bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–04–13
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. Cancer-associated fibroblasts secrete CSF3 to promote TNBC progression via enhancing PGM2L1-dependent glycolysis reprogramming.
  2. Lipid metabolism associated PLPP4 gene drives oncogenic and adipogenic potential in breast cancer cells.
  3. Extracellular Fibronectin and Hyaluronic Acid Effects on Tumorigenic Functions of Triple-Negative Breast Cancer Cells.
  4. The transcriptional regulators GATA6 and TET1 regulate the TGF-β pathway in cancer-associated fibroblasts to promote breast cancer progression.
  5. Inhibition of IL-8/CXCR2 signaling axis prevents tumor growth and metastasis in triple negative breast cancer cells.
  6. From Fat Providers to Cancer Therapy: Adipocytes as Unexpected Allies.
  7. Estrogen-induced FXR1 promotes endocrine resistance and bone metastasis in breast cancer via BCL2 and GPX4.
  8. Matrix metalloproteinase-driven epithelial-mesenchymal transition: implications in health and disease.
  1. Cell Death Dis. 2025 Apr 04. 16(1): 249
    Cancer-associated fibroblasts secrete CSF3 to promote TNBC progression via enhancing PGM2L1-dependent glycolysis reprogramming.
    Wenqi Qin, Bing Chen, Xin Li, Wenjing Zhao, Lijuan Wang, Ning Zhang, Xiaolong Wang, Dan Luo, Yiran Liang, Yaming Li, Xi Chen, Tong Chen, Qifeng Yang.
      Triple-negative breast cancer (TNBC) is characterized by a pronounced hypoxic tumor microenvironment, with cancer-associated fibroblasts (CAFs) serving as the predominant cellular component and playing crucial roles in regulating tumor progression. However, the mechanism by which CAFs affect the biological behavior of tumor cells in hypoxic environment remain elusive. This study employed a bead-based multiplex immunoassay to analyze a panel of cytokines/chemokines and identified colony stimulating factor 3 (CSF3) as a significantly elevated component in the secretome of hypoxic CAFs. We found that CSF3 promoted the invasive behavior of TNBC cells by activating the downstream signaling pathway of its receptor, CSF3R. RNA sequencing analysis further revealed that phosphoglucomutase 2-like 1 (PGM2L1) is a downstream target of the CSF3/CSF3R signaling, enhancing the glycolysis pathway and providing energy to support the malignant phenotype of breast cancer. In vivo, we further confirmed that CSF3 promotes TNBC progression by targeting PGM2L1. These findings suggest that targeting CSF3/CSF3R may represent a potential therapeutic approach for TNBC.
    DOI:  https://doi.org/10.1038/s41419-025-07580-6
  2. Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Apr 03. pii: S1388-1981(25)00017-4. [Epub ahead of print] 159609
    Lipid metabolism associated PLPP4 gene drives oncogenic and adipogenic potential in breast cancer cells.
    Sneha Soni, Sweta H Makwana, Shivani Bansal, Monika Kumari, Chandi C Mandal.
      Lipid metabolic reprogramming plays a pivotal role in cancer cell evolution and causing subsequent cancer growth, metastasis and therapy resistance. Cancer associated adipocyte and/or cancer derived adipocyte-like cells often supply fuels and various factors to fulfill the cells bioenergetics to enhance oncogenic potential. This study intends to find out a set of dysregulated genes involved in lipid metabolism in breast cancer studies and uncovers the role of unexplored dysregulated gene in cancer potential. Cancer database analysis determines seven seed signature genes (PLPP2, PLPP4, CDS1, ASAH2, LCLAT1, LPCAT1 and LASS6/CERS6) concluded from relative expression and survival analysis. Furthermore, experimental analysis unveils the gene PLPP4 (Phospholipid Phosphatase 4) as oncogene confirmed by knockdown and overexpression studies in MDA-MB 231 and MCF-7 breast cancer cells. PLPP4 enzyme is involved in regulation of triacyl glycerol metabolism. Lipid accumulation along with other studies documented enhanced lipid droplets, TAG formation and glycerol release with concomitant increased expressions of various adipogenic markers (e.g., PPARγ, perilipin 1 and leptin) in breast cancer cells transfected with PLPP4 gene expressing plasmid whereas downregulation of PLPP4 gene diminished lipid accumulation and adipocyte marker gene expressions. Our findings also revealed that BMP2 induced adipogenic potential in breast cancer cells was mitigated in response to downregulation of PLPP4 gene expression. All these findings together, for first time, demonstrated that BMP2 drives PLPP4 to enhance both oncogenic and adipogenic potential in breast cancer cells. This article uncovers the perturbed lipid metabolism associated PLPP4 acts as oncogene presumably by modulating adipogenic activity in cancer cells.
