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Temporo-spatial cellular atlas of the regenerating alveolar niche in idiopathic pulmonary fibrosis
Abstract Healthy alveolar repair relies on the ability of alveolar stem cells to differentiate into specialized epithelial cells for gas exchange. In chronic fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF), this regenerative process is abnormal but the underlying mechanisms remain unclear. Here, using human lung tissue that represents different stages of disease and a 33-plex single-cell imaging mass cytometry (IMC), we present a high-resolution, temporo-spatial cell atlas of the regenerating alveolar niche. With unbiased mathematical methods which quantify statistically enriched interactions, CD206himacrophage subtype and an alveolar basal intermediate epithelial cell emerge as the most statistically robust spatial association in the epithelial and immune cell interactome, found across all stages of disease. Spatially resolved receptor–ligand analysis further offers an in silico mechanism by which these macrophages may influence epithelial regeneration. These findings provide a foundational step toward understanding immune–epithelial dynamics in aberrant alveolar regeneration in IPF.
Blood Lipoproteins Shape the Phenotype and Lipid Content of Early Atherosclerotic Lesion Macrophages: A Dual-Structured Mathematical Model
AbstractMacrophages in atherosclerotic lesions exhibit a spectrum of behaviours or phenotypes. The phenotypic distribution of monocyte-derived macrophages (MDMs), its correlation with MDM lipid content, and relation to blood lipoprotein densities are not well understood. Of particular interest is the balance between low density lipoproteins (LDL) and high density lipoproteins (HDL), which carry bad and good cholesterol respectively. To address these issues, we have developed a mathematical model for early atherosclerosis in which the MDM population is structured by phenotype and lipid content. The model admits a simpler, closed subsystem whose analysis shows how lesion composition becomes more pathological as the blood density of LDL increases relative to the HDL capacity. We use asymptotic analysis to derive a power-law relationship between MDM phenotype and lipid content at steady-state. This relationship enables us to understand why, for example, lipid-laden MDMs have a more inflammatory phenotype than lipid-poor MDMs when blood LDL lipid density greatly exceeds HDL capacity. We show further that the MDM phenotype distribution always attains a local maximum, while the lipid content distribution may be unimodal, adopt a quasi-uniform profile or decrease monotonically. Pathological lesions exhibit a local maximum in both the phenotype and lipid content MDM distributions, with the maximum at an inflammatory phenotype and near the lipid content capacity respectively. These results illustrate how macrophage heterogeneity arises in early atherosclerosis and provide a framework for future model validation through comparison with single-cell RNA sequencing data.
Advection-dominated models of atherosclerotic plaque composition: The impacts of cell death and cholesterol toxicity.
Advanced atherosclerotic plaques are characterised by a large necrotic core containing highly inflammatory lipids and debris from dead cells. In large plaques, newly recruited macrophages fail to penetrate this core, and instead push existing material deeper inside the plaque. In this paper, we consider two multiphase models for early atherosclerotic plaque growth, and we analyse their behaviour in the limiting regime where bulk advection drives mass transport of cells and lipids. In this regime, the dynamics of the deep plaque can be approximated by a system of advection-reaction equations. By applying the method of characteristics to these equations, we derive a set of ODEs that describes the evolution of individual segments of plaque tissue. We apply this approximation to a simple 1D three-phase model comprising macrophage foam cells, dead cells, and modified LDL, and we investigate how plaque tissue composition depends on the relative rates of cell death and efferocytosis (cell recycling). We also consider a six-phase model in which death rates depend on intracellular cholesterol content. We use this model to study the effects of cholesterol-induced toxicity, and the beneficial effects of high density lipoproteins (HDL), which can remove excess cholesterol from macrophages. We show that for both multiphase models, the advection-reaction approximations capture key structural features of the full model solutions, including the relative proportions of live and dead cells, and persistent spatial heterogeneities that arise from time-varying boundary influxes of LDL and HDL.
Proneural-Mesenchymal hybrid glioblastoma cells are resistant to therapy and dependent on nuclear import.
