bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–08–31
ten papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. TGFβ1-TNFα regulated secretion of neutrophil chemokines is independent of epithelial-mesenchymal transition in breast tumor cells.
  2. Adipocyte-derived factors induce adherent to suspension transition in breast and pancreatic cancer cells through lipid metabolic alteration.
  3. Oncogenic effects of ECM remodeling in obesity and breast cancer.
  4. NSUN2-tRNAVal-CAC-axis-regulated codon-biased translation drives triple-negative breast cancer glycolysis and progression.
  5. H4K79 and H4K91 histone lactylation, newly identified lactylation sites enriched in breast cancer.
  6. Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis.
  7. LRRC75A-AS1 facilitates breast cancer cell proliferation and invasion via functioning as a CeRNA to modulate miR489-3p/ARD1.
  8. SPOCK1 promotes the progression of breast cancer by modulating cancer-associated fibroblasts and exerts a synergistic effect with ANXA2.
  9. Adipocyte-derived IL6 and triple-negative breast cancer cell-derived CXCL1 co-activate STAT3/NF-κB pathway to mediate the crosstalk between adipocytes and triple-negative breast cancer cells.
  10. SLAMF1 expression in breast cancer cells delays tumor growth in vivo.
  1. Mol Biol Cell. 2025 Aug 20. mbcE25070340
    TGFβ1-TNFα regulated secretion of neutrophil chemokines is independent of epithelial-mesenchymal transition in breast tumor cells.
    Shuvasree SenGupta, Erez Cohen, Joseph Serrenho, Kaleb Ott, Pierre A Coulombe, Carole A Parent.
      Neutrophils exert tumor-promoting roles in breast cancer and are particularly prominent in aggressive breast tumors. The pro-inflammatory signals TGF-β1 and TNF-α are upregulated in breast tumors and induce epithelial-to-mesenchymal transitions (EMT), a process linked to cancer cell aggressiveness. Here, we investigated the roles of TGF-β1 and TNF-α in the recruitment of neutrophils by breast cancer cells. Dual treatment with TGF-β1 and TNF-α induces EMT signatures in premalignant M2 cells, which are part of the MCF10A breast cancer progression model. Conditioned media (CM) harvested from M2 cells treated with TGF-β1/TNF-α gives rise to amplified neutrophil chemotaxis compared to CM from vehicle-treated M2 cells. This response correlates with higher levels of the neutrophil chemokines CXCL1 and CXCL8, in a p38MAPK-dependent manner, and is attenuated by CXCL8-neutralizing antibodies. We combined gene editing, immunological and biochemical assays to show that neutrophil recruitment and EMT are uncoupled in treated M2 cells. Finally, analysis of transcriptomic databases of cancer cell lines revealed a significant correlation between CXCL8 and TGF-β1/TNF-α-regulated or effector genes in breast cancer. These findings establish a novel role for the TGF-β1/TNF-α/p38 MAPK signaling axis in regulating neutrophil recruitment in breast cancer, independent of their profound impact on EMT.
    DOI:  https://doi.org/10.1091/mbc.E25-07-0340
  2. Sci Rep. 2025 Aug 20. 15(1): 30552
    Adipocyte-derived factors induce adherent to suspension transition in breast and pancreatic cancer cells through lipid metabolic alteration.
    Doru Kwon, Hyun Woo Park, Byung Soh Min, Junjeong Choi.
