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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.
C57BL/6 congenic mouse NRASQ61K melanoma cell lines are highly sensitive to the combination of Mek and Akt inhibitors in vitro and in vivo
AbstractRAS is frequently mutated in various tumors and known to be difficult to target. NRASQ61K/R are the second most frequent mutations found in human skin melanoma after BRAFV600E. Aside from surgery, various approaches, including targeted therapies, immunotherapies, and combination therapies, are used to treat patients carrying NRAS mutations, but they are inefficient. Here, we established mouse NRASQ61K melanoma cell lines and genetically derived isografts (GDIs) from Tyr::NRASQ61K mouse melanoma that can be used in vitro and in vivo in an immune‐competent environment (C57BL/6) to test and discover novel therapies. We characterized these cell lines at the cellular, molecular, and oncogenic levels and show that NRASQ61K melanoma is highly sensitive to the combination of Mek and Akt inhibitors. This preclinical model shows much potential for the screening of novel therapeutic strategies for patients harboring NRAS mutations that have limited therapeutic options and resulted in poor prognoses.
Risk factors of metabolic dysfunction-associated steatotic liver disease in a cohort of patients with chronic hepatitis B.
Background and aimsChronic hepatitis B (CHB) and metabolic dysfunction-associated steatotic liver disease (MASLD) commonly co-exist, with conflicting data in prevalence and disease severity. We aimed to investigate these discrepancies.MethodsThis multicentre study included consecutive CHB patients from 19 European centres. A survey on standard of care for MASLD screening in CHB was circulated.Results1709 CHB patients were included; median age: 53 (42-64), males 60.7%, BMI 25.6 (14-63), 57.3% White. MASLD prevalence (1510 consecutive patients) was 42.3%. BMI (OR=1.27, 95% CI:1.19-1.36), ferritin (OR=1.00, 95% CI:1.00-1.00) and type-2-diabetes (T2DM) (OR=2.60, 95% CI:1.12-6.02) were independently associated with MASLD. The prevalence of advanced fibrosis was 18% (255/1420) in the whole cohort, 25.4% (162/639) among CHB with MASLD, and 13.7% in those without MASLD. Independent predictors of advanced fibrosis were MASLD (OR:2.76, 95%CI:1.50-5.05), BMI (OR:1.08, 95%CI:1.02-1.15), ALT (OR:1.01, 95%CI:1.00-1.03), lower PLTs (OR:0.99, 95%CI:0.98-0.99), insulin-treatment (OR:13.88, 95%CI:2.95-65.28) and long-term antivirals (OR:4.86, 95%CI:2.40-9.85). During follow-up (48 months), only patients without MASLD showed significant LSM improvement over time (p<0.001). Among patients with MASLD, FIB-4 and LSM performed moderately at predicting advanced fibrosis (AUROC 0.71 vs 0.70, p=0.38), against histology. As standard of care, 68.4% centres screened all CHB patients for MASLD. 52.6% followed the same treatment indication in those with CHB and MASLD vs CHB only.ConclusionIn this large European cohort, MASLD and fibrosis were highly prevalent among CHB, while MASLD aggravated liver fibrosis. Though screening strategies remain inconsistent, ferritin levels, increased BMI and T2DM may inform on the presence of MASLD. Biomarkers showed modest performance in predicting fibrosis.
JCMM Annual Review on Advances in Biotechnology for the Treatment of Haematological Malignancies: A Review of the Latest In‐Patient Developments 2024–2025
ABSTRACTAdvances in biotechnology are set to revolutionise the treatment of haematological malignancies. Current treatments have limited efficacy due to their high toxicity and poor long‐term outcomes, particularly in acute myeloid leukaemia (AML). In 2024–2025, emerging targeted therapies promise improved results with reduced adverse effects. This review is the first of an annual series exploring the latest in‐patient developments in several key areas, focusing on mechanisms. We present advances in the use and action of several therapies including epigenetic modulators, protein degraders, apoptotic inducers, gene editing, and immunotherapy. We discuss the individual molecular mechanisms and clinical findings of these developments, emphasising their potential to improve survival and offer renewed hope for individuals with blood cancer. Importantly, such novel approaches with testing in patients should lead to further intensive efforts both at basic and translational research levels aiming at effective targeted and immunotherapy in blood cancers.