BackgroundDespite extensive research efforts, glioblastoma (GBM) remains a deadly disease with poor prognosis. Although previous studies have identified various cell states within GBM tumors, the molecular mechanism underlying adaptive GBM cell plasticity induced by conventional therapy remains unclear.MethodsWe used fluorescent reporters for proneural (PN) and mesenchymal (MES) subtypes to monitor GBM cell plasticity in real-time across multiple patient-derived cell lines. This approach revealed cells that concurrently expressed both proneural and mesenchymal markers. To investigate this unique hybrid population, we implemented a comprehensive methodological approach encompassing bulk and single-cell RNA sequencing, single-cell ChIP sequencing, nuclear proteomics, high-resolution imaging, orthotopic mouse models, clinical dataset analysis, and pharmacological and genetic techniques. This multifaceted strategy allowed us to gain functional and molecular insights into this distinct cellular population.ResultsWe showed that these hybrid cells are increased by conventional therapies, and are resistant to these therapies. At the molecular level, hybrid cells display significant alterations in chromatin structure and nuclear protein composition, elevated transcriptional activity, Myc activation, and improved transport between the nucleus and cytoplasm. Genetic and pharmaceutical inhibition of the nuclear import/export shuttling machinery, increased in hybrid cells, effectively suppressed adaptive GBM cell plasticity and hybrid identity, thereby enhancing the sensitivity of GBM cells to therapies.ConclusionOur results indicate that GBM hybrid cells play a crucial role in chemoradiation resistance. The nuclear transport machinery presents a potential therapeutic target for hybrid cells, offering a way to counteract the typical resistance to treatment observed in GBM.
BRN2 is a non-canonical melanoma tumor-suppressor
AbstractWhile the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, in a BrafV600EPtenF/+ context, we show that BRN2 haplo-insufficiency promotes melanoma initiation and metastasis. However, metastatic colonization is less efficient in the absence of Brn2. Mechanistically, BRN2 directly induces PTEN expression and in consequence represses PI3K signaling. Moreover, MITF, a BRN2 target, represses PTEN transcription. Collectively, our results suggest that on a PTEN heterozygous background somatic deletion of one BRN2 allele and temporal regulation of the other allele elicits melanoma initiation and progression.
Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A
Abstract Chromothripsis, the chaotic shattering and repair of chromosomes, is common in cancer. Whether chromothripsis generates actionable therapeutic targets remains an open question. In a cohort of 64 patients in blast phase of a myeloproliferative neoplasm (BP-MPN), we describe recurrent amplification of a region of chromosome 21q (‘chr. 21amp’) in 25%, driven by chromothripsis in a third of these cases. We report that chr. 21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. DYRK1A, a serine threonine kinase, is the only gene in the 2.7-megabase minimally amplified region that showed both increased expression and chromatin accessibility compared with non-chr. 21amp BP-MPN controls. DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development and is essential for BP-MPN cell proliferation in vitro and in vivo, and represents a druggable axis. Collectively, these findings define chr. 21amp as a prognostic biomarker in BP-MPN, and link chromothripsis to a therapeutic target.
Targeting GRPR for sex hormone-dependent cancer after loss of E-cadherin
Abstract Sex inequalities in cancer are well documented, but the current limited understanding is hindering advances in precision medicine and therapies1. Consideration of ethnicity, age and sex is essential for the management of cancer patients because they underlie important differences in both incidence and response to treatment2,3. Age-related hormone production, which is a consistent divergence between the sexes, is underestimated in cancers that are not recognized as being hormone dependent4–6. Here, we show that premenopausal women have increased vulnerability to cancers, and we identify the cell–cell adhesion molecule E-cadherin as a crucial component in the oestrogen response in various cancers, including melanoma. In a mouse model of melanoma, we discovered an oestrogen-sensitizing pathway connecting E-cadherin, β-catenin, oestrogen receptor-α and GRPR that promotes melanoma aggressiveness in women. Inhibiting this pathway by targeting GRPR or oestrogen receptor-α reduces metastasis in mice, indicating its therapeutic potential. Our study introduces a concept linking hormone sensitivity and tumour phenotype in which hormones affect cell phenotype and aggressiveness. We have identified an integrated pro-tumour pathway in women and propose that targeting a G-protein-coupled receptor with drugs not commonly used for cancer treatment could be more effective in treating E-cadherin-dependent cancers in women. This study emphasizes the importance of sex-specific factors in cancer management and offers hope of improving outcomes in various cancers.