      Adipocytes play a dynamic role in the tumor microenvironment (TME) by acting as facilitators, providing cytokines and metabolites that regulate cancer progression and metastasis. Despite metastasis being a major contributor to cancer-associated mortality, our understanding of how adipocytes influence this process remains limited. This study aims to elucidate the regulatory mechanism of Adherent to Suspension Transition (AST) reprogramming within the adipocyte, driven by anchorage dependency. AST facilitates the conversion of adherent tumor cells into suspension cells, thereby contributing to the generation of circulating tumor cells (CTCs). We have evaluated generating AST cells from primary tumors using a dissemination assay that mimics CTCs in vitro. Additionally, we examined AST cell formation when incubated with human adipocyte-conditioned media (ADCM) using the InCucyte live-cell imaging system. Through this approach, we effectively assessed the impact of the tumor-adipocyte interactions on CTC formation from the perspective of AST. As a metastasis-initiating marker, CD36 is pivotal in fatty acid (FA) acquisition and regulates lipid metabolic remodeling during the AST. The generation of AST cells through AST reprogramming is controlled by fatty acid oxidation (FAO), and pharmacological blockade of CD36 and FAO significantly reduced AST cell generation. This demonstrates that CD36 plays a key role in the early stages of AST-induced dissemination. Additionally, promoting cancer cell aggressiveness through ADCM enhances metastatic potency and upregulates the expression of AST reprogramming factors. Inhibition of lipid metabolism not only suppresses AST cell formation but also decreases survival in suspension. This indicates that exogenous lipid uptake and FAO via CD36 play crucial roles in the metastasis process, facilitating the dissemination of primary tumors into the bloodstream. Adipocytes contribute to cancer progression by supplying various metabolites to cancer cells. While primary tumors predominantly rely on glucose as a major energy source, cellular remodeling during dissemination shifts metabolic dependency toward lipids. In the TME, where adipocytes are abundant, tumor cells acquire FA through CD36-mediated uptake for metabolic adaptation. This shift to lipid metabolism is essential for AST, and thus, targeting lipid metabolism via inhibition of CD36 and FAO could serve as a potential therapeutic strategy for AST.
    Keywords:  AST; Adipocytes; CD36; Circulating tumor cell; Lipid metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.1038/s41598-025-13309-4
  3. Oncogene. 2025 Aug 22.
    Oncogenic effects of ECM remodeling in obesity and breast cancer.
    Mackenzie L Hawes, Marcus A Moody, Caroline R McCauley, Abigail G Huddleston, Maansi Solanky, Dara H Khosravi, Ayushi R Patel, Ronald M Lynch, Suresh K Alahari, Bruce A Bunnell, Jorge A Belgodere, Van T Hoang, Matthew E Burow, Elizabeth C Martin.
      Extracellular matrix (ECM) components are key regulators in breast cancer progression, as ECM remodeling is essential for breast cancer cells to invade into surrounding tissue. This process is characterized by the alignment of fibrillar collagens, breakdown of basement membrane components, and increased interstitial collagen stiffness. In patients with obesity, pre-existing ECM changes, including excessive collagen deposition and heightened matrix stiffness, mimic alterations detected in breast cancer. Given that obesity is a predictor of poor prognosis and resistance to treatment in breast cancer, it is crucial to understand how ECM conditioned by obesity affects disease outcomes. In this review, we highlight known ECM changes that occur with breast cancer and obesity and describe how these changes impact cancer cell metastasis, disease progression, and the breast cancer tumor microenvironment. We examine how obesity driven ECM remodeling affects treatment response and resistance. Further, we discuss how the compounding factor of age contributes to remodeling and current preclinical models of ECM in breast cancer.
    DOI:  https://doi.org/10.1038/s41388-025-03521-x
  4. Cell Mol Biol Lett. 2025 Aug 25. 30(1): 100
    NSUN2-tRNAVal-CAC-axis-regulated codon-biased translation drives triple-negative breast cancer glycolysis and progression.
    Wenlong Wang, Ying Ding, Haixi Zhao, Shouman Wang, Juan Huang, Lunquan Sun.
       BACKGROUND: Epitranscriptomic data indicate that aberrant tRNA modifications in malignant diseases can promote tumor growth by facilitating oncogene translation. NSUN2, a 5-methylcytosine (m5C) methyltransferase of tRNA, is elevated in an array of solid cancers, including triple-negative breast cancer (TNBC). However, it remains unclear how NSUN2 drives aggressive behavior and if NSUN2 could be an effective therapeutic target for TNBC.
