Biology subjects

Ackermann, S.

Publications and source records attributed to Ackermann, S..

4 recordsLinked to original sources

bioRxiv2025

Pan-Cancer PDOs Preserve Tumor Heterogeneity and Uncover Therapeutic Vulnerabilities

We developed a tumor-matched, pan-cancer patient-derived organoid (PDO) platform comprising 220 PDOs from 190 patients across 15 cancer types to advance functional precision oncology. Our comprehensively characterized PDOs showed 93% histopathology concordance, 80% median genomic concordance for driver mutations, and a 0.85 median gene expression correlation with parent tumors. Gene expression in PDOs remained stable across [≥] 10 passages, supporting reproducibility for long-term drug screening. Even PDOs with low genomic concordance retained oncogenic drivers, supporting their use as disease models. Clonality analysis revealed that 85% of PDOs preserved dominant tumor clones. Higher genomic concordance was associated with greater clonal similarity, while lower genomic concordance was associated with clonal divergence. Functional assays showed that 58% of PDOs from a subset of patients ineligible for FDA-approved PARP inhibitors responded to Talazoparib, with sensitivity linked to alterations in DNA damage repair. Combination screens revealed drugs that effectively overcame resistance, especially in TP53-mutant PDOs. In summary, our platform supports investigation of targeted therapies, identification of molecular features linked to drug sensitivity, and translational discovery, offering insights into personalized cancer treatment beyond current biomarker guidelines.

cancer biology↗

bioRxiv2024

OSBA: An open neonatal neuroimaging atlas and template for spina bifida aperta

We present the Open Spina Bifida Aperta (OSBA) atlas, an open atlas and set of neuroimaging templates for spina bifida aperta (SBA). Traditional brain atlases may not adequately capture anatomical variations present in pediatric or disease-specific cohorts. The OSBA atlas fills in this gap by representing the computationally averaged anatomy of the neonatal brain with SBA after fetal surgical repair. The OSBA atlas was constructed using structural T2-weighted and diffusion tensor MRI of 28 newborns with SBA who underwent prenatal surgical correction. The corrected gestational age at MRI was 38.1 {+/-} 1.1 weeks (mean {+/-} SD). The OSBA atlas consists of T2-weighted and fractional anisotropy templates, along with 9 tissue prior maps and region of interest (ROI) delineations. The OSBA atlas offers a standardized reference space for spatial normalization and anatomical ROI definition. Our image segmentation and cortical ribbon definition is based on a human-in-the-loop approach including manual segmentation. The precise alignment of the ROIs was achieved by a combination of manual image alignment and automated, non-linear image registration. By providing a dedicated neonatal atlas for SBA, we enable more accurate spatial standardization and support advanced analyses such as diffusion tractography and connectomic studies in newborns affected by this condition.

neuroscience↗

bioRxiv2023

Unicellular propagules, cancer, and competition: Are unicellular propagules part of the optimal life-history strategy in the face of both cancer and competition?

Evolutionary transitions in individuality introduce new levels of selection and thus enable discordant selection, threatening the stability of the transition. Cheating is such a problem for multicellularity. So why have so many transitions to multicellularity persisted? One possibility is that the unicellular propagule maintains cooperation among cells by purging cheaters. The evolution of propagule size has been modeled previously, but in the absence of competition between individuals, which may often select for larger propagules. How does the nature of competition between individuals affect the optimal propagule size in the presence of cheating? Here we take a model of early multicellularity, add phenotypic switching between cheating and cooperative phenotypes, and simulate size-dependent competition on a lattice, which allows us to tune the strength of interspecific vs. intraspecific competition via dispersal. As expected, cheating favors strategies with unicellular propagules while size-dependent competition favors strategies with few large propagules (binary fragmentation). How these opposing forces resolve depends on dispersal. Local dispersal, which intensifies intraspecific competition, favors binary fragmentation, which reduces intraspecific competition for space, with one unicellular propagule. Global dispersal instead favours multiple fission when cheating is common. We also find that selfishness promotes smaller body size, despite direct opposing selection from competition. Our results shed light on the evolution of multicellular life cycles and the prevalence of a unicellular stage in the multicellular life cycle across the tree of life. Author summaryA multicellular organism is a group of cooperating cells. But wherever there is cooperation there is the temptation to cheat. Having offspring that start as a single cell (a unicellular bottleneck) has been hypothesized as an adaptation to purge lineages of cheating cells. We model the evolution of offspring size but add competition between individuals, which may select against small unicellular offspring. We find that having some unicellular offspring is still a successful strategy, but how many depends on the nature of competition.

evolutionary biology↗

bioRxiv2023

Novel co-culture strategies of tumor organoids with autologous T-cells reveal clinically relevant combinations of immune-checkpoint and targeted therapies

Patient derived tumor organoids (PDTOs) have become relevant pre-clinical models for therapeutic modelling since they highly recapitulate patients response to treatment. Nevertheless, their value for immunotherapy modelling has not been fully explored. We developed a tumor processing protocol that enable the establishment of PDTOs and tumor infiltrating lymphocytes (TILs) isolation. By the optimization of functional assays, we compared the T-cells effector functions of matching PBMCs and TILs, demonstrating that PBMCs after co-culture and TILs after initial expansion display similar responses. In addition, the evaluation of cytokine production by fluorospot in combination with an image-based killing assay enable the screening of different immune-checkpoint inhibitors as well as its combination with target inhibitors. Our proof-of-concept functional assays showed the potential and versatility of PDTOs and T-cells co-culture systems for immunotherapy screening. The optimization of scalable functional assays downstream co-culture represents a significant step forward to increase the value of PDTOs as pre-clinical models for immunotherapeutic screens.

immunology↗