated macrophages (TAMs) are key mediators of tumor immunosuppression, yet the factors governing their polarization remain poorly understood, especially in highly immunosuppressive cancers, including cancers affecting the central nervous system. This study investigates the molecular pathways underlying TAM polarization in glioblastoma, one of the most immunosuppressive cancer types. Using a multi-omics approach integrating spatial proteomics, RNA-sequencing, and proteomic profiling of tumor cells and macrophages, we demonstrate that circulating monocytes polarize toward an immunosuppressive state when they exit tumor blood vessels, in response to glioblastoma cell-secreted cytokines. In situ and in vitro data shows that macrophage polarization is regulated via the cAMP-CREB signaling-transcription axis.

cancer biology↗

bioRxiv2022

The calcium channel Orai1 is required for osteoblast development: studies in a chimeric mouse with variable in vivo Runx-cre deletion of Orai-1

The calcium-selective ion channel Orai1 has a complex role in bone homeostasis, with defects in both bone production and resorption detected in Orai1 germline knock-out mice. To determine whether Orai1 has a direct, cell-intrinsic role in osteoblast differentiation and function, we bred Orai1 flox/flox (Orai1f/f) mice with Runx2-cre mice to eliminate its expression in osteoprogenitor cells. Interestingly, Orai1 was expressed in a mosaic pattern in Orai1f/f-Runx2-cre bone. Specifically, antibody labeling for Orai1 in vertebral sections was uniform in wild type animals, but patchy regions in Orai1f/f-Runx2-cre bone revealed Orai1 loss while in other areas expression persisted. Nevertheless, by micro-CT, bones from Orai1f/f-Runx2-cre mice showed reduced bone mass overall, with impaired bone formation identified by dynamic histomorphometry. Cortical surfaces of Orai1f/f-Runx2-cre vertebrae however exhibited patchy defects. In cell culture, Orai1-negative osteoblasts showed profound reductions in store-operated Ca2+ entry, exhibited decreased alkaline phosphatase activity, and had markedly impaired substrate mineralization. We conclude that defective bone formation observed in the absence of Orai1 reflects an intrinsic role for Orai1 in differentiating osteoblasts.

developmental biology↗

bioRxiv2018

Massive osteopetrosis caused by giant, non-functional osteoclasts in R51Q SNX10 mutant mice

The molecular mechanisms that regulate fusion of monocytes into functional osteoclasts are virtually unknown. We describe a knock-in mouse model for the R51Q mutation in sorting nexin 10 (SNX10) that exhibits osteopetrosis and related symptoms of patients of autosomal recessive osteopetrosis linked to this mutation. Osteopetrosis arises in homozygous R51Q SNX10 mice due to a unique combination of reduced numbers of osteoclasts that are non-functional. Fusion of mutant monocytes is deregulated and occurs rapidly and continuously to form giant, non-functional osteoclasts. Mutant osteoclasts mature quickly and survive poorly in vitro, possibly accounting for their scarcity in vivo. These cells also exhibit impaired ruffled borders, which are required for bone resorption, providing an additional basis for the osteopetrotic phenotype. More broadly, we propose that the maximal size of osteoclasts is actively determined by a genetically-regulated, cell-autonomous mechanism that limits precursor cell fusion, and for which SNX10 is required.

cell biology↗