Biology subjects

Bexell, D.

Publications and source records attributed to Bexell, D..

8 recordsLinked to original sources

bioRxiv2026

SUMOylation is a Therapeutic Vulnerability in High-risk Neuroblastoma

Neuroblastoma (NB) is one of the most common solid malignancies in children, and high-risk patients have poor prognosis, underscoring the need for novel therapeutic agents. The small ubiquitin-like modifier (SUMO) is a reversible post-translational modification that regulates various protein functions, and the first-in-class SUMOylation inhibitor TAK-981 (subasumstat) is currently in clinical trials in adult cancer patients. However, the role of SUMOylation in NB pathogenesis remains poorly characterized. We show that SUMOylation-catalyzing enzymes, SAE1, SAE2, and UBE2I, are highly expressed in malignant neuroendocrine cells, and their expression correlate with poor survival in NB patients and associate with advanced stage, MYCN amplifications, and downregulation of late differentiation markers. The peripheral nervous system lineage and NB cell lines are highly sensitive to the CRISPR knockout of SAE1 and SAE2, suggesting SUMOylation as promising therapeutic target in NB. Accordingly, TAK-981-mediated inhibition of SUMOylation reduces growth of NB cells in both in vitro and in vivo models through induction of apoptosis and perturbation of differentiation-associated pathways. Sensitivity to SUMOylation inhibition is greatest in NB cells with low expression of favorable late neuroblast markers and is independent of MYCN amplification status. Moreover, TAK-981 is effective in combination with differentiation-inducing all-trans retinoic acid and the DNA methyltransferase inhibitor decitabine. Mechanistically, combination of TAK-981 and retinoic acid potently downregulates retinoic acid receptor alpha (RAR) expression, whereas inhibition of SUMOylation combined with decitabine induces a strong accumulation of DNA damage. Taken together, these findings establish SUMO pathway components as potential prognostic markers and SUMOylation as a therapeutic vulnerability in high-risk NB.

cancer biology↗

bioRxiv2026

De novo Design of Macrocyclic Molecular Glues

The engineering of induced proximity has transformed drug discovery, yet the development of molecular glues remains largely serendipitous and restricted to the retrospective optimisation of accidental discoveries. Here, we present EvoBind-multimer, a deep learning framework for the de novo design of molecular glues directly from protein sequences. Unlike structure-based docking, our method generates small macrocyclic peptides that bridge user-defined protein pairs without requiring prior interface knowledge or existing ligands. We applied this framework to recruit the E3 ligase VHL to two challenging oncoproteins: KRAS and BRD4. Live-cell NanoBRET demonstrated robust design-induced proximity for both pairs. Mechanistic validation demonstrated that the generated macrocycles form functional VHL-target ternary complexes capable of driving Cullin-RING ligase-dependent proteasomal degradation and downstream signalling shutdown. Finally, evaluation in patient-derived xenograft neuroblastoma tumoroids revealed that ternary complex processing is deeply context-dependent: identical macrocycles acted as potent degraders in one patient model, yet functioned as stabilising "LOCKTACs" in another, driving VHL-dependent target sequestration without turnover. By enabling the de novo design of induced proximity from sequence alone, EvoBind-multimer provides a route towards designing new protein functions.

bioinformatics↗

bioRxiv2026

ALK R1275Q mutation drives expansion of SCP-like cells during sympathoadrenal commitment and primes neuroblastoma initiation.

Neuroblastoma (NB) is a pediatric malignancy developing in the sympathoadrenal lineage of the neural crest, characterized by clinical heterogeneity ranging from spontaneous regression to poor outcomes. Activating mutations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) are frequently observed in both sporadic and familial NB, yet the functional role of ALK in tumor initiation is not fully understood. Using a patient-derived human induced pluripotent stem cell (iPSC) model of sympathoadrenal development, we show that upon sympathoadrenal lineage commitment, ALK R1275Q, the most common hotspot mutation found in familial NB, sustain a proliferative, immature Schwann cell precursor (SCP)-like cell state with elevated ALK signaling and increased susceptibility to MYCN-driven transformation. While ALK-mutant cells alone did not form tumors in vivo, they cooperated with MYCN to accelerate tumor initiation, suggesting that ALK R1275Q creates a permissive but insufficient state for transformation. These findings define an ALK-driven cell progenitor-like state that facilitates the initiation of NB during embryonal development.

cancer biology↗

bioRxiv2025

Repurposing statins and phenothiazines to treat chemoresistant neuroblastoma.