UVB radiation suppresses Dicer expression through β-catenin
ABSTRACT Ultraviolet (UV) rays prompt a natural response in epidermal cells, particularly within melanocytes. The changes in gene expression and related signaling pathways in melanocytes following exposure to UV radiation are still not entirely understood. Our findings reveal that UVB irradiation suppresses the expression of Dicer (also known as Dicer1). This repression is intricately linked to the activation of the phosphoinositide 3-kinase (PI3K), ribosomal S6 kinase (RSK) and Wnt–β-catenin signaling pathways, and is directly associated with transcriptional repression by β-catenin (also known as CTNNB1). Notably, we have identified specific binding sites for the TCF/LEF–β-catenin complex in the Dicer promoter. Collectively, these results emphasize the significance of the UV-induced pathway involving the TCF/LEF–β-catenin complex, which impacts Dicer expression. UV radiation also reduced the levels of specific microRNAs known to be important in the biology of melanocytes. This pathway holds potential importance in governing melanocyte physiology.
Targeting GPCRs and Their Signaling as a Therapeutic Option in Melanoma
G-protein-coupled receptors (GPCRs) serve prominent roles in melanocyte lineage physiology, with an impact at all stages of development, as well as on mature melanocyte functions. GPCR ligands are present in the skin and regulate melanocyte homeostasis, including pigmentation. The role of GPCRs in the regulation of pigmentation and, consequently, protection against external aggression, such as ultraviolet radiation, has long been established. However, evidence of new functions of GPCRs directly in melanomagenesis has been highlighted in recent years. GPCRs are coupled, through their intracellular domains, to heterotrimeric G-proteins, which induce cellular signaling through various pathways. Such signaling modulates numerous essential cellular processes that occur during melanomagenesis, including proliferation and migration. GPCR-associated signaling in melanoma can be activated by the binding of paracrine factors to their receptors or directly by activating mutations. In this review, we present melanoma-associated alterations of GPCRs and their downstream signaling and discuss the various preclinical models used to evaluate new therapeutic approaches against GPCR activity in melanoma. Recent striking advances in our understanding of the structure, function, and regulation of GPCRs will undoubtedly broaden melanoma treatment options in the future.
Efficacy of Targeted Radionuclide Therapy Using [131I]ICF01012 in 3D Pigmented BRAF- and NRAS-Mutant Melanoma Models and In Vivo NRAS-Mutant Melanoma
Purpose: To assess the efficiency of targeted radionuclide therapy (TRT), alone or in combination with MEK inhibitors (MEKi), in melanomas harboring constitutive MAPK/ERK activation responsible for tumor radioresistance. Methods: For TRT, we used a melanin radiotracer ([131I]ICF01012) currently in phase 1 clinical trial (NCT03784625). TRT alone or combined with MEKi was evaluated in three-dimensional melanoma spheroid models of human BRAFV600E SK-MEL-3, murine NRASQ61K 1007, and WT B16F10 melanomas. TRT in vivo biodistribution, dosimetry, efficiency, and molecular mechanisms were studied using the C57BL/6J-NRASQ61K 1007 syngeneic model. Results: TRT cooperated with MEKi to increase apoptosis in both BRAF- and NRAS-mutant spheroids. NRASQ61K spheroids were highly radiosensitive towards [131I]ICF01012-TRT. In mice bearing NRASQ61K 1007 melanoma, [131I]ICF01012 induced a significant extended survival (92 vs. 44 days, p < 0.0001), associated with a 93-Gy tumor deposit, and reduced lymph-node metastases. Comparative transcriptomic analyses confirmed a decrease in mitosis, proliferation, and metastasis signatures in TRT-treated vs. control tumors and suggest that TRT acts through an increase in oxidation and inflammation and P53 activation. Conclusion: Our data suggest that [131I]ICF01012-TRT and MEKi combination could be of benefit for advanced pigmented BRAF-mutant melanoma care and that [131I]ICF01012 alone could constitute a new potential NRAS-mutant melanoma treatment.