Biology subjects

Lauriola, M.

Publications and source records attributed to Lauriola, M..

8 recordsLinked to original sources

bioRxiv2026

Hierarchical and context-dependent GR-MR signalling governs endogenous corticosteroid decoding in the heart

Endogenous corticosteroids bind both the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), yet how this shared ligand input is decoded in the heart remains unclear. Previous work established that corticosterone suppresses postnatal cardiomyocyte proliferation through GR. Here we show that corticosteroid responses are governed by a functional GR-MR hierarchy and by cellular context. Genetic or pharmacological GR inhibition redirects corticosterone towards cardiomyocyte proliferation, and MR antagonism or silencing abolishes this effect. GR disruption also enhances aldosterone-induced proliferation in cardiomyocyte-enriched cultures, indicating that GR restrains MR output beyond ligand allocation. However, aldosterone fails to increase cardiomyocyte proliferation in mixed cultures and instead stimulates fibroblast proliferation and activation. By contrast, corticosterone combined with GR inhibition promotes cardiomyocyte proliferation without inducing stromal proliferation or profibrotic activation. Both treatments induce MR nuclear localisation in fibroblasts, showing that their divergent stromal effects arise despite comparable receptor nuclear engagement. Following myocardial infarction, circulating corticosterone increases and GR inhibition enhances cardiomyocyte MR nuclear localisation. In adult murine myocardium, corticosterone plus GR antagonism increases cardiomyocyte cell-cycle activity in an MR-dependent manner, with analogous responses observed in porcine and human myocardium. These findings identify hierarchical and context-dependent GR-MR signalling as a mechanism of corticosteroid decoding and a potential route to cardiac regeneration.

molecular biology↗

bioRxiv2026

Neuroendocrine-like/EMT dedifferentiation mediates resistance to EGFR inhibitors via the NRG1/HER3 axis

Patients with non-small cell lung cancer (NSCLC) carrying activating EGFR mutations typically respond favorably to third-generation EGFR tyrosine kinase inhibitors (TKIs) such as osimertinib. Nevertheless, resistance almost inevitably emerges, ultimately limiting the durability of these treatments. We investigated non-genomic mechanisms enabling drug-tolerant persister cells to survive EGFR inhibition, likely co-opting compensatory HER3 activation, whose underlying mechanisms remain unclear. Using a combination of immortalized and patient-derived cellular models, together with single-cell RNA sequencing, we demonstrate that activation of EGFR/HER3 axis constitutes an early adaptive response to TKI exposure enriched in pulmonary alveolar type I and type II cancer cells. This response is driven by neuregulin-1 (NRG1), produced by stromal cells and by cancer cells undergoing NE-like/EMT dedifferentiation. Importantly, in vivo studies demonstrated that combining EGFR inhibition and NRG1 neutralization by monoclonal antibody successfully eradicated tumors. Together, these findings point to a therapeutic strategy to overcome TKI resistance in NSCLC through targeting HER3 signalling, its interplay with EGFR, and tumor microenvironment-derived cues.

cancer biology↗

bioRxiv2025

Identification of first-in-class small molecule potential inhibitor of GDF15

BackgroundGrowth Differentiation Factor 15 (GDF15), a mitokine implicated in stress response, has been associated with numerous diseases, particularly cancer cachexia. Many approaches, including monoclonal antibodies and peptide antagonists, have been implemented to inhibit GDF15 activity. It is currently unknown whether it is possible to inhibit GDF15 using small organic molecules (SOMs). MethodsA structure-based in silico screening workflow of a curated compound library was implemented to identify SOMs capable of binding to the monomeric or dimeric form of GDF15. The three top-ranking SOMs of each group were then tested in vitro on normal and cancer cells. ResultsAmong all tested SOMs, dioxoimidazolidin derivative named SOM D resulted capable of inhibiting GDF15 dimer formation and decreasing binding to GFRAL. Furthermore, it was found to be devoid of acute cytotoxicity both in normal cells (dermal fibroblasts, DFs) and tumor cells (OV90), to significantly slow proliferation and modify the expression of genes involved in GDF15 signaling or in cell cycle and senescence in OV90, but not in DFs. Interestingly, simultaneous treatment with SOMs and doxorubicin (doxo) failed in arresting the cell cycle compared to doxo alone. ConclusionsThe in silico screening has proven effective in identifying SOMs putatively capable of inhibiting GDF15, among which SOM D appears the most promising. Further characterizations will be necessary to better understand the exact mechanisms of action. Furthermore, the observation that SOMs have an opposite effect on proliferation in cancer versus normal cellular context suggests a dual role in cell-cycle control in presence of cancer aberration.