    Keywords:  Adipogenic potential; Breast cancer; Lipid metabolism; Phospholipid Phosphatase 4
    DOI:  https://doi.org/10.1016/j.bbalip.2025.159609
  3. J Biomed Mater Res A. 2025 Apr;113(4): e37906
    Extracellular Fibronectin and Hyaluronic Acid Effects on Tumorigenic Functions of Triple-Negative Breast Cancer Cells.
    Jacob Heiss, Nina Treacher, Astha Lamichhane, Anju Rana Magar, Hossein Tavana.
      The extracellular matrix (ECM) in solid tumors provides structural support and signaling cues to cancer cells. Altered ECM in tumors promotes local invasion of cancer cells, a key step toward metastasis. Engineered tumor models that are used to study cancer invasion often focus on the effects of an individual ECM molecule on specific functions of cancer cells. However, how different components of ECM in a complex tumor model may co-regulate cancer invasion and the underlying signaling pathways is understudied. We developed a 3D tumor model of triple-negative breast cancer (TNBC) to study the effects of fibronectin and hyaluronic acid, alone or in combination, on TNBC cell invasion of collagen-based hydrogels. Our focus on these molecules was due to their significance in breast tumors, disease progression, and association with worse outcomes in patients. Results showed that fibronectin and hyaluronic acid significantly increase collagen invasion of TNBC cells and oncogenic signaling but not in combination, potentially due to differences in the microstructure of the hydrogels. Fibronectin and hyaluronic acid in composite hydrogels also promoted drug resistance and cancer stemness. This study demonstrated the utility of a 3D tumor model for functional and mechanistic studies to define complex effects of ECM in solid cancers.
    Keywords:  breast tumor model; cancer stemness; cell invasion; extracellular matrix
    DOI:  https://doi.org/10.1002/jbm.a.37906
  4. Cell Death Discov. 2025 Apr 11. 11(1): 164
    The transcriptional regulators GATA6 and TET1 regulate the TGF-β pathway in cancer-associated fibroblasts to promote breast cancer progression.
    Mohammad H Ghazimoradi, Sadegh Babashah.
      Cancer-associated fibroblasts (CAFs) are pivotal drivers of tumor progression, yet the molecular mechanisms underlying their activation remain incompletely understood. Here, we identified the TET1/SMAD4/GATA6 regulatory axis as a central mechanism governing CAF transformation and function in breast cancer. Through integrative in vitro and in vivo models, we demonstrated that TET1, an epigenetic modulator, demethylates the SMAD4 promoter, enhancing SMAD4 expression. SMAD4 transcriptionally upregulates GATA6, which amplifies TGF-β signaling by directly activating the TGF-β promoter, establishing a self-reinforcing feedforward loop critical for CAF identity and stromal-tumor crosstalk. GATA6 and TET1 were significantly upregulated in breast CAFs compared to normal fibroblasts (NFs) and TGF-β-induced CAFs. Loss- or gain-of-function experiments revealed that these regulators control CAF survival, marker expression, and secretion of pro-tumorigenic factors. Knockdown of GATA6 or TET1 reduced CAF-mediated migration and invasion of breast cancer cells in vitro, while their overexpression enhanced cancer cell aggressiveness. Mechanistically, TET1-mediated epigenetic remodeling and GATA6-driven transcriptional activation converge on the TGF-β/SMAD pathway, sustaining CAF activation. In vivo, tumors derived from GATA6- or TET1-depleted CAFs exhibited reduced growth, proliferation, and CAF engraftment, underscoring their role in tumor progression. These findings position GATA6 and TET1 as promising targets to disrupt CAF-driven tumorigenesis, offering novel strategies for breast cancer treatment. By unraveling the epigenetic-transcriptional interplay within the tumor microenvironment, this study advances our understanding of stromal reprogramming and its implications for precision oncology.
