Biology subjects

Heuser, M.

Publications and source records attributed to Heuser, M..

5 recordsLinked to original sources

bioRxiv2026

Targeting IGF2BP1 Creates a Mitotic Vulnerability in Colorectal Carcinoma

Background Mitotic dysregulation is a common feature of colorectal cancer (CRC), yet the contribution of post-transcriptional mechanisms remain incompletely understood. We investigated how the oncofetal RNA-binding protein IGF2BP1 supports mitotic integrity and exposes therapeutic vulnerabilities in CRC. Methods We integrated patient cohort analyses with genetic and pharmacological perturbation of IGF2BP1, transcriptomics, proteomics, RNA-binding assays and functional studies. Xenografts assessed tumor formation, while BTYNB-paclitaxel responses were examined in CRC cell lines and patient-derived organoids. Results IGF2BP1 expression was elevated in CRC, increased with tumor stage, and associated with poor survival and proliferative gene signatures. Genetic depletion or pharmacological inhibition of IGF2BP1 impaired cell viability, induced mitotic abnormalities, and promoted apoptosis, whereas its re-expression enhanced tumor formation in vivo. Integrated molecular analyses identified the chromosomal passenger complex (CPC) as a previously unrecognized downstream target of IGF2BP1. IGF2BP1 bound transcripts encoding CPC components and its depletion consistently reduced their expression across multiple cancer cell models. BTYNB disrupted IGF2BP1 association with INCENP, CDCA8, and BIRC5 transcripts and accelerated INCENP mRNA decay. Functionally, INCENP depletion recapitulated the mitotic defects and impaired viability observed upon IGF2BP1 inhibition. Exploiting this mitotic vulnerability, BTYNB synergized with paclitaxel in CRC cell lines and across four independent IGF2BP1-positive patient-derived organoid models. Conclusions Our findings uncover an IGF2BP1-dependent post-transcriptional regulatory mechanism sustaining CPC expression and mitotic integrity in CRC. Targeting this mechanism exposes a therapeutically exploitable mitotic vulnerability and provides a rationale for combining IGF2BP1 inhibition with microtubule-targeting agents.

cancer biology↗

bioRxiv2024

Base edited "universal" donor CAR T cell strategies for acute myeloid leukaemia

Acute myeloid leukaemia (AML) is often aggressive and life-threatening with limited curative options. Immunotherapies including chimeric antigen receptor (CAR) T cell approaches are under investigation, but high levels of disease heterogeneity remain a major hurdle to achieving durable responses. Targeting of multiple surface antigens may ensure complete immunological coverage of leukemic blast populations, but such antigens are often also present on healthy haematopoietic populations. To address likely aplasia, strategies can be designed to bridge CAR T cell therapies to allogeneic stem cell transplantation (allo-SCT), as demonstrated in recent anti-CD7 CAR T cell studies. Here we report that monotherapy using base edited (BE) universal donor CAR T cells against CD33, CLL-1, or CD7 delivered inhibition of AML in immunodeficient mice when antigen expression was homogenous, but combined use of BE-CAR33 and BE-CARCLL-1 T cells was required to address heterogenous CLL-1-/+CD33-/+ disease. We also demonstrate that removal of shared CD7 antigens enabled compatibility of BE-CAR33 with BE-CAR7 T cells, including in a patient-derived xenograft (PDX) model of AML. Therapeutic strategies envisage pick and mix applications of base edited universal CAR T cells in combinations determined by patient-specific antigen profiles. Such approaches also offer the possibility of deep, cell-based, de-bulking and preparative conditioning ahead of allo-SCT followed by donor-derived reconstitution.

immunology↗

bioRxiv2024

Microcystin shapes the Microcystis phycosphere through community filtering and by influencing cross-feeding interactions

