Biology subjects

Moeller, L. C.

Publications and source records attributed to Moeller, L. C..

6 recordsLinked to original sources

bioRxiv2025

ALK Inhibition Prolongs Survival in a Mouse Model of ALK-positive Anaplastic Thyroid Cancer

BackgroundAnaplastic thyroid cancer (ATC) is the most aggressive thyroid cancer with a median survival of about 6 months. So far, no therapies offering a survival benefit are established. Thus, new therapeutic approaches are urgently needed. In general, genetic alterations leading to ATC increase PI3K and MAPK/ERK signalling and include mutations in receptor tyrosine kinases and tumour suppressor genes. They often occur together with the loss of P53, the most prevalent mutation in human ATC. Among such mutations are mutations and rearrangements of the anaplastic lymphoma kinase (ALK) gene. MethodsTo study ATC and potential treatment options, we generated a mouse model with inducible thyrocyte-specific expression of constitutively active mutant ALKF1174L and homozygous deletion of Trp53 due to a Cre recombinase under control of the thyroglobulin promoter (Tg-CreERT2+/0;LSL-ALKF1174L/+;Trp53LoxP/LoxP mice, here referred to as Trp53KO/ALKF1174L mice). Moreover, we established several primary thyroid cancer cell lines harbouring ALKF1174L and Trp53KO and investigated the effects of ALK inhibition in vitro and in vivo. ResultsMedian survival of Trp53KO/ALKF1174L mice was severely reduced and the mice showed massively enlarged thyroids. Histopathology confirmed development of locally invasive and metastatic ATC. Treatment of primary Trp53KO/ALKF1174L ATC cells with the ALK inhibitor TAE-684 decreased AKT and ERK phosphorylation and induced a dose-dependent cytotoxicity. Trp53KO/ALKF1174L mice treated with TAE-684 showed significantly extended median survival compared to the solvent group (66 days vs. 18 days, p < 0.0001). ConclusionOur data demonstrate that the combination of ALKF1174L mutation with Trp53 loss leads to the development of ATC. This study provides first functional data supporting the use of ALK inhibitors in patients with ALK-driven ATC. Our novel ATC mouse model and the derived cell lines offer valuable tools to explore the molecular characteristics of ATC, especially signalling pathway activation and tumour microenvironment, and to test novel therapeutics for the treatment of advanced thyroid cancers.

cancer biology↗

bioRxiv2024

msiFlow: Automated Workflows for Reproducible and Scalable Multimodal Mass Spectrometry Imaging and Immunofluorescence Microscopy Data Processing and Analysis

Multimodal imaging by matrix-assisted laser desorption ionisation mass spectrometry imaging (MALDI MSI) and immunofluorescence microscopy holds great potential for understanding pathological mechanisms by mapping molecular signatures from the tissue microenvironment to specific cell populations. However, existing open-source software solutions for analysis of MALDI MSI data are incomplete, require programming skills and contain laborious manual steps, hindering broadly applicable, reproducible, and high-throughput analysis to generate impactful biological discoveries across interdisciplinary research fields. Here we present msiFlow, an accessible open-source, platform-independent and vendor-neutral software for end-to-end, high-throughput, transparent and reproducible analysis of multimodal imaging data. msiFlow integrates all necessary steps from import and pre-processing of raw MALDI MSI data to visual analysis output, as well as registration, along with state-of-the-art and newly developed algorithms, into automated workflows. Using msiFlow, we unravel the molecular heterogeneity of leukocytes in infected tissues by spatial regulation of ether-linked phospholipids containing arachidonic acid. We anticipate that msiFlow will facilitate the broad applicability of MSI in the emerging field of multimodal imaging to uncover context-dependent cellular regulations in disease states.

bioinformatics↗

bioRxiv2023

Comparative phenotyping of mice reveals canonical and noncanonical physiological functions of TRα and TRβ

Thyroid hormone (TH) effects are mediated through TH receptors (TRs) TR1, TR{beta}1, and TR{beta}2. The TRs bind to thyroid hormone responsive elements on the DNA and regulate expression of TH target genes as ligand dependent transcription factors (canonical signaling). In addition, the TRs and {beta} mediate activation of signaling pathways, e.g. the PI3K/AKT and MAPK/ERK pathways (noncanonical signaling). Whether such DNA-binding independent TR action contributes to the spectrum of physiological TH effects is largely unknown. The aim of this study was to attribute physiological effects to the two TR isoforms and {beta} and their canonical and noncanonical signaling. We conducted multi-parameter phenotyping in male and female TR knockout mice (TRKO, TR{beta}KO), mice with disrupted canonical signaling due to a mutation in the TR DNA-binding domain (TRGS, TR{beta}GS) and their respective wild-type littermates. Perturbations in senses, especially hearing (mainly TR{beta} with a lesser impact of TR), visual acuity and retinal thickness (TR and TR{beta}), in muscle metabolism (TR) and in heart rate (TR) highlighted the role of canonical TR action. Strikingly, selective abrogation of canonical TR action often had little to no phenotypic consequence, suggesting that noncanonical TR action sufficed to maintain the wild-type phenotype for specific effects. For instance, macrocytic anemia, reduced retinal vascularization or increased anxiety related behavior were only observed in TRKO, but not TRGS mice. Noncanonical TR action increased the efficiency of energy utilization and prevented hyperphagia observed in TRKO mice. In summary, by examining the phenotypes of TR and TR{beta} knockout models alongside their DNA-binding-deficient GS mutants and wildtype counterparts, we could establish that the independent noncanonical actions of TR and TR{beta} play a crucial role in modulating sensory, behavioral, and metabolic functions. This comparison underscores the significance of the TRs in orchestrating a spectrum of physiological processes beyond their traditional genomic pathways.

