bims-merabr 2026-08-23 papers

Cancer Res Commun. 2026 Aug 19.

FGFR1 suppresses STING-mediated interferon response in endocrine therapy resistant breast cancer.

Torbjørn Amundsen Lien, Sushil Dhakal, Anne Marthe Fosdahl Wium, Helga Bergholtz, Serhat Gunesten, Helene Midtun Flatekvål, Daniel Nebdal, Phuong Vu, Antoni Hurtado, Jens Henrik Norum, Therese Sorlie.

Fibroblast growth factor receptor 1 (FGFR1) amplification is frequently observed in ER⁺/HER2⁻ breast cancer and has been linked to poor response to endocrine therapy. While FGFR1 has been implicated in therapeutic resistance, its role in regulating interferon (IFN) response in the context of endocrine resistance remains unclear. We investigated whether FGFR1 modulates the IFN response through the GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in tamoxifen-resistant breast cancer. We employed tamoxifen-resistant ER⁺ breast cancer cell lines and a tamoxifen-sensitive FGFR1-amplified patient-derived xenograft (PDX) model to examine the impact of FGFR1 inhibition on the IFN response through RNA sequencing, FGFR1 knockdown or pharmacologic inhibition, and functional assays. Clinical relevance was evaluated in breast cancer cohorts. Tamoxifen-resistant cells exhibited increased cytosolic, cGAS-positive dsDNA foci alongside elevated p-IRF3, indicating constitutive engagement of the cGAS-STING pathway. FGFR1 inhibition re-sensitized resistant cells to tamoxifen and induced IFN response gene expression, which was further amplified by tamoxifen co-treatment. FGFR1 inhibition similarly potentiated tamoxifen-induced IFN response gene expression in vivo in a FGFR1-amplified PDX model. Mechanistically, FGFR1 knockdown enhanced STING-mediated IFNB1 expression in response to cytosolic DNA. In the METABRIC breast cancer cohort, FGFR1 amplification was associated with poor prognosis specifically in tumors with high STING1 expression. These findings identify FGFR1 as a suppressor of cGAS-STING-mediated interferon response, driven by tamoxifen in ER⁺ breast cancer. Attenuation of this response may represent a previously unrecognized contribution of FGFR1 to tamoxifen resistance.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0821

Front Pharmacol. 2026 ;17 1887125

UNC93B1 drives IL-6/STAT3-dependent tumor-macrophage crosstalk and epithelial-mesenchymal transition in breast cancer.

Xinpeng Li, Hua Hao.

Background: Lipid metabolic reprogramming is increasingly recognized as a driver of breast cancer progression; however, how lipid metabolism-associated risk states are translated into immune remodeling and epithelial-mesenchymal transition (EMT) remains unclear. This study aimed to identify a lipid metabolism-related regulator that mediates tumor-macrophage crosstalk and to experimentally define its role in breast cancer progression.
Methods: Lipid metabolism-related immune regulatory candidates were identified through integrated bulk transcriptomic, machine-learning, single-cell, and spatial transcriptomic analyses. UNC93B1 was prioritized for experimental validation using immunohistochemistry, gain- and loss-of-function assays, tumor cell-macrophage co-culture, ELISA, IL-6 neutralization, and STAT3 inhibition/rescue experiments.
Results: Integrated multi-omics analysis prioritized UNC93B1 as a lipid metabolism-associated immune regulatory hub in breast cancer. UNC93B1 was associated with high lipid metabolism risk status, invasive tumor phenotypes, and stronger expression in aggressive molecular contexts, particularly HER2-enriched and triple-negative breast cancer samples. Single-cell and spatial transcriptomic analyses further linked UNC93B1 to myeloid/macrophage-enriched states, M2-like macrophage polarization, and Toll-like receptor-related immune niches. Experimentally, UNC93B1 knockdown suppressed breast cancer cell proliferation, migration, invasion, STAT3 activation, and EMT, whereas UNC93B1 overexpression produced the opposite effects. In tumor cell-macrophage co-culture systems, tumor cell-derived UNC93B1 enhanced IL-6 secretion, activated STAT3 signaling in macrophages, and promoted M2-like polarization. Reciprocally, macrophage-associated IL-6/STAT3 signaling reinforced EMT and invasive behavior in breast cancer cells. IL-6 neutralization and STAT3 inhibition markedly disrupted this paracrine feedback loop, confirming that UNC93B1 promotes breast cancer progression through an IL-6/STAT3-dependent tumor-macrophage crosstalk axis.
Conclusion: This study identifies UNC93B1 as a macrophage-associated immune regulatory factor linked to lipid metabolism-related risk in breast cancer. Integrated multi-omics analyses and functional experiments demonstrate that UNC93B1 promotes IL-6/STAT3-dependent tumor-macrophage communication, thereby enhancing M2-like macrophage polarization, EMT activation, and invasive tumor behavior. These findings support UNC93B1 as a potential biomarker and intervention target in immunologically aggressive breast cancer. However, the direct role of UNC93B1 in lipid metabolic remodeling remains to be validated through lipidomic and metabolic flux analyses, and its tumor- and microenvironment-dependent effects require further confirmation in orthotopic or immune-competent in vivo breast cancer models.