    DOI:  https://doi.org/10.1038/s41420-025-02438-4
  5. Pharmacology. 2025 Apr 04. 1-17
    Inhibition of IL-8/CXCR2 signaling axis prevents tumor growth and metastasis in triple negative breast cancer cells.
    Yisun Jeong, Sun Young Yoon, Seung Pil Jung, Seok Jin Nam, Jeong Eon Lee, Sangmin Kim.
       INTRODUCTION: Previously, we reported that interleukin-8 (IL-8) was associated with poor prognosis of basal like breast cancer patients and has been identified as a pro-tumorigenic factor, facilitating cell invasion and migration. Here, we investigated the pharmacological impact of inhibitors targeting the chemokine receptors, CXCR1 and CXCR2, which are activated by IL-8.
    METHODS: The survival rates of TNBC patients by IL-8 were analyzed by the Kaplan-Meier plotter. The levels of mRNA and protein expression were analyzed by real-time PCR and western blotting. The alteration of apoptotic cell death-related proteins by SB225002 was analyzed by the Proteome Profiler Human Apoptosis Array. Cell growth was analyzed by MTT and colony forming assay. Apoptosis and cell cycle were analyzed by FACS.
    RESULTS: Aberrant IL-8 expression is involved with the prognosis of triple-negative breast cancer (TNBC) patients. Basal IL-8 levels are markedly elevated in TNBC cells compared to those in HER2+ and/or ER+ breast cancer cells. Furthermore, recombinant human IL-8 treatment enhanced cell invasiveness in TNBC cells. To counteract the tumor-promoting effects of IL-8, we assessed the therapeutic potential of CXCR1 and CXCR2 inhibitors. Notably, while reparixin, a CXCR1-specific inhibitor, exhibited no impact on cell viability, SB225002, a CXCR2-specific inhibitor, significantly reduced cell viability in a dose-dependent manner. There was a noticeable reduction in the levels of anti-apoptotic biomarkers, including Bcl-2, cIAP-1, cIAP-2, Survivin, XIAP, HIF-1α, and HO-1, following SB225002 treatment. Our findings indicate an increase in the apoptotic cell population with SB225002 treatment in TNBC cells. In xenograft models, SB225002 effectively diminished the metastatic potential of 4T1 cells, which are known to metastasize to the lung and liver.
    CONCLUSION: Our results underscore the significant role of the IL-8/CXCR2 signaling axis in the metastasis of TNBC and suggest that CXCR2 inhibitors such as SB225002 may be promising therapeutic agents for TNBC patients.
    DOI:  https://doi.org/10.1159/000545659
  6. Cancer Res. 2025 Apr 09.
    From Fat Providers to Cancer Therapy: Adipocytes as Unexpected Allies.
    Camille Attané, Catherine Muller.
      Adipocytes from white adipose tissue support cancer progression by supplying fatty acids to tumor cells while cold-activated brown adipose tissue has been shown to inhibit tumor growth by disrupting cancer cell metabolism. In a groundbreaking study published in Nature Biotechnology, Nguyen and colleagues developed Adipose-Modified Therapy (AMT), a strategy that genetically reprograms white adipocytes to outcompete tumors for key nutrients. Using CRISPR activation technology, researchers enhanced adipocyte glucose and fatty acid consumption, by inducing a stable browning phenotype. In vitro, browned adipocytes reduced glycolysis and fatty acid oxidation in cancer cells, inhibiting their proliferation. Implantation of engineered adipose organoids adjacent to tumors suppressed tumor growth, reduced angiogenesis, and altered metabolic gene expression in xenograft models. AMT also prevented tumor development in genetic mouse models of cancer, suggesting a role in cancer prevention. Finally, modified human mammary adipocytes inhibited the growth of patient-derived breast cancer organoids. This therapy, based on autologous fat transplantation, could offer a reversible and patient-specific approach. Challenges remain, including metabolic plasticity in cancer cells and the fragility of mature adipocytes in cell culture. AMT represents a paradigm shift in cancer therapy, leveraging adipocytes as metabolic competitors rather than tumor facilitators, opening new avenues for metabolism-targeted cancer treatments.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1511
  7. Front Cell Dev Biol. 2025 ;13 1563353
    Estrogen-induced FXR1 promotes endocrine resistance and bone metastasis in breast cancer via BCL2 and GPX4.
