Biology subjects

Franz, A.

Publications and source records attributed to Franz, A..

9 recordsLinked to original sources

bioRxiv2026

Distinct functions of PBRM1 and BAP1 reconcile the course of kidney cancer evolution and disease progression

Clear cell renal cell carcinoma (ccRCC) progresses along two predominant evolutionary trajectories, defined by PBRM1 ([~]40%) or BAP1 ([~]15%) mutations on a VHL-inactivated background. They have distinct patterns of evolutionary tempo and mode, and vastly different clinical outcomes, yet the underlying genotype-specific molecular phenotypic programmes are unknown. We established a patient-derived preclinical model biobank that captures the genetic diversity of ccRCC. Through integrative analyses of preclinical models and tumour bulk and single cell profiling, we identified transcriptional and epigenetic changes specific to PBRM1- and BAP1-driven ccRCC. Modelling PBRM1 loss in vitro demonstrates that it reinforces renal lineage identity and maintains progenitor-like cell state. In contrast, BAP1 loss drives inflammatory signalling and chromosomal instability. These insights reconcile the distinct evolutionary modes (branched versus punctuated), tempo (slow versus fast) and clinical outcomes associated with PBRM1 and BAP1 mutations, respectively, establishing a framework for patient stratification and genotype-directed therapeutic development.

cancer biology↗

bioRxiv2025

Design of combination therapeutics from protein response to drugs in ovarian cancer cells

High-grade serous ovarian cancer (HGSOC) remains the most lethal gynecologic malignancy, and novel treatment approaches are needed. Here, we used unbiased quantitative protein mass spectrometry to assess the cellular response profile to drug perturbations in ovarian cancer cells for the rational design of potential combination therapies. Analysis of the perturbation profiles revealed proteins responding across several drug perturbations (called frequently responsive below) as well as drug-specific protein responses. The frequently responsive proteins included proteins that reflected general drug resistance mechanisms, such as changes in drug efflux pumps. Network analysis of drug-specific protein responses revealed known and potential novel markers of resistance, which were used to rationalize the design of anti-resistance drug pairs. We experimentally tested the anti-proliferative effects of 12 of the proposed drug combinations in 6 HGSOC cell lines. While response typically varies across different cell lines, 10 of the 12 combinations tested have either an additive or synergistic CI index in at least one cell line and may therefore be plausible candidates for overcoming or preventing resistance to single agents. Serendipitously, we observed an unexpectedly strong 0.05-0.11 micromolar response to GPX4 inhibitors as single agents in the OVCAR-4 cell line. We propose several drug combinations as potential therapeutic candidates in ovarian cancer, as well as GPX4 inhibitors as single agents. HighlightsO_LI5000-protein response to 7 drugs in an ovarian cancer cell line profiled by protein mass spectrometry C_LIO_LINetwork analysis suggested potential pathways of drug resistance inferred from response profiles C_LIO_LIDemonstration of a general method for profiling adaptive response to therapeutic interventions with implications for the development of anti-resistance therapy C_LIO_LIPlausible anti-resistance drug combinations tested for antiproliferative effect in up to 6 ovarian cancer cell lines C_LIO_LIDrug combinations with additive or synergistic antiproliferative effects are plausible pre-clinical candidates for overcoming or preventing resistance to single agents C_LIO_LISeveral combinations were synergistic in some cell lines (with PARPi, MEKi, and SRCi) C_LIO_LIWe observed 0.05-0.11 micromolar response to GPX4 inhibitors as single agents in the OVCAR-4 cell line C_LI

cancer biology↗

bioRxiv2025

Apical-basal polarity regulates Collagen IV-dependent cell-cell adhesion in the Drosophila adipose tissue

