bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–07–27
seven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. LMO2 regulates epithelial-mesenchymal plasticity of mammary epithelial cells.
  2. ATG7-deficient fibroblast promotes breast cancer progression via exosome-mediated downregulation of SCARB1.
  3. MSN/STAT3 drives cancer stemness and chemoresistance via IL-6/LPAR1 ligand receptor complex in triple-negative breast cancer.
  4. The USP1-WDR48 deubiquitinase complex functions as a molecular switch regulating tumor-associated macrophage activation and anti-tumor response.
  5. Hypoxic cancer-associated fibroblast exosomal circSTAT3 drives triple negative breast cancer stemness via miR-671-5p/NOTCH1 signaling.
  6. Tethered Exosomes Containing the Matrix Metalloproteinase MT1-MMP Contribute to Extracellular Matrix Degradation.
  7. Metabolic reprogramming in breast cancer: Pathways driving progression, drug resistance, and emerging therapeutics.
  1. Res Sq. 2025 Jul 15. pii: rs.3.rs-7034669. [Epub ahead of print]
    LMO2 regulates epithelial-mesenchymal plasticity of mammary epithelial cells.
    Veronica Haro-Acosta, Maria A Juarez, Isobel J Fetter, Andrew Olander, Shaheen S Sikandar.
      Cellular plasticity in mammary epithelial cells enables dynamic cell state changes essential for normal development but can be hijacked by breast cancer cells to drive tumor progression. However, the molecular factors that maintain cellular plasticity through the regulation of a hybrid cell state (epithelial/mesenchymal) are not fully defined. As LMO2 has been previously shown to regulate metastasis, here we determined the role of LMO2 in the normal mammary epithelial cells. Using lineage tracing and knockout mouse models we find that Lmo2 lineage-traced cells persist long-term in the mammary gland, both in the luminal and basal layer but have limited proliferative potential. Lmo2 loss does not impact mammary gland development, but acute deletion decreases in vivo reconstitution. Moreover, LMO2 knockdown in mouse and human mammary epithelial cells (MECs) reduces organoid formation. We find that LMO2 maintains a hybrid cell state in MECs and LMO2 knockdown promotes mesenchymal differentiation. Transcriptional profiling of LMO2 knockdown cells reveals significant enrichment in the epithelial-mesenchymal transition (EMT) pathway and upregulation of MCAM, a negative regulator of regenerative capacity in the mammary gland. Altogether, we show that LMO2 plays a role in maintaining cellular plasticity in MECs, adding insight into the normal differentiation programs hijacked by cancer cells to drive tumor progression.
    DOI:  https://doi.org/10.21203/rs.3.rs-7034669/v1
  2. Cell Death Dis. 2025 Jul 24. 16(1): 556
    ATG7-deficient fibroblast promotes breast cancer progression via exosome-mediated downregulation of SCARB1.
    Kangdi Li, Ting Liu, Zhihong Luo, You Yu, Yi Liu, Zhaoqing Zhang, Wenhua Li.
      Although autophagy-related gene 7 (ATG7) acts as an E1-like activating enzyme and is essential for autophagy, it frequently performs broader roles involved in the modulation of diverse signaling pathways that affect cell proliferation, survival, migration and transformation. ATG7 is often downregulated in various cancers. However, the role of ATG7 in fibroblasts in regulating breast carcinoma remains poorly understood. Herein, we revealed that aberrantly low expression of ATG7 in breast stroma is clinically relevant to breast cancer progression. Loss of ATG7 expression results in fibroblasts acquiring the hallmarks of cancer-associated fibroblasts (CAFs), which finally promote the proliferation, metastasis of breast cancer in vivo and vitro. Detailed regulatory mechanisms showed that ATG7-deficient fibroblasts secrete a new miRNA (miR-6803b) and are then transported into breast cancer cells by exosomes. In breast cancer, miR-6803b targets the SCARB1 gene to inhibit its expression and then promote cancer cell metastasis, resulting in cancer progression. Thus, our results indicate that ATG7 expression in fibroblasts plays a vital role in regulating breast cancer tumorigenesis and progression by modifying stromal-epithelial crosstalk and remodeling the tumor microenvironment (TME). These results suggest that ATG7 can function as a tumor suppressor and represent a new candidate for prognosis and targeted therapy.
    DOI:  https://doi.org/10.1038/s41419-025-07885-6
  3. Breast Cancer Res. 2025 Jul 22. 27(1): 136
    MSN/STAT3 drives cancer stemness and chemoresistance via IL-6/LPAR1 ligand receptor complex in triple-negative breast cancer.
    Cheng Hyun Lee, Soo Young Park, Jae Seok Lee, Da Sol Kim, Ha Yeon Kim, Min Ji Song, Seock-Ah Im, Kyung-Hun Lee, Dae-Won Lee, Ilias P Nikas, Ji Won Koh, So Hyeon Yang, Hyebin Lee, Han Suk Ryu.
       BACKGROUND: Resistance to chemotherapy remains a major clinical challenge in triple-negative breast cancer (TNBC), an intrinsic subtype with limited available therapeutic options. The expression of moesin (MSN) is upregulated in TNBC patients, but little is known about the role of MSN in breast carcinogenesis.
