Biology subjects

Westermark, B.

Publications and source records attributed to Westermark, B..

3 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

BMP4 induces a p21-dependent cell state shift in glioblastoma linking mesenchymal transition to senescence

Bone morphogenetic protein 4 (BMP4) has emerged as a potential glioblastoma therapy due to its anti- proliferative effect via SOX2 downregulation and differentiation promotion. However, BMP4 responses vary across and within tumors. Our previous data indicate that BMP4 induces transition to a mesenchymal-like cell state. Mesenchymal transition is associated with therapy-resistance and tumor recurrence, as is senescence in cancer. In this study, we investigated BMP4s potential to induce senescence in primary glioblastoma cells, including proneural- and mesenchymal-like clones derived from the same tumor. BMP4 treatment induced senescence-associated genes and phenotypic changes such as cell enlargement, senescence- associated-{beta}-gal expression, lamin B1 downregulation, and elevated p21 levels. The most robust senescence induction was observed in the mesenchymal-like clone, compared to its proneural counterpart. Notably, mesenchymal-like cells displayed high basal levels of p21 and other senescence- associated markers, suggesting a convergence of mesenchymal and senescent traits. p21 knockout abolished BMP4-induced senescence, maintaining proliferation and cell size despite SOX2 downregulation. Additionally, senolytic treatment effectively eliminated senescent cells through apoptosis, thereby favoring survival of cells retaining normal p21 levels. Our findings demonstrate BMP4s ability to induce p21-dependent senescence in glioblastoma, particularly in therapy-resistant mesenchymal-like cells. These insights provide potential therapeutic strategies targeting senescence pathways in this challenging disease.

cancer biology↗

bioRxiv2019

Live detection of neural stem and glioblastoma cells by an oligothiophene derivative

Here we report a luminescent conjugated oligothiophene (LCO), named p-HTMI, for non-invasive and non-amplified real-time detection of live human patient-derived glioblastoma (GBM) cells and embryonic neural stem cells (NSCs). While p-HTMI stained only a small fraction of other cell types investigated, the mere addition of p-HTMI to the cell culture resulted in efficient detection of NSCs or GBM cells from rodents and humans within minutes. p-HTMI is functionalized with a methylated imidazole moiety resembling the side chain of histidine/histamine, and non-methylated analogues were not functional. p-HTMI were readily able to detect a subpopulation of human cells in vivo in mouse brain sections with tumors developed from orthotopically transplanted patient-derived GBM cells. Cell sorting experiments of human GBM cells demonstrated that p-HTMI labeled the same population as CD271, a proposed marker for stem cell-like cells and rapidly migrating cells in glioblastoma. Our results suggest that the LCO p-HTMI is a versatile tool for immediate and selective detection of subpopulations of neural stem and glioma cells.

bioengineering↗