E-Cadherin-based adherens junctions are the main type of junctional compartment in epithelia mediating cell-cell adhesion. The apical-basal cell polarity machinery positions adherens junctions at the apical-lateral border. The Drosophila adipose tissue, called the fat body, forms a monolayer in which cells adhere to each other through the binding of Integrin to pericellular Collagen IV concentrations. It is currently not known, how these atypical adhesion complexes form. Here we examine the epithelial apical-basal cell polarity network in the larval fat body. We find that this tissue displays an apical-basal cell polarity, with the apical proteins aPKC, Crumbs and Par-6 and the basolateral proteins Lgl and Dlg on opposite sides. Crumbs, aPKC, Scribble, and Lgl knockdown in the fat body leads to cell-cell-adhesion defects. We find that aPKC plays a key role in mediating cell-cell adhesion by regulating the formation of Collagen IV-Intercellular-Adhesion-Concentrations. We further show that during fat body remodeling, the steroid hormone Ecdysone regulates the loss of apical-basal polarity and Collagen IV-Intercellular-Adhesion-Concentrations to induce cell-cell dissociation and initiation of amoeboid swimming cell migration. Our work hence uncovers a novel role for the apical-basal polarity machinery in the Drosophila adipose tissue in regulating cell-cell adhesion via Collagen IV-Intercellular-Adhesion-Concentrations.

developmental biology↗

bioRxiv2024

Cell deformations generated by dynamic cortical actin waves drive in vivo swimming migration

Amoeboid cell migration drives many important developmental and disease-related processes including immune responses and cancer metastasis. Swimming cell migration is a subtype of amoeboid migration observed in cells in suspension ex vivo. However, the mechanism underlying swimming migration in vivo under physiological conditions is unknown. Using Drosophila fat body cells (FBCs) as a model, we show that FBCs actively swim to patrol the pupa. Their stop-and-go random walk is powered through the generation of oscillatory actomyosin waves, rather than persistent actin flows used by cells swimming in vitro. These actomyosin waves exert peristaltic compressive forces as they move to the cell rear. This causes cell elongation towards the front to propel the cell forward. In addition, we demonstrate that, unlike in other types of amoeboid migration, all three RhoGTPases, RhoA, Cdc42 and Rac1, are required for FBC migration. They control actin wave formation by regulating actin polymerisation through the formin Dia. Furthermore, RhoA at the cell rear induces actomyosin contractions via Rho kinase and myosin II to generate cell deformations. Importantly, our work reveals that swimming migration is a novel in vivo migration mode for rapid and long-range cell dispersal, potentially also used by other cells such as immune cells and cancer cells when encountering an aqueous environment.

cell biology↗

bioRxiv2022

Branch point evolution controls species-specific alternative splicing and regulates long term potentiation

Regulation and functionality of species-specific alternative splicing has remained enigmatic to the present date. Calcium/calmodulin-dependent protein kinase II{beta} (CaMKII{beta}) is expressed in several splice variants and plays a key role in learning and memory. Here, we identify and characterize several primate-specific CAMK2B splice isoforms, which show altered kinetic properties and changes in substrate specificity. Furthermore, we demonstrate that primate-specific Camk2{beta} alternative splicing is achieved through branch point weakening during evolution. We show that reducing branch point and splice site strengths during evolution globally renders constitutive exons alternative, thus providing a paradigm for cis-directed species-specific alternative splicing regulation. Using CRISPR/Cas9 we introduced a weaker human branch point into the mouse genome, resulting in human-like CAMK2B splicing in the brain of mutant mice. We observe a strong impairment of long-term potentiation in CA3-CA1 synapses of mutant mice, thus connecting branch point-controlled, species-specific alternative splicing with a fundamental function in learning and memory.

molecular biology↗

bioRxiv2022

CaMKII activity spreads by inter-holoenzyme phosphorylation

The dodecameric protein kinase CaMKII is expressed throughout the body. The alpha isoform is responsible for synaptic plasticity and participates in memory through its phosphorylation of synaptic proteins. Its elaborate subunit organization and propensity for autophosphorylation allow it to preserve neuronal plasticity across space and time. The prevailing hypothesis for the spread of CaMKII activity, involving shuffling of subunits between activated and naive holoenzymes, is broadly termed subunit exchange. In contrast to the expectations of previous work, we found little evidence for subunit exchange upon activation, and no effect of restraining subunits to their parent holoenzymes. Rather, mass photometry, crosslinking mass spectrometry, single molecule TIRF microscopy and biochemical assays identify inter-holoenzyme phosphorylation (IHP) as the mechanism for spreading phosphorylation. The transient, activity-dependent formation of groups of holoenzymes is well suited to the speed of neuronal activity. Our results place fundamental limits on the activation mechanism of this kinase.

