Biology subjects

Heldin, C.-H.

Publications and source records attributed to Heldin, C.-H..

2 recordsLinked to original sources

bioRxiv2026

Inhibition of HVEM suppresses invasion and growth of mesenchymal glioblastoma

Mesenchymal glioblastoma is a subtype of glioblastoma multiforme (GBM) characterized by pronounced inflammatory features and resistance to conventional therapies. Proneural GBM acquires a mesenchymal phenotype through proneural-mesenchymal transition (PMT), in which NF-{kappa}B signaling plays a central role. Through RNA-sequencing analysis of glioma-initiating cells (GICs), we found that expression of herpes virus entry mediator (HVEM or TNFRSF14) is highly expressed in mesenchymal GBM cells. Functional analyses revealed that HVEM promotes GIC proliferation, neurosphere formation, and invasive capacity in vitro, and enhances tumor formation following intracranial transplantation of GICs in mice. Among the TNF superfamily ligands, a proliferation-inducing ligand (APRIL or TNFSF13) binds to HVEM and activates NF-{kappa}B signaling, thereby inducing a mesenchymal phenotype in GBM cells. Furthermore, HVEM expression contributed to resistance to anticancer drugs, which was relieved by knockout of HVEM expression in the mesenchymal GICs. To therapeutically target this pathway, we generated nanobodies from camelid-derived heavy-chain-only antibodies against human HVEM. An anti-human HVEM nanobody, which binds to the cysteine-rich domain 1 (CRD1) of human HVEM, significantly inhibited the invasion of mesenchymal GICs in organotypic cultures and suppressed tumor growth in a mouse xenograft model. In addition to APRIL, HVEM binds to multiple ligands, of which B and T lymphocyte attenuator (BTLA) plays a critical role in immune evasion via binding to HVEM. The anti-human HVEM nanobody blocked interaction between HVEM and BTLA. Collectively, these findings suggest that the anti-human HVEM nanobody regulates multiple signaling pathways, and that HVEM represents a promising therapeutic target for the treatment of mesenchymal GBM. One Sentence SummaryHVEM drives aggressive glioblastoma by boosting tumor growth and invasion upon binding of APRIL, while an anti-HVEM nanobody slows tumor progression.

cancer biology↗

bioRxiv2024

Glutamine deprivation alters TGF-β signaling in hepatocellular carcinoma

Metabolic reprogramming is one of the hallmarks of cancer. Glutamine is one of the most important nutrients that fuels the TCA cycle and therefore takes part in the production of energy. Glutamine is used as starting metabolite for the synthesis of nucleotides, fatty acids and non-essential amino acids. Since nutrients are uptaken from the blood stream, and considering the 3-dimensional state of solid tumors, access of nutrients is highly dependent on the location of individual cells within a tumor, which results in affecting their metabolic activity. This gives rise to two disctincts cell population: the ones that have access to nutrient and the ones that are nutrient-deprived. We studied the effect of the lack of glutamine by creating glutamine-resistent hepatocellular carcinoma cell lines chosen based on their epithelial (Hep3B) or mesenchymal phenotype (SNU-499 and HLF). We found that glutamine deprivation decreased the proliferation rate, clonogenicity and stemness frequency of the three cell lines but in a greater extent of the mesenchymal cells. Transcriptomic analysis performed in HLF cells showed that glutamine deprivation decreased the activation of signaling pathways involved in cell-cell junction, cell-extracellular matrix interactions and decreased the expression of the hallmarks of epithelial-to-mesenchymal transition. We therefore investigated the role of TGF{beta}, a master regulator of these three processes, by transcriptomic and functional analyses in epithelial (Hep3B) and mesenchymal cells (HLF). We found that the lack of glutamine strongly impared the activation of TGF{beta} signaling which correlated with an altered regulation of TGF{beta} target genes: the expression of mesenchymal genes was no longer induced by TGF{beta} while the epithelial genes were more strongly induced. Functional analyses showed that glutamine deprivation abolished the invasive capacities of HCCs and decreased cell adhesion. Altogehter, our results show that glutamine metabolism is necessary to maintain a mesenchymal phenotype and to maintain an efficient TGF{beta} signaling in hepatocellularcarcinoma.

cancer biology↗