Biology subjects

Doerr, J.

Publications and source records attributed to Doerr, J..

6 recordsLinked to original sources

bioRxiv2025

Pharmacological targeting of SOS1-RAS interaction triggers pancreatic β-cell proliferation and sustainably reverses diabetic hyperglycemia

Clinical studies have suggested that restoring a sufficient mass of functional {beta} cells can provide an effective treatment option for diabetes, however, it remains unclear whether this can be achieved through pharmacological stimulation of endogenous {beta}-cell proliferation. We demonstrate here that ectopic expression of a constitutively active form of Kras (KrasG12D) exclusively in pancreatic endocrine cells suppresses {beta}-cell proliferation, resulting in a dramatic reduction in {beta}-cell numbers and islet size. Conversely, we demonstrate that the potent and selective SOS1-RAS interaction inhibitor BI-3406 promotes unprecedented levels of {beta}-cell proliferation in primary human islets, both in culture and following transplantation in immunocompromised diabetic mice. Importantly, using murine models of streptozotocin-induced diabetes, we show that BI-3406 treatment restores {beta}-cell mass, leading to a gradual normalization of blood glucose and insulin levels, as well as to sustainable improvement in glucose tolerance. Our data provide the first pre-clinical evidence of an orally bioavailable KRAS inhibitor that can directly induce {beta}-cell regeneration.

cell biology↗

bioRxiv2025

Oncogene Silencing via ecDNA Micronucleation

Extrachromosomal DNA (ecDNA) contributes to cancer genome instability by enabling high-copy oncogene amplification, intratumoural heterogeneity and rapid genetic change. Micronuclei (MN) are frequently observed in chromosomally unstable cancers, yet their origins and relevance in ecDNA-driven tumours remain incompletely understood. Here, we investigate the relationship between ecDNA segregation errors and MN formation. We find that ecDNA frequently localizes to MN and represents a prominent source of MN content in ecDNA-positive cancer cells. Mitotic clustering of oncogene-bearing ecDNAs is associated with asymmetric inheritance and mis-segregation into MN. Transfer of oncogenes from ecDNA into MN is accompanied by reduced transcriptional output. Single-MN sequencing shows that individual MN are enriched for ecDNA to a degree that exceeds expectations from stochastic mis-segregation and that in MN oncogenes originating from multiple distinct ecDNAs coalesce. Using live-cell imaging, we observe that cells inheriting ecDNA-positive MN show limited proliferative capacity and an increased likelihood of cell death. In neuroblastoma patients with MYCN-amplified ecDNA, higher frequencies of ecDNA-positive MN at diagnosis are associated with improved event-free and overall survival. Together, these findings link ecDNA mis-segregation to MN formation and reduced cellular fitness, suggesting that ecDNA-positive MN may reflect a state of impaired oncogenic ecDNA function with potential relevance for clinical outcome.

cancer biology↗

bioRxiv2023

Spatial Transcriptomic Characterization of Novel Pathologic Niches in IPF

An unmet medical need persists in Idiopathic Pulmonary fibrosis (IPF), for which treatments additional to anti-fibrotic therapy are needed. Single cell RNA sequencing (scRNA-seq) has advanced our understanding of IPF with cell type-specific insights but lacks cellular tissue context. Spatial transcriptomics addresses this by providing spatially resolved gene expression, enabling gene and cell type localization within the tissue environment. We profiled IPF and control patient lung tissue sections using spatial transcriptomics and combined the data with an atlas of integrated IPF scRNA-seq datasets. Through computational analysis, we identified three disease-associated pathologic niches with unique cellular composition / localization and analyzed their cell-cell communication. We identified the Fibrotic niche, comprising Myofibroblasts and Aberrant Basaloid cells, preferentially located around airways and close to the Airway Macrophage niche in the lumen, containing SPP1+ Macrophages. We also identified the Immune niche, distinct foci of lymphoid cells in fibrotic tissue, surrounded by remodeled endothelial vessels. TEASERSpatial transcriptomics localizes genes and cell types in the tissue and identifies pathological cellular niches in IPF and control lungs.

systems biology↗

bioRxiv2023

Mutation-specific CAR T cells as precision therapy for IGLV3-21R110 expressing high-risk chronic lymphocytic leukemia