molecular biology↗

bioRxiv2025

Co-targeting MERTK and EGFR with a Bispecific Antibody Overcomes Drug Resistance Across Mutations in Exons 19, 20, and 21

Resistance of lung cancer to EGFR-specific tyrosine kinase inhibitors (TKIs), such as osimertinib, often arises from secondary mutations or the activation of bypass signaling pathways. We noted elevated levels of GAS6 and its receptor, MERTK, in patients acquiring resistance to osimertinib, hence hypothesized that the GAS6-MERTK axis can serve as a therapeutic target. GAS6 promoted cell survival and an anti-GAS6 antibody we generated delayed tumor relapses in a xenograft model. Likewise, MERTK ablation sensitized lung cancer cells to osimertinib due to a newly described EGFR-to-MERTK crosstalk. Hence, we developed Bis3, a bispecific antibody targeting both MERTK and EGFR and promoting their degradation. Bis3 plus TKIs cooperatively inhibited the growth of TKI-resistant lung cancer spheroids and markedly delayed relapses of patient-derived xenografts harboring the clinically challenging exon-20 mutations. These findings establish the GAS6-MERTK axis as a driver of drug resistance and provide a rationale for clinical development of Bis3.

cancer biology↗

bioRxiv2025

Harnessing glucocorticoid receptor antagonization to enhance the efficacy of cardiac regenerative growth factors and cytokines

Severe myocardial injuries in mammals lead to cardiomyocyte loss and heart failure. Activation of Glucocorticoid Receptor (GR) by endogenous glucocorticoids limit cardiomyocyte proliferation and cardiac regeneration. Here, we reveal that glucocorticoids suppress the proliferative response of cardiomyocytes to a diverse range of regenerative factors, including Neuregulin 1 (NRG1), FGF1, IGF2, IGF1, BMP7, Oncostatin M (OSM), LIF, RANKL, IL6, IL13, IL4, and IL1-beta. Transcriptomic analyses revealed that glucocorticoids-GR axis induces the expression of MAPK/ERK pathway inhibitors ERRFI1/MIG6 and DUSP1. Using NRG1 as a model system for cardiac regenerative factors, we demonstrate that glucocorticoids suppress growth factor-induced ERK activation, nuclear translocation, and transcriptional output. Knockdown experiments confirmed that ERRFI1 and DUSP1 are key mediators of glucocorticoid-mediated suppression of cardiomyocyte proliferation induced by growth factors. The cardiac expression of GR target genes, including Dusp1 and Errfi1, increases during early postnatal development, coinciding with the transition to post-mitotic cardiomyocytes. In juvenile and adult stage, regenerative growth factors failed to activate MAPK/ERK pathway and induce proliferation effectively; however, DUSP1 inhibition rescues these responses. Consistently, GR antagonization during early postnatal development preserved MAPK/ERK pathway activity. Importantly, GR antagonization or deletion reinstated growth-factor-induced proliferation of postmitotic cardiomyocytes. Finally, GR antagonization enhanced the in vivo effectiveness of growth factor-based regenerative therapy in an adult mouse model of myocardial injury, enhancing cardiomyocyte proliferation and cardiac function. These findings reveal a previously unrecognized mechanism by which systemic hormones, specifically glucocorticoids, regulate the regenerative potential of cardiac paracrine factors. This study highlights transient glucocorticoid inhibition as a promising strategy to enhance the therapeutic efficacy of growth factor-based cardiac regenerative approaches. HighlightsO_LIPhysiological glucocorticoids suppress the proliferative response of cardiomyocytes to regenerative growth factors and cytokines. C_LIO_LIGlucocorticoids inhibit growth factor-induced MAPK/ERK activation in cardiomyocytes by upregulating the expression of negative regulators DUSP1 and ERRFI1. C_LIO_LIIncreased glucocorticoid-induced expression of DUSP1 and ERRFI1 during early postnatal development impairs the mitogenic activity of cardiac regenerative factors. C_LIO_LIGR antagonization restores growth factor-induced MAPK signaling and mitogenic activity in postmitotic cardiomyocytes and enhances the efficacy of growth factor-based regenerative therapies following myocardial injury. C_LI