    METHODS: We investigated the MSN-dependent autocrine loop between extracellular interleukin 6 (IL-6) and NF-κB, along with a signaling cascade involving GTPase-mediated STAT3 phosphorylation. Various in vitro and in vivo assays were used to evaluate tumor initiation, growth, and stemness properties in TNBC models.
    RESULTS: High MSN expression was correlated with shorter overall and disease-free survival in TNBC patients. In vivo, MSN promotes tumor initiation and growth. Mechanistically, MSN-mediated IL-6/NF-κB autoregulatory feedback enhances IL-6 transcription. IL-6 binding to LPAR1 activated MSN phosphorylation, which then sequentially phosphorylated the CDC42-PAK4 complex, triggering nuclear translocation of the pSTAT3-MSN complex. This led to pSTAT3-mediated activation of cancer stemness genes (IGFN1, EML1, and SRGN), contributing to Adriamycin resistance. Notably, combination treatment with the FDA-approved STAT3 inhibitor Atovaquone and Adriamycin restored drug sensitivity.
    CONCLUSIONS: Our findings uncover the critical role of MSN in regulating STAT3-mediated cancer stemness via the IL-6/NF-κB signaling axis. These results provide a strong rationale for repositioning STAT3 inhibitors such as Atovaquone as a therapeutic strategy in Adriamycin-resistant TNBC patients exhibiting pSTAT3-MSN complex upregulation.
    Keywords:  Adriamycin resistance; Atovaquone; Cancer stemness; Moesin (MSN); Triple-negative breast cancer (TNBC)
    DOI:  https://doi.org/10.1186/s13058-025-02072-z
  4. Cell Death Differ. 2025 Jul 24.
    The USP1-WDR48 deubiquitinase complex functions as a molecular switch regulating tumor-associated macrophage activation and anti-tumor response.
    Dianwen Han, Lijuan Wang, Shan Jiang, Peng Su, Bing Chen, Wenjing Zhao, Tong Chen, Ning Zhang, Xiaolong Wang, Yiran Liang, Yaming Li, Chen Li, Xi Chen, Dan Luo, Qifeng Yang.
      M2-like tumor-associated macrophages (TAMs) are the main immunosuppressive cells infiltrating the tumor microenvironment (TME), the activation of which is essential for cancer progression and resistance promotion to immunotherapy. However, the regulatory mechanisms underlying TAM activation have not been fully elucidated. Utilizing a CRISPR-Cas9-based genetically engineered mouse model, we discovered that USP1fl/flLyz2cre/+ and WDR48fl/flLyz2cre/+ mice exhibited decreased tumor formation and lung metastasis. Mechanistically, the USP1-WDR48 deubiquitinase complex regulated M2-TAM activation and infiltration in the TME by modulating DDX3X ubiquitination. Specifically, this complex interacted with the N-terminal RecA-like domain 1 of DDX3X, leading to K48-linked deubiquitination and stabilization of DDX3X. Then, DDX3X promoted the translation of signaling molecules Jak1 and Rac1 via its RNA helicase activity, activating the Jak1-Stat3/6 and Rac1-Akt pathways to drive M2-TAM activation. Furthermore, combined inhibition of the USP1/WDR48 and CD47/SIRPα signaling pathways showed synergistic antitumor effects in immunocompetent mice. Notably, USP1 protein expression in tumor stromal tissues independently predicts prognosis in breast cancer patients. These findings indicated the role of the USP1-WDR48 complex as a critical molecular switch controlling TAM activation, presenting novel and promising targets for breast cancer treatment.
    DOI:  https://doi.org/10.1038/s41418-025-01548-x
  5. J Transl Med. 2025 Jul 23. 23(1): 814
    Hypoxic cancer-associated fibroblast exosomal circSTAT3 drives triple negative breast cancer stemness via miR-671-5p/NOTCH1 signaling.
    Lu Yang, Siyuan Zhao, Xu Liu, Yuchen Zhang, Shaorong Zhao, Xuan Fang, Jin Zhang.
       BACKGROUND: The hypoxic tumor microenvironment, particularly hypoxia-conditioned cancer-associated fibroblasts (CAFs), drives breast cancer (BC) progression and therapy resistance. However, the molecular mechanisms linking hypoxic CAFs to BC plasticity and chemoresistance remain elusive.
    METHODS: Primary CAFs were isolated from high-grade BC tissues (Grade III) and characterized (α-SMA⁺/CD34⁻/pan-CK⁻), with normal fibroblasts (NFs) from reduction mammoplasty as controls. Hypoxic CAF-derived exosomal circSTAT3 stability was validated using RNase R resistance and actinomycin D assays. Exosomes were characterized via transmission electron microscopy (TEM), dynamic light scattering (DLS), and marker profiling (CD63⁺/TSG101⁺/Alix⁺, calnexin⁻). Functional effects of hypoxic CAF exosomes on TNBC cells (MDA-MB-231, SUM159) were assessed through proliferation/migration assays, stemness/epithelial-mesenchymal transition (EMT) marker analysis, and siRNA-mediated circSTAT3 knockdown. Mechanistic studies employed luciferase assays and RNA immunoprecipitation (RIP). Chemoresistance was evaluated by cisplatin half-maximal inhibitory concentration (IC₅₀). In vivo tumor growth and stemness enrichment were analyzed in xenografts. Clinical validation used BC tissues (n = 60) and plasma exosomes from BC patients (n = 40) versus healthy controls (n = 25).