biophysics↗

bioRxiv2021

Pancreatic cancer risk predicted from disease trajectories using deep learning

Pancreatic cancer is an aggressive disease that typically presents late with poor patient outcomes. There is a pronounced medical need for early detection of pancreatic cancer, which can be addressed by identifying high-risk populations. Here we apply artificial intelligence (AI) methods to a dataset of 6 million patient records with 24,000 pancreatic cancer cases in the Danish National Patient Registry (DNPR) and, for comparison, a dataset of three million records with 3,900 pancreatic cancer cases in the United States Department of Veterans Affairs (US-VA) healthcare system. In contrast to existing methods that do not use temporal information, we explicitly train machine learning models on the time sequence of diseases in patient clinical histories and test the ability to predict cancer occurrence in time intervals of 3 to 60 months after risk assessment. For cancer occurrence within 36 months, the performance of the best model (AUROC=0.88, DNPR), trained and tested on disease trajectories, exceeds that of a model without longitudinal information (AUROC=0.85, DNPR). Performance decreases when disease events within a 3 month window before cancer diagnosis are excluded from training (AUROC[3m]=0.83). Independent training and testing on the US-VA dataset reaches comparable performance (AUROC=0.78, AUROC[3m]=0.76). These results raise the state-of-the-art level of performance of cancer risk prediction on real-world data sets and provide support for the design of prediction-surveillance programs based on risk assessment in a large population followed by affordable surveillance of a relatively small number of patients at highest risk. Use of AI on real-world clinical records has the potential to shift focus from treatment of late-stage to early-stage cancer, benefiting patients by improving lifespan and quality of life.

bioinformatics↗

bioRxiv2021

Molecular Response to PARP1 Inhibition in Ovarian Cancer Cells as Determined by Mass Spectrometry Based Proteomics

Poly (ADP)-ribose polymerase (PARP) inhibitors have entered routine clinical practice for the treatment of high-grade serous ovarian cancer (HGSOC), yet the molecular mechanisms underlying treatment response to PARP1 inhibition (PARP1i) are not fully understood. Here, we used unbiased mass spectrometry based proteomics with data-driven protein network analysis to systematically characterize how HGSOC cells respond to PARP1i treatment. We found that PARP1i leads to pronounced proteomic changes in a diverse set of cellular processes in HGSOC cancer cells, consistent with transcript changes in an independent perturbation dataset. We interpret decreases in the levels of the pro-proliferative transcription factors SP1 and {beta}-catenin and in growth factor signaling as reflecting the anti-proliferative effect of PARP1i; and the strong activation of pro-survival processes NF-{varkappa}B signaling and lipid metabolism as PARPi-induced adaptive resistance mechanisms. Based on these observations, we nominate several protein targets for therapeutic inhibition in combination with PARP1i. When tested experimentally, the combination of PARPi with an inhibitor of fatty acid synthase (TVB-2640) has a 3-fold synergistic effect and is therefore of particular pre-clinical interest. Our study improves the current understanding of PARP1 function, highlights the potential that the anti-tumor efficacy of PARP1i may not only rely on DNA damage repair mechanisms and informs on the rational design of PARP1i combination therapies in ovarian cancer.

cancer biology↗

bioRxiv2020

Polyphosphate Functions In Vivo as Iron Chelator and Fenton Inhibitor

Maintaining cellular iron homeostasis is critical for organismal survival. Whereas iron depletion negatively affects the many metabolic pathways that depend on the activity of iron-containing enzymes, any excess of iron can cause the rapid formation of highly toxic reactive oxygen species (ROS) through Fenton chemistry. Although several cellular iron chelators have been identified, little is known about if and how organisms can prevent the Fenton reaction. By studying the effects of cisplatin, a commonly used anticancer drug and effective antimicrobial, we discovered that cisplatin elicits severe iron stress and oxidative DNA damage in bacteria. We found that both of these effects are successfully prevented by polyphosphate (polyP), an abundant polymer consisting solely of covalently linked inorganic phosphates. Subsequent in vitro and in vivo studies revealed that polyP provides a crucial iron reservoir under non-stress conditions, and effectively complexes free iron and blocks ROS formation during iron stress. These results demonstrate that polyP, a universally conserved biomolecule, plays a hitherto unrecognized role as an iron chelator and an inhibitor of the Fenton reaction.

microbiology↗