    Yinzhong Shang, Tingfang Cao, Xin Ma, Le Huang, Mingming Wu, Junchao Xu, Jiarui Wang, Hao Wang, Sheng Wu, Vijay Pandey, Zhengsheng Wu, Weijie Zhang, Peter E Lobie, Xinghua Han, Tao Zhu.
      Estrogen signaling dysregulation plays a critical role in the development of anti-estrogen resistance and bone metastasis of ER+ mammary carcinoma. Using quantitative proteomic screening, we identified FXR1 as an estrogen-regulated RNA-binding protein associated with anti-estrogen resistance. Mechanistically, estrogen and IGF1 facilitate FXR1 protein translation via the PI3K/AKT/mTOR/EIF4E pathway. FXR1 enhances cellular resistance to apoptosis and ferroptosis by facilitating the maturation of BCL2 pre-mRNA and stabilizing GPX4 mRNA, respectively. Anti-estrogen resistant cells exhibit elevated FXR1 expression, and FXR1 depletion restores their sensitivity to tamoxifen. Moreover, combining FXR1 depletion with a ferroptosis inducer induces synergistic lethal in anti-estrogen resistant cells. Finally, we provide proof-of-concept evidence supporting FXR1 antagonism as a potential treatment for bone metastases in ER+ breast cancer. Our findings highlight FXR1 as a promising therapeutic target to improve existing therapeutic regimes for ER+ breast cancer patients.
    Keywords:  FXR1; anti-estrogen resistance; apoptosis; estrogen; ferroptosis
    DOI:  https://doi.org/10.3389/fcell.2025.1563353
  8. J Transl Med. 2025 Apr 11. 23(1): 436
    Matrix metalloproteinase-driven epithelial-mesenchymal transition: implications in health and disease.
    Ghazaleh Khalili-Tanha, Evette S Radisky, Derek C Radisky, Alireza Shoari.
      Epithelial-mesenchymal transition (EMT) is a process in which epithelial cells, defined by apical-basal polarity and tight intercellular junctions, acquire migratory and invasive properties characteristic of mesenchymal cells. Under normal conditions, EMT directs essential morphogenetic events in embryogenesis and supports tissue repair. When dysregulated, EMT contributes to pathological processes such as organ fibrosis, chronic inflammation, and cancer progression and metastasis. Matrix metalloproteinases (MMPs)-a family of zinc-dependent proteases that degrade structural components of the extracellular matrix-sit at the nexus of this transition by dismantling basement membranes, activating pro-EMT signaling pathways, and cleaving adhesion molecules. When normally regulated, MMPs promote balanced ECM turnover and support the cyclical remodeling necessary for proper development, wound healing, and tissue homeostasis. When abnormally regulated, MMPs drive excessive ECM turnover, thereby promoting EMT-related pathologies, including tumor progression and fibrotic disease. This review provides an integrated overview of the molecular mechanisms by which MMPs both initiate and sustain EMT under physiological and disease conditions. It discusses how MMPs can potentiate EMT through TGF-β and Wnt/β-catenin signaling, disrupt cell-cell junction proteins, and potentiate the action of hypoxia-inducible factors in the tumor microenvironment. It discusses how these pathologic processes remodel tissues during fibrosis, and fuel cancer cell invasion, metastasis, and resistance to therapy. Finally, the review explores emerging therapeutic strategies that selectively target MMPs and EMT, ranging from CRISPR/Cas-mediated interventions to engineered tissue inhibitors of metalloproteinases (TIMPs), and demonstrates how such approaches may suppress pathological EMT without compromising its indispensable roles in normal biology.
    Keywords:  Cancer metastasis; Epithelial–mesenchymal transition (EMT); Extracellular matrix (ECM) remodeling; Matrix metalloproteinases (MMPs)
    DOI:  https://doi.org/10.1186/s12967-025-06447-w
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