physiology↗

bioRxiv2023

Canonical and noncanonical contribution of thyroid hormone receptor isoforms alpha and beta to cardiac hypertrophy and heart rate in male mice

BackgroundStimulation of ventricular hypertrophy and heart rate are two major cardiac effects of thyroid hormone (TH). Aim of this study was to determine in vivo which TH receptor (TR), or {beta}, and which mode of TR action, canonical gene expression or DNA-binding independent noncanonical action, mediate these effects. Material and methodsWe compared global TR and TR{beta} knockout mice (TRKO; TR{beta}KO) with WT mice to determine the TR isoform responsible for T3 effects. The relevance of TR DNA- binding was studied in mice with a mutation in the DNA-binding domain that selectively abrogates DNA binding and canonical TR action (TRGS; TR{beta}GS). Hearts were studied with echocardiography at baseline and after seven weeks T3-treatment. Gene expression was measured with real-time PCR. Heart rate was recorded with radiotelemetry transmitters for seven weeks in untreated, hypothyroid and T3-treated mice. ResultsT3 induced ventricular hypertrophy in WT and TR{beta}KO mice, but not in TRKO mice. Hypertrophy was also induced in TRGS mice. Thus, hypertrophy is mostly mediated by noncanonical TR action. Similarly, repression of Mhy7 occurred in WT and TRGS mice. Basal heart rate was largely dependent on canonical TR action. But responsiveness to hypothyroidism and T3-treatment as well as expression of pacemaker gene Hcn2 were still preserved in TRKO mice, demonstrating that TR{beta} could compensate for absence of TR. ConclusionT3-induced cardiac hypertrophy could be attributed to noncanonical TR action, whereas heart rate regulation was mediated by canonical TR action. TR{beta} could substitute for canonical, but not noncanonical TR action.

physiology↗

bioRxiv2023

Partial resistance to thyroid hormone-induced tachycardia and cardiac hypertrophy in mice lacking thyroid hormone receptor beta

BackgroundThyroid hormones regulate cardiac functions mainly via direct actions in the heart and binding to the thyroid hormone receptor (TR) isoforms 1 and {beta}. While the role of the most abundantly expressed isoform, TR1, is widely studied and well characterized, the role of TR{beta} in regulating heart functions is still poorly understood, primarily due to the accompanying elevation of circulating thyroid hormone in mice lacking TR{beta} (TR{beta}-KO). However, their hyperthyroidism is ameliorated at thermoneutrality, which allows studying the role of TR{beta} without this confounding factor. MethodsHere we non-invasively monitored heart rate in TR{beta}-KO mice over several days using radiotelemetry at different housing temperatures (22{degrees}C and 30{degrees}C), and upon T3 administration in comparison to wildtype animals. ResultsTR{beta}-KO mice displayed normal average heart rate at both 22{degrees}C and 30{degrees}C with only minor changes in heart rate frequency distribution, which was confirmed by independent electrocardiogram recordings in freely-moving conscious mice. Parasympathetic nerve activity was, however, impaired in TR{beta}-KO mice at 22{degrees}C, and only partly rescued at 30{degrees}C. As expected, oral treatment with pharmacological doses of T3 at 30{degrees}C led to tachycardia in wildtypes, accompanied by broader heart rate frequency distribution and increased heart weight, while TR{beta}-KO mice showed blunted tachycardia, as well as resistance to changes in heart rate frequency distribution and heart weight. At the molecular level, these observations were paralleled by a blunted cardiac mRNA induction of several important genes, including the pacemaker channels Hcn2 and Hcn4, as well as Kcna7. ConclusionsThe phenotyping of TR{beta}-KO mice conducted at thermoneutrality allows novel insights on the role of TR{beta} in cardiac functions in absence of the usual confounding hyperthyroidism. Even though TR{beta} is expressed at lower levels than TR1 in the heart, our findings demonstrate an important role for this isoform in the cardiac response to thyroid hormones.

physiology↗

bioRxiv2023

Cardiac recovery from pressure overload is not altered by thyroid hormone status in old mice

1Thyroid hormones (TH) are known to have various effects on the cardiovascular system. However, the impact of TH levels on preexisting cardiac diseases are still unclear. Pressure overload due to arterial hypertension or aortic stenosis and aging are major risk factors for the development of structural and functional abnormalities and subsequent heart failure. Here, we assessed the sensitivity to altered TH levels in aged mice with maladaptive cardiac hypertrophy and cardiac dysfunction induced by transverse aortic constriction (TAC). Mice at the age of 12 months underwent TAC and after induction of left ventricular pressure overload, received T4 or anti-thyroid medication in the drinking water over the course of 4 weeks. T4 excess or deprivation in older mice had no or only very little impact on cardiac function (fractional shortening), cardiac remodeling (cardiac wall thickness, heart weight, cardiomyocyte size, apoptosis and interstitial fibrosis) and mortality. This is surprising, because T4 excess or deprivation had significantly changed the outcome after TAC in young 8-week-old mice. In summary, our study shows that low and high TH availability have little impact on cardiac function and remodeling in older mice with preexisting pressure induced cardiac damage. This suggests that even though cardiovascular risk is increasing with age, the response to TH stress may be dampened in certain conditions.

physiology↗