Keywords: IL-6/STAT3 signaling; UNC93B1; epithelial–mesenchymal transition; lipid metabolism-related risk; macrophage polarization; single-cell sequencing

DOI: https://doi.org/10.3389/fphar.2026.1887125

Cell Signal. 2026 Aug 20. pii: S0898-6568(26)00480-8. [Epub ahead of print] 112822

NID2 drives paclitaxel resistance in triple-negative breast cancer via an LDHA-lactate-histone lactylation axis.

Siliang Wang, Yitong Wang, Kaicheng Bao, Siyu Chen, Guoqing Song, Yi Zhao.

Paclitaxel resistance remains a major barrier to effective treatment of triple-negative breast cancer (TNBC). Nidogen-2 (NID2), an extracellular matrix protein, has been implicated in tumor progression, but its contribution to taxane response is unclear. Here, we integrate patient-derived evidence with mechanistic experiments to delineate the role of NID2 in paclitaxel resistance. In TNBC patient data, higher NID2 is associated with reduced paclitaxel sensitivity and increased histone lactylation signatures. In SUM149 models, NID2 silencing decreases glycolytic output, lowers extracellular lactate, and reduces global lysine lactylation, including H3K18la and H3K9la. These changes are accompanied by downregulation of key glycolysis and lactate-transport components (LDHA and MCT1) and a marked increase in paclitaxel responsiveness. In xenograft tumors, NID2 knockdown similarly suppresses glycolysis- and lactylation-related proteins and enhances the antitumor effect of paclitaxel, whereas paclitaxel alone shows limited impact on the lactylation axis. Together, our findings identify NID2 as a stromal-metabolic regulator that promotes a lactate-histone lactylation program linked to paclitaxel resistance in TNBC, and suggest NID2 as a potential target to improve taxane efficacy.

Keywords: Chemoresistance; Extracellular matrix; Glycolysis; Histone lysine lactylation; LDHA; Lactate metabolism; Metabolic reprogramming; NID2; Paclitaxel resistance; Triple-negative breast cancer

DOI: https://doi.org/10.1016/j.cellsig.2026.112822

Signal Transduct Target Ther. 2026 Aug 21. pii: 341. [Epub ahead of print]11(1):

Glycolytic enolase 1-induced H4K12 lactylation activates quiescent breast cancer stem-like cells in triple-negative breast cancer.

Activation of quiescent or extremely slow-cycling breast cancer stem-like cells (qsBCSCs) contributes to tumor progression, yet the regulatory mechanisms involved in triple-negative breast cancer (TNBC) remain elusive. We developed a dual-reporter system combining NANOG-EGFP and H2B-mCherry pulse-chase labeling to separately identify qsBCSCs and active BCSCs (aBCSCs) in vitro and in vivo. aBCSCs display significant enrichment of glycolysis and lactylation signatures, a finding corroborated by single-cell RNA sequencing (scRNA-seq) of TNBC patient samples. Glycolytic enzyme Enolase 1 (ENO1) expression is positively correlated with elevated histone H4 lysine 12 lactylation (H4K12la) in aBCSCs. Functional studies revealed a positive feedback circuit in which ENO1-increased lactate promotes H4K12la, which in turn activates ENO1 transcription. The ENO1-lactate-H4K12la axis enhances proliferating cell nuclear antigen (PCNA) transcription to activate qsBCSCs. Suppression of ENO1 or H4K12la prevents PCNA upregulation and qsBCSC activation. Importantly, PCNA knockdown alone blocks the activation of qsBCSCs induced by exogenous sodium L-lactate (NALA). In orthotopic breast cancer mouse models, both genetic depletion of ENO1 and pharmacological inhibition of lactate production attenuated tumor growth by blocking qsBCSC activation. Clinically, ENO1 expression was strongly correlated with PCNA expression, with high expression predicting poor OS, RFS, and DMFS. Our results establish the ENO1-H4K12la-PCNA axis as a key metabolic‒epigenetic driver of qsBCSC activation and a therapeutic target in TNBC.

