bims-raghud 2026-05-31 papers

Issue of 2026–05–31
three papers selected by
Irene Sambri, TIGEM

Ther Adv Respir Dis. 2026 Jan-Dec;20:20 17534666261451630

Novel FLCN mutations in Birt-Hogg-Dubé patients and potential intervention of FLCN mRNA.

Wenxue Bai, Mengyao Guo, Lijuan Hua, Xuezhao Wang, Lirong Chen, Bingyi Liu, Yi Wang, Ying Zhou, Qi Wang, Ni Zhang, Lan Chen, Min Wu, Zongzhe Li, Min Xie.

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder caused by folliculin (FLCN) gene mutations, with ethnically heterogeneous mutational spectra. Current management is primarily supportive and lacks curative therapies.
OBJECTIVES: This study aimed to characterize the clinical features and genetic variants in two distinct Chinese families with BHD syndrome and to preliminarily explore the feasibility of an mRNA-based protein replacement approach.
DESIGN: A family-based prospective cohort study was conducted to identify FLCN mutations in two BHD families carrying rare FLCN variants enrolled in 2023.
METHODS: Whole-exome sequencing (WES) identified candidate mutations in probands, which were validated by Sanger sequencing (p.W376R and p.Q44*). Structural/functional impacts of p.W376R were analyzed via bioinformatics and qPCR. HEK293T cells were transfected with empty vector, wild-type FLCN, or mutant plasmids (p.W376R and p.Q44*), followed by co-transfection with or without synthetic FLCN mRNA. FLCN expression and mTORC1 signaling were assessed.
RESULTS: Affected members in both families predominantly presented with respiratory symptoms, lacking typical skin lesions and kidney tumors. WES identified the FLCN variants p.W376R (previously classified as a Variant of Uncertain Significance, VUS) and a novel nonsense mutation p.Q44*. Genotype-phenotype co-segregation was confirmed for p.W376R. In vitro analyses demonstrated that both mutations reduced FLCN protein expression, leading to mTORC1 hyperactivation. Exogenous FLCN mRNA delivery rescued functional protein expression and reversed mTORC1 dysregulation.
CONCLUSION: We provide co-segregation and functional evidence supporting the reclassification of the FLCN p.W376R variant as pathogenic according to ACMG guidelines and report a novel pathogenic mutation, p.Q44*, expanding the known FLCN mutational spectrum. Importantly, FLCN mRNA supplementation restored FLCN expression in vitro, providing preliminary evidence for mRNA-based therapeutic strategies in BHD syndrome.

Keywords: BHD syndrome; FLCN; mRNA intervention; p.Q44*; p.W376R

DOI: https://doi.org/10.1177/17534666261451630

bioRxiv. 2026 May 13. pii: 2026.05.09.724025. [Epub ahead of print]

Divergent signaling profiles in mTOR gain-of-function Smith-Kingsmore syndrome (SKS) and TSC2 deficiency.

Curtis R Carlson, Yang Shen, Hongzhi He, Erwin K Gudenschwager, Chunyan Hou, Junfeng Ma, Joanna C Chiu, Andrew C Liu.

Smith-Kingsmore syndrome (SKS) is a rare neurodevelopmental disorder caused by gain-of-function mutations in MTOR , yet whether these mutations phenocopy TSC2 loss or establish a distinct signaling state remains unclear. Using quantitative proteomics, phosphoproteomics, and transcriptomics in isogenic cell models of SKS ( MTOR Δ4aa ), TSC2 loss ( TSC2 -/- ), and wild-type controls under glucose depletion and refeeding, we find that MTOR Δ4aa and TSC2 -/- cells occupy fundamentally distinct regulatory states. TSC2 -/- cells exhibit broad anabolic remodeling and a transcriptional program dominated by NF-κB- and STAT-driven inflammatory responses. MTOR Δ4aa cells instead display enrichment of nuclear and RNA processing programs, E2F/MYC-driven transcription, and a constrained proteomic dynamic range across nutrient states. Phosphoproteomic analysis of MTOR Δ4aa reveals rerouting of nutrient-responsive signaling toward MAPK/ERK- and Ca 2+ /CaMK-dependent pathways with limited canonical mTORC1/S6K1 engagement. These findings establish SKS as a signaling rewiring disorder distinct from classical mTORC1 hyperactivation, with implications for therapeutic targeting.

DOI: https://doi.org/10.64898/2026.05.09.724025

Biochim Biophys Acta Rev Cancer. 2026 May 27. pii: S0304-419X(26)00093-4. [Epub ahead of print] 189621

The role of hippo pathway in cancer progression: Implications for cancer stem cells and EMT.

Xiao Han, Lu Wang, Ying Li, Yifan Wang.

Cancer is a major global cause of mortality, underscoring the urgent need to decode its fundamental biology and advance targeted therapeutic strategies. The Hippo pathway, a highly conserved signaling cascade, plays indispensable roles in regulating organ size, suppressing tumorigenesis and sustaining stem cell self-renewal. Within tumors, a subpopulation of cancer stem cells (CSCs) possesses the dual capacity for self-renewal and differentiate, thereby driving tumor growth and heterogeneity. Notably, CSC-like cells can be produced by the aberrant activation of epithelial-mesenchymal transition (EMT), a de-differentiation program promoting tumor progression. Emerging evidence indicates that dysregulation of Hippo pathway signaling leads to tumor progression by enhancing CSC characteristics and facilitating EMT. The Hippo pathway also has tissue specific regulatory patterns and plays context dependent dual roles in the tumor microenvironment, either as a tumor suppressor or as an oncogenic driver. Whereas early-stage clinical trials targeting the Hippo pathway have both confirmed the therapeutic potential and revealed major challenges associated with on-target specificity and safety. This review synthesizes recent breakthroughs in our understanding of the mechanistic links between Hippo signaling, CSCs and tumor progression, offering novel perspectives on potential therapeutic vulnerabilities.

Keywords: Cancer stem cells; EMT; Hippo pathway; Metastasis; Tumor microenvironment

DOI: https://doi.org/10.1016/j.bbcan.2026.189621