Relapse and treatment resistance are common in children with high-risk neuroblastoma, and novel therapies are needed. Conventional drug discovery is slow, expensive, often fails in practice, and consequently falls short in addressing pediatric and rare conditions. In such instances, drug repurposing is a promising strategy. Here, we used two independent in silico prediction tools including machine learning to identify approved drugs for repurposing against neuroblastoma. The combination of statins and phenothiazines showed strong synergistic effects in human neuroblastoma organoids, decreased tumor growth and prolonged survival in MYCN-amplified neuroblastoma patient-derived xenografts. The drug combination altered cholesterol metabolism through a dual-hit mechanism and induced a phenotypic switch towards an adrenergic cell state accompanied by increased sensitivity to chemotherapy. Integration of the drug combination into standard-of-care chemotherapy regressed tumors and prolonged survival in chemoresistant patient-derived xenografts. Thus, a combination of safe and approved medications added to standard-of-care chemotherapy outperforms chemotherapy alone in chemoresistant neuroblastoma. TeaserUsing in silico prediction tools we repurposed statins and phenothiazines as a combination with translational potential in high-risk neuroblastoma.

cancer biology↗

bioRxiv2022

Inherent evolutionary unpredictability in cancer model system

Despite the advent of personalized medicine, it is still difficult to predict how a cancer develops over time at the level of the individual patient or even in cancer model systems which begs the question whether certain aspects of cancer can ever be predicted or if there is an inherent unpredictability in cancer, similar to other complex biological systems, We demonstrate by a combination of agent-based mathematical modelling and analysis of data from patient-derived xenograft systems from multiple cancer types that certain conditions may invoke chaotic fluctuations in the clonal landscape of cancer cells. Our findings indicate that under those conditions, the cancer genome behaves as a complex dynamic system, making its long-term evolution inherently unpredictable.

evolutionary biology↗

bioRxiv2022

Clinically-relevant treatment of PDX models reveals patterns of neuroblastoma chemoresistance

Chemotherapy resistance and relapses are common in high-risk neuroblastoma (NB), an aggressive pediatric solid tumor of the sympathetic nervous system. Here, we developed a clinically-relevant in vivo treatment protocol mimicking the first line five-chemotherapy treatment regimen of high-risk NB and applied this protocol to mice with MYCN-amplified NB patient-derived xenografts (PDXs). Genomic and transcriptomic analyses were used to reveal the genetic and non-genetic mechanisms involved in NB chemoresistance. We observed convergent and parallel evolution of key NB genetic aberrations over time. Intrinsic resistance to chemotherapy was associated with high genetic diversity and an embryonic phenotype. Relapsed NB PDX tumors with acquired resistance showed an immature mesenchymal-like phenotype resembling multipotent Schwann cell precursors that are found in the adrenal gland. NBs with a successful treatment response presented a lineage-committed adrenergic phenotype similar to normal neuroblasts, reduced cell cycle gene expression, and negative regulation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) cascade. NB organoids established from relapsed PDX tumors retained drug resistance, tumorigenicity, and transcriptional cell states ex vivo. This work sheds light on mechanisms involved in NB chemotherapy response in vivo and ex vivo using a clinically-relevant protocol, and emphasizes the importance of transcriptional cell states in treatment response. Detailed characterization of resistance mechanisms is essential for the development of novel treatment strategies in non-responsive or relapsed high-risk NB. One Sentence SummaryCOJEC chemotherapy treatment of neuroblastoma PDX models uncovers patterns of transcriptional plasticity and chemoresistance.

cancer biology↗

bioRxiv2021

Engineering of human mini-bones for the standardized modeling of healthy hematopoiesis, leukemia and solid tumor metastasis

The bone marrow microenvironment provides indispensable factors to sustain blood production throughout life. It is also a hotspot for the progression of hematologic disorders and the most frequent site of solid tumor metastasis. Pre-clinical research relies on xenograft mouse models, precluding the human-specific functional interactions of stem cells with their bone marrow microenvironment. Human mesenchymal cells can be exploited for the in vivo engineering of humanized ossicles (hOss). Those mini-bones provide a human niche conferring engraftment of human healthy and malignant blood samples, yet suffering from major reproducibility issue. Here, we report the standardized generation of hOss by developmental priming of a custom-designed human mesenchymal cell line. We demonstrate superior engraftment of cord blood hematopoietic cells and primary acute myeloid leukemia samples, but also validate our hOss as metastatic site for breast cancer cells. Finally, we report the first engraftment of neuroblastoma patient-derived xenograft cells in a humanized model, recapitulating clinically reported osteolytic lesions. Collectively, our hOss constitute a powerful standardized and malleable platform to model normal hematopoiesis, leukemia and solid tumor metastasis.

bioengineering↗

bioRxiv2021

An immature subset of neuroblastoma cells synthesizes retinoic acid and depends on this metabolite

Neuroblastoma is a pediatric tumor of the adrenergic sympathetic lineage. Most high risk neuroblastoma go in complete clinical remission by chemotherapy, which is subsequently complemented by retinoic acid (RA) maintenance therapy. However, by unresolved mechanisms most tumors ultimately relapse as therapy-resistant disease. Neuroblastoma cell lines were recently found to include, besides lineage committed adrenergic (ADRN) tumor cells, also immature mesenchymal (MES) tumor cells. Here, we report that MES-type cells synthesize RA and require this metabolite for proliferation and motility. MES cells are even resistant to RA in vitro. MES cells appear to resemble Schwann Cell Precursors (SCP), which are motile precursors of the adrenergic lineage. MES and SCP cells express shared RA-synthesis and RA-target genes. Endogenous RA synthesis and RA resistance thus stem from normal programs of lineage precursors that are maintained in an immature tumor cell fraction. These cells are fully malignant in orthotopic patient-derived xenograft models and may mediate development of drug-resistant relapses.

cancer biology↗