The concept of precision cell therapy targeting tumor-specific mutations is appealing but requires surface-exposed neoepitopes, which is a rarity in cancer. B cell receptors (BCR) of mature lymphoid malignancies are exceptional in that they harbor tumor-specific-stereotyped sequences in the form of point mutations that drive self-engagement of the BCR and autologous signaling. Here, we used a BCR light chain neoepitope defined by a characteristic point mutation (IGLV3-21R110) for selective targeting of a poor-risk subset of chronic lymphocytic leukemia (CLL) with chimeric antigen receptor (CAR) T cells. We developed murine and humanized CAR constructs expressed in T cells from healthy donors and CLL patients that eradicated IGLV3-21R110 expressing cell lines and primary CLL cells, but not polyclonal healthy B cells. In vivo experiments confirmed epitope-selective cytolysis in xenograft models using engrafted IGLV3-21R110 expressing cell lines or primary CLL cells. We further demonstrate in two humanized mouse models lack of cytotoxicity towards human B cells. These data provide the basis for novel avenues of resistance-preventive and biomarker-guided cellular targeting of functionally relevant lymphoma driver mutations sparing normal B cells.

cancer biology↗

bioRxiv2021

Surveillance of in situ tumor arrays reveals early environmental control of cancer immunity

The immune phenotype of a tumor is a key predictor of its response to immunotherapy1-4. Patients who respond to immune checkpoint blockade generally present with tumors that are infiltrated by activated T cells, a tumor-immune phenotype referred to as immune inflamed5-7. However, not all immune inflamed tumors respond to therapy, and in addition the majority of patients presents with tumors that lack T cells ( immune desert) or that exclude T cells in the periphery of the tumor islet ( immune excluded)8. Despite the importance of these tumor-immune phenotypes in patients, little is known about their development, heterogeneity or dynamics due to an inability to model these features pre-clinically. Here, we describe an approach designated STAMP (skin tumor array by micro-poration), which combines in vivo noninvasive, high-throughput time-lapse imaging with excisional biopsies and next generation sequencing to characterize the establishment of the immunological niche and follow its evolution during immunotherapy. STAMP involves the seeding of dozens to hundreds clonal tumors in the superficial dermis of a single mouse ear that can be visualized in situ over weeks to months. Using this approach, we found that genetically identical tumors could display surprisingly different immune phenotypes. Although individual tumors of the same array were populated by the same T cell clonotypes, regression or progression of individual tumors were associated with distinct patterns of spatial organization of the T cells. In situ imaging of 14K tumors revealed that immune phenotypes were not static over-time but could rather evolve with tumor growth and response to treatment. Therapy-induced or spontaneous early conversion to the immune inflamed phenotype correlated with tumor regression and enhanced cytotoxic T cell activity. Therefore, STAMP provides a flexible approach to study the relationship between tumor evolution, immune cell dynamics, and tumor microenvironment with therapeutic response.

cancer biology↗

bioRxiv2021

Limiting factors for queen conch (Lobatus gigas) reproduction: A simulation-based evaluation

Queen conch are among the most economically, socially, and culturally important fishery resources in the Caribbean. Despite a multitude of fisheries management measures enacted across the region, populations are depleted and failing to recover. It is believed that queen conch are highly susceptible to depensatory processes, impacting reproductive success and contributing to the lack of recovery. We developed a model of reproductive dynamics to evaluate how variations in biological factors such as population density, movement speeds, movement restrictions, rest periods between mating events, sexual facilitation, and perception of conspecifics affect reproductive success and overall reproductive output. We compared simulation results to empirical observations of mating and spawning frequencies from conch populations in the central Bahamas and Florida Keys. Our results confirm that low probability of mate finding associated with decreased population density is the primary driver behind observed breeding behavior in the field, although additional factors also play important roles. In particular, sexual facilitation and perception of conspecifics may explain observed lack of mating at low densities and differences between mating frequencies in the central Bahamas and Florida Keys, respectively. Our simulations suggest densities greater than 200 adults/ha are needed for high levels of spawning output, supporting the suggestion that effective management strategies for queen conch should aim to protect high-density reproductive aggregations and critical breeding habitats.

ecology↗