The Lipid Droplet Protein DHRS3 Is a Regulator of Melanoma Cell State
ABSTRACTLipid droplets are fat storage organelles composed of a protein envelope and lipid‐rich core. Regulation of this protein envelope underlies differential lipid droplet formation and function. In melanoma, lipid droplet formation has been linked to tumor progression and metastasis, but it is unknown whether lipid droplet proteins play a role. To address this, we performed proteomic analysis of the lipid droplet envelope in melanoma. We found that lipid droplet proteins were differentially enriched in distinct melanoma states; from melanocytic to undifferentiated. DHRS3, which converts all‐trans‐retinal to all‐trans‐retinol, is upregulated in the MITFLO/undifferentiated/neural crest‐like melanoma cell state and reduced in the MITFHI/melanocytic state. Increased DHRS3 expression is sufficient to drive MITFHI/melanocytic cells to a more undifferentiated/invasive state. These changes are due to retinoic acid‐mediated regulation of melanocytic genes. Our data demonstrate that melanoma cell state can be regulated by expression of lipid droplet proteins which affect downstream retinoid signaling.
Spatio-Temporal Dynamics of M<sub>1</sub> and M<sub>2</sub> Macrophages in a Multiphase Model of Tumor Growth.
This study investigates the complex dynamics of vascular tumors and their interplay with macrophages, key agents of the innate immune response. We model the tumor microenvironment as a multiphase fluid, with each cellular population treated as a distinct, non-mixing phase. The framework also incorporates diffusible species that are critical for processes such as nutrient transport, angiogenesis, chemotaxis, and macrophage activation. A central contribution of this work is the explicit modeling of macrophage infiltration and polarization within the tumor microenvironment. The model captures the divergent roles of M1 (anti-tumor) and M2 (pro-tumor) macrophages and their influence on tumor aggressiveness and progression. Through numerical simulations, we demonstrate the emergence of both spatial and phenotypic heterogeneity in the macrophage population, including their peripheral localization and limited core infiltration -patterns consistent with experimental observations. Furthermore, this is the first multiphase model to incorporate the effects of TGF- β -targeting immunotherapy using vactosertib. Our simulations demonstrate that treatment initially enhances the presence of anti-tumor macrophages, followed by a relapse period where tumor dynamics returns to pre-treatment trends. Model parameters are grounded in experimental data and clinically relevant dosage protocols.
NUC-7738 regulates β-catenin signalling resulting in reduced proliferation and self-renewal of AML cells
Acute myeloid leukemia (AML) stem cells are required for the initiation and maintenance of the disease. Activation of the Wnt/β-catenin pathway is required for the survival and development of AML leukaemia stem cells (LSCs) and therefore, targeting β-catenin is a potential therapeutic strategy. NUC-7738, a phosphoramidate transformation of 3’-deoxyadenosine (3’-dA) monophosphate, is specifically designed to generate the active anti-cancer metabolite 3’-deoxyadenosine triphosphate (3’-dATP) intracellularly, bypassing key limitations of breakdown, transport, and activation. NUC-7738 is currently in a Phase I/II clinical study for the treatment of patients with advanced solid tumors. Protein expression and immunophenotypic profiling revealed that NUC-7738 caused apoptosis in AML cell lines through reducing PI3K-p110α, phosphorylated Akt (Ser473) and phosphorylated GSK3β (Ser9) resulting in reduced β-catenin, c-Myc and CD44 expression. NUC-7738 reduced β-catenin nuclear expression in AML cells. NUC-7738 also decreased the percentage of CD34+ CD38- CD123+ (LSC-like cells) from 81% to 47% and reduced the total number and size of leukemic colonies. These results indicate that therapeutic targeting of the PI3K/Akt/GSK3β axis can inhibit β-catenin signalling, resulting in reduced clonogenicity and eventual apoptosis of AML cells.