cell biology↗

bioRxiv2023

BMP7 promotes cardiomyocyte regeneration

Zebrafish has a remarkable and lifelong ability for cardiac regeneration after severe damage, whereas mammals lose their innate capacity for heart regeneration during early postnatal development. This study aimed to investigate whether the decreased production of growth factors during postnatal mammalian development contributes to the exit of cardiomyocytes from the cell cycle and the reduction in cardiac regenerative ability. We identified growth factors with declining expression levels during early postnatal life in the mouse model and assessed the pro-proliferative ability of these factors on neonatal murine primary cardiomyocytes in vitro. Our findings confirmed the previously reported pro-proliferative effects of NRG1, IL1b, RANKL, IGF2 and IL6, while also identifying novel potential pro-regenerative growth factors. Among them, BMP7 exhibited the most pronounced efficacy. Bmp7 knockdown interfered with the proliferation of neonatal mouse cardiomyocytes in culture and adult bmp7 mutant zebrafish displayed reduced cardiomyocyte proliferation during heart regeneration, indicating that Bmp7 is crucial for cardiomyocyte proliferation in the regenerative stages of mouse and zebrafish hearts. Conversely, bmp7 overexpression was sufficient to boost cardiomyocyte cycling in regenerating zebrafish hearts, while BMP7 administration stimulated mouse cardiomyocyte cycling at postnatal-day-7, when cardiomyocytes ceased to proliferate, and enhanced cardiomyocyte regeneration in vivo in adult mice following myocardial infarction. Mechanistically, BMP7-induced proliferation was mediated by type I BMP receptors BMPR1A and ACVR1, and type II receptors ACVR2A and BMPR2. Downstream signalling involved SMAD5, ERK and AKT. In conclusion, the administration of BMP7 holds promise as a strategy to stimulate heart regeneration following cardiac injury.

molecular biology↗

bioRxiv2020

Pharmacological inhibition of the ALK axis elicits therapeutic potential in Consensus Molecular Subtype 1 colon cancer patients

In the last years, several efforts have been made to classify colorectal cancer (CRC) into well-defined molecular subgroups, representing the intrinsic inter-patient heterogeneity, known as Consensus Molecular Subtypes (CMSs). In this work, we performed a meta-analysis of 1700 CRC patients stratified into four CMSs. We identified a negative correlation between a high level of anaplastic lymphoma kinase (ALK) expression and relapse-free survival, exclusively in CMS1 subtype. Stemming from this observation, we tested several CMSs in vitro models with crizotinib (CZB) or alectinib (ALC), potent ALK inhibitors, already approved for clinical use. ALK interception strongly inhibits cell proliferation already at nanomolar doses, specifically in CMS1 cell lines, while no effect was found in CMS2/3/4 groups. Furthermore, in vivo imaging identified a role for ALK in the dynamic formation of 3D spheroids, which was impaired by the pharmacological inhibition of ALK. Consistently, CZB was responsible for the dampened activation of ALK along with the downstream AKT cascade. Mechanistically, we found a specific pro-apoptotic effect of ALK inhibition in CMS1 cell lines, both in 2D and 3D. Confocal analysis suggests that inhibition in CMS1 cells enhances cell-cell adhesion when growing in 3D. In agreement with our findings, an ALK signature encompassing 65 genes statistically associated with worse relapse-free survival in CMS1 subtype. Finally, the efficacy of ALK inhibition treatment was demonstrated in patient-derived organoids. Collectively, our findings suggest that ALK inhibition may represent an attractive therapy for CRC, and CMS classification may provide a useful tool to identify patients who could benefit from this treatment. These findings offer rationale and pharmacological strategies for the treatment of CMS1 CRC.

cancer biology↗

bioRxiv2020

Glucocorticoid Receptor ablation promotes cardiac regeneration by hampering cardiomyocyte terminal differentiation

In mammals, glucocorticoid levels rise dramatically shortly before birth and prepare the foetus for post-natal life by promoting the maturation of the lungs and other organs. However, their impact on cardiac postnatal growth and regenerative plasticity is unknown. Here, we demonstrate that exposure to endogenous glucocorticoids facilitates cell cycle exit and reduces the proliferation of neonatal cardiomyocytes. This cytostatic activity is shared by several synthetic glucocorticoid receptor (GR) agonists routinely used in clinical settings. We also observed that GR levels increase in cardiomyocytes during early post-natal development. Importantly, in vivo cardiomyocyte-specific GR ablation delayed the transition from hyperplastic (increase in cell number) to hypertrophic (increase in cell size) growth. Further, GR ablation partially impaired cardiomyocyte maturation, reducing myofibrils-mitochondria organization along with the expression of genes involved in fatty acid metabolism, mitochondrial respiration and energy transfer from mitochondria to the cytosol. Finally, we show increased cardiomyocyte proliferation in GR ablated juvenile and adult cardiomyocytes in response to myocardial infarction in vivo, thus promoting cardiac tissue regeneration. We suggest that GR antagonization could serve as a strategy for heart regeneration based on endogenous cardiomyocyte renewal.

cell biology↗