    RESULTS: Hypoxic CAF-derived exosomes efficiently transferred circSTAT3 to TNBC cells, promoting proliferation, migration, EMT, and stemness marker expression. SiRNA-mediated circSTAT3 knockdown reversed these effects. Mechanistically, circSTAT3 acted as a competitive endogenous RNA (ceRNA), sponging miR-671-5p to derepress NOTCH1. Hypoxic CAF exosomes increased cisplatin IC₅₀ in TNBC cells, while circSTAT3 depletion restored chemosensitivity. In vivo, hypoxic CAF exosomes accelerated tumor growth, enriched CD44⁺/NOTCH1⁺ populations, and elevated circulating exosomal circSTAT3. Clinically, circSTAT3 was significantly upregulated in advanced BC tissues (p < 0.01) and patient plasma exosomes (p < 0.01), correlating with lymph node metastasis.
    CONCLUSION: This study identifies a hypoxia-driven feedforward loop wherein CAF-derived exosomal circSTAT3 promotes TNBC stemness and chemoresistance via miR-671-5p/NOTCH1 signaling. CircSTAT3 redefines stromal-tumor crosstalk as a circRNA-driven process and serves as both a circulating non-invasive biomarker and a promising therapeutic target to disrupt stromal-mediated resistance in aggressive TNBC.
    Keywords:  Cancer-associated fibroblasts; CircSTAT3; Hypoxia; Triple negative breast cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12967-025-06794-8
  6. J Extracell Vesicles. 2025 Jul;14(7): e70122
    Tethered Exosomes Containing the Matrix Metalloproteinase MT1-MMP Contribute to Extracellular Matrix Degradation.
    Roberta Palmulli, Hannah K Jackson, James R Edgar.
      For cancer cells to escape from the primary tumour and metastasize, they must degrade and navigate through the extracellular matrix (ECM). The transmembrane protease MT1-matrix metalloprotease (MMP) plays a key role in localized matrix degradation, and its overexpression promotes cancer invasion. In this study, we demonstrate that MT1-MMP is trafficked to the intraluminal vesicles of multivesicular endosomes, and subsequently released from cells on exosomes, a subtype of extracellular vesicle that can be retained to the surface of the originating cell by the anti-viral restriction factor, tetherin. Although tetherin overexpression is linked to increased cell migration and invasion in various cancers, its role in these processes remains unclear. Our findings reveal that expression of tetherin by breast cancer cells promotes the retention of MT1-MMP-positive exosomes at their cell surface, while tetherin loss enhances exosome escape and impairs ECM degradation. Thus, tethered exosomes promote the retention of MT1-MMP at the surface of cells, aiding the degradation of the ECM and promoting cancer cell invasion.
    Keywords:  cancer; exosome; extracellular matrix; tetherin
    DOI:  https://doi.org/10.1002/jev2.70122
  7. Biochim Biophys Acta Rev Cancer. 2025 Jul 21. pii: S0304-419X(25)00138-6. [Epub ahead of print]1880(5): 189396
    Metabolic reprogramming in breast cancer: Pathways driving progression, drug resistance, and emerging therapeutics.
    Pankaj Garg, Gargi Singhal, David Horne, Ravi Salgia, Sharad S Singhal.
      Breast cancer (BC), one of the most frequent causes of cancer-related death in women, is known to be a highly heterogeneous disease in regard to molecular subtypes, which seem to possess different metabolic profiles. Aberrant metabolism is well understood as one of the hallmarks of cancer and it contributes to BC progression, therapeutic resistance, and metastasis. Here, we analyze BC metabolism and how certain cancer types, such as hormone receptor-positive, HER2-positive, and triple-negative BC, use glycolysis, lipid metabolism, amino acid compulsion, and mitochondrial biogenesis to feed and proliferate. These metabolic hallmarks, in the context of the tumor microenvironments, are illustrated to highlight the metabolic byproducts that are derived from reprogrammed pathways and are vital to immunosuppression and tumor survival under low oxygen and nutrient availability. Furthermore, we emphasize novel trends in anticancer drugs designed to strike on these metabolic dependencies to suppress tumor growth. In addition to summing up current knowledge about metabolic reprogramming in BC, this review reveals new targets for specific treatments that might enhance prognosis in certain types of BC. This review aims to bridge basic scientific insights and clinical perspectives, guiding future metabolic interventions in BC toward clinically relevant, subtype-specific therapeutic strategies.
    Keywords:  Biomarker driven therapies; Breast cancer; Metabolic pathway inhibition; Metabolic reprogramming; Therapeutic resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189396
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