DOI: https://doi.org/10.1038/s41392-026-02916-w

Int Immunopharmacol. 2026 Aug 21. pii: S1567-5769(26)01155-0. [Epub ahead of print]188 117308

Metabolic crosstalk between extracellular matrix, cancer-associated fibroblasts and tumor cells: drivers of tumor progression and therapeutic resistance.

Chenyu Wei, Haolin Sun, Jianglan Long, Xiaojia Liu, Quanfu Li, Bangwei Cao.

The tumor microenvironment (TME) is a critical regulator of cancer progression, with extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) as core components. Metabolic reprogramming is a hallmark of cancer, yet the metabolic crosstalk between ECM, CAFs and tumor cells updates rapidly and remains incompletely understood, and effective therapeutic strategies targeting this axis are lacking. This review summarizes that ECM stiffness and components remodel glucose, lipid, and amino acid metabolism in tumor cells via mechanotransduction and signaling pathways. Meanwhile, metabolic adaptations in turn drive ECM remodeling. In addition, CAFs exhibit high heterogeneity and undergo glycolytic, lipid, and amino acid metabolic reprogramming, providing metabolites to fuel tumor growth and mediate therapeutic resistance. Importantly, this metabolic rewiring profoundly reshapes the tumor immune microenvironment by promoting M2-like tumor-associated macrophage polarization, regulatory T cell expansion, and inhibiting CD8+ T cell mediated anti-tumor responses etc., thereby fostering immune evasion and therapeutic resistance. The reciprocal interactions among ECM, CAFs, metabolic reprogramming, and immunosuppression form a vicious cycle that drives tumor progression, metastasis, and drug resistance. Distinct from prior reviews that independently elaborate ECM mechanometabolism or CAF metabolic reprogramming, this review establishes a unified tripartite conceptual framework termed the ECM-CAF-Tumor Reciprocal Metabolic Cycle, integrating mechanical, metabolic, and immunological dimensions. This review clarifies the metabolic crosstalk mechanisms between ECM, CAFs and tumor cells, providing a theoretical basis for developing combinatorial therapeutic designs integrating metabolism-targeted agents, stroma-directed therapies and immunotherapy to amplify anti-tumor efficacy.

Keywords: Anti-tumor therapy; Cancer-associated fibroblasts; Extracellular matrix; Metabolic reprogramming; Tumor progression

DOI: https://doi.org/10.1016/j.intimp.2026.117308

bioRxiv. 2026 Jul 30. pii: 2026.07.29.741485. [Epub ahead of print]

Genomic Profiling of Estrogen-Related Receptor Identifies Adult Adipocyte-Specific Targets in Drosophila.

Jun Yin, Douglas B Rusch, Jitika S Bhatta, David M Merritt, Lesley N Weaver.

Adipose tissue is a key metabolic organ for carbohydrate and lipid metabolism. Multiple nutrient sensing pathways and metabolic enzymes operate in adipocytes to control energy production and lipid mobilization in response to physiological conditions. Important regulators of glycolytic and lipid metabolism in many species are members of the estrogen-related receptor (ERR) family of nuclear receptors. We previously showed that ERR is required for transcriptional regulation of glycolytic and pentose phosphate pathway enzymes in adult Drosophila females, consistent with what is observed in ERR mutant males and larvae. However, the cell-type specific targets of ERR in adipose and other tissues have not been fully elucidated. Here, using a modified targeted DamID approach (NanoDam), we identified ERR occupancy specifically in adult adipocytes at the loci that encode genes involved in glycolysis, the pentose phosphate pathway, and fatty acid metabolism. Overall, our results predict that ERR centrally functions in adipose tissue to regulate multiple metabolic pathways.

DOI: https://doi.org/10.64898/2026.07.29.741485