The cyanobacterium Microcystis causes harmful algal blooms (cyanoHABs) that pose a major threat to human health and ecosystem services, particularly due to the prevalence of the potent hepatotoxin microcystin. With their pronounced EPS layer, Microcystis colonies also serve as a hub for heterotrophic phycosphere bacteria. Here, we tested the hypothesis that the genotypic plasticity in its ability to produce microcystin influences the composition and assembly of the Microcystis phycosphere microbiome. In an analysis of individual colonies of a natural Microcystis bloom, we observed a significantly reduced richness of the community in the presence of microcystin biosynthesis genes. A subsequent synthetic community experiment with 21 heterotrophic strains in co-cultivation with either the wild-type strain M. aeruginosa PCC 7806 or the microcystin-free mutant {Delta}mcyB revealed not only a tug-of-war between phototrophic and heterotrophic bacteria, but also a reciprocal dominance of two isolates of the genus Sphingomonas and Flavobacterium. In contrast, an Agrobacterium isolate thrived equally well in both consortia. In substrate utilization tests, Sphingomonas showed the strongest dependence on Microcystis exudates with a clear preference for the wild-type strain. Genome sequencing revealed a high potential for complementary cross-feeding, particularly for the Agrobacterium and Sphingomonas isolates but no potential for microcystin degradation. We postulate that strain-specific functional traits, such as the ability to perform photorespiration and to produce vitamin B12, play a crucial role in the cross-feeding interactions, and that microcystin is one of the determining factors in the Microcystis phycosphere due to its interference with inorganic carbon metabolism.

microbiology↗

bioRxiv2024

Competition and interdependence define multifaceted interactions of symbiotic Nostoc sp. and Agrobacterium sp. under inorganic carbon limitation

Cyanobacteria of the Nostoc genus are capable of forming symbiotic relationships with plants, thus transitioning to a heterotrophic lifestyle in return for providing bioavailable nitrogen to the host. The diazotrophic photoautotrophs also serve as a hub for specialized heterotrophic bacterial communities whose physiological contributions are poorly understood. By comparing the axenic strain Nostoc punctiforme PCC 73102 and the related strains Nostoc sp. KVJ2 and KVJ3, which still maintain their heterotrophic microbiome, we were able to demonstrate an almost obligate dependence of the cyanobacteria on the heterotrophic partners under carbon-limiting conditions. Detailed analysis of the intimate bilateral relationship between N. punctiforme and the isolate Agrobacterium tumefaciens Het4 using shotgun proteomics and microscopy uncovered a complex partnership characterized, among other traits, by competition for iron and facilitation for carbon. Although competitive interactions with A. tumefaciens Het4 compromise nitrogen fixation and stimulate the degradation of cyanophycin, mutualistic dependency prevails under inorganic carbon limitation. Both the absence of the high affinity bicarbonate uptake transporter SbtA and the prevalent extracarboxysomal localization of the carbon-fixing enzyme RubisCO, as detected by immunofluorescence microscopy, suggest that a weak carbon concentrating mechanism in N. punctiforme enforces a dependence on heterotrophic bacteria. Further, immunofluorescence, electron microscopic and proteomic analyses reveal a pronounced extracellular recycling of proteins under N- and C-limiting conditions. Our study shows that the pivotal influence of heterotrophic bacteria on symbiotic Nostoc strains should be considered when analyzing these cyanobacteria, especially in the free-living state. This work also sheds new light on how Nostoc benefits from the organic carbon provided by plant hosts.

microbiology↗

bioRxiv2022

Nanoparticle-mediated Targeting of the Fusion Gene RUNX1/ETO in t(8;21)-positive Acute Myeloid Leukaemia

A hallmark of acute myeloid leukaemias (AMLs) are chromosomal rearrangements that give rise to novel leukaemia-specific fusion genes. Most of these fusion genes are both initiating and driving events in AML and therefore constitute ideal therapeutic targets but are challenging to target by conventional drug development. siRNAs are frequently used for the specific suppression of fusion gene expression but require special formulations for efficient in vivo delivery. Here we describe the use of siRNA-loaded lipid nanoparticles for the specific therapeutic targeting of the leukaemic fusion gene RUNX1/ETO. Transient knockdown of RUNX1/ETO reduces its binding to its target genes and alters the binding of RUNX1 and its co-factor CBF{beta}. Transcriptomic changes in vivo were associated with substantially increased median survival of a t(8;21)-AML mouse model. Importantly, transient knockdown in vivo causes long-lasting inhibition of leukaemic proliferation and clonogenicity, induction of myeloid differentiation and a markedly impaired re-engraftment potential in vivo. These data strongly suggest that temporary inhibition of RUNX1/ETO results in long-term restriction of leukaemic self-renewal. Our results provide proof for the feasibility of targeting RUNX1/ETO in a pre-clinical setting and support the further development of siRNA-LNPs for the treatment of fusion gene-driven malignancies.

cancer biology↗