    METHODS: Functional experiments, including RNA interference, lentivirus transduction, and in vivo xenograft models, were conducted to evaluate the role of NSUN2 in TNBC cell proliferation, metastasis, and chemoresistance. Ribosome sequencing (Ribo-seq), tRNA m5C bisulfite sequencing, and codon usage bias analysis were employed to explore the translational mechanisms underlying NSUN2-mediated tRNA modifications. Glycolysis assays and molecular docking were used to investigate metabolic reprogramming and protein interactions.
    RESULTS: NSUN2 was significantly upregulated in TNBC and correlated with poor patient prognosis. Mechanistically, NSUN2 mediates m5C modification of tRNAVal-CAC, enhancing the codon-frequency-dependent translation of key glycolysis-related genes, including ALDH3A2, ALDH7A1, HK1, and PFKM. Depletion of NSUN2 disrupted tRNAVal-CAC m5C modification, impairing the translation of these metabolic enzymes and suppressing glycolysis, which ultimately inhibited TNBC cell proliferation, migration, and invasion both in vitro and in vivo. Furthermore, NSUN2 overexpression conferred resistance to docetaxel, while its inhibition sensitized TNBC cells to docetaxel treatment. Clinically, elevated expression levels of NSUN2 and glycolysis-related genes were observed in docetaxel-resistant TNBC tissues, further supporting the role of NSUN2 in chemoresistance.
    CONCLUSIONS: This study identifies NSUN2 as a critical regulator of TNBC progression through tRNAVal-CAC m5C modification and codon-biased translation of glycolysis-related mRNAs. Our findings reveal a novel NSUN2-tRNAVal-CAC axis that orchestrates metabolic reprogramming and translational control in TNBC, offering a promising prognostic biomarker and therapeutic target.
    Keywords:  Metabolism reprogramming; NSUN2; Triple-negative breast cancer; m5C modification; tRNA
    DOI:  https://doi.org/10.1186/s11658-025-00781-z
  5. J Exp Clin Cancer Res. 2025 Aug 23. 44(1): 252
    H4K79 and H4K91 histone lactylation, newly identified lactylation sites enriched in breast cancer.
    Jiena Liu, Liuying Zhao, Meisi Yan, Shengye Jin, Lingmin Shang, Jianyu Wang, Qin Wang, Shilu Zhao, Zibo Shen, Tong Liu, Hao Wu, Da Pang.
      Metabolic reprogramming and epigenetic modification are two hallmarks of cancer. Protein lysine lactylation (Kla) is a novel type of glycolysis lactate-triggered posttranslational modification. However, the role of Kla in breast cancer (BC) remains largely unknown. Here, western blot, and immunohistochemical (IHC) staining of BC tissues revealed that global Kla levels were upregulated in BC tissues, and high levels of Kla were correlated with poor prognosis of patients with BC. A series of in vitro and in vivo assays demonstrated that interruption of glycolysis by lactate dehydrogenase (LDH) inhibitor or silencing LDHA and LDHB repressed the malignant behaviors of BC cells. Moreover, 4D label-free quantitative lactylproteomics analysis of BC tissues and cells revealed that lactylated proteins widely existed in several subcellular compartments and were closely associated with various cancer-related biological processes. Notably, two previously unresearched sites of histone lactylation, H4K79 lactylation (H4K79la) and H4K91 lactylation (H4K91la), were identified to be hyperlactylated in cancer tissues and cells. Glycolytic genes, such as lactate dehydrogenase A (LDHA), phosphoglycerate kinase 1 (PGK1), and hexokinase 1 (HK1) were identified to be the potential candidate genes epigenetically regulated by H4K79la and H4K91la by intersecting through chromatin immunoprecipitation sequencing (ChIP-seq), RNA sequencing (RNA-seq), and TCGA-BRCA database. Pharmacological inhibition of glycolysis downregulated H4K79 and H4K91 lactylation and suppressed the expression of glycolytic genes, whereas treatment with sodium lactate exhibited the opposite effects. Additionally, E1A-binding protein p300 (P300) acted as lysine lactyltransferase to regulate H4K79la and H4K91la, and control the transcription and expression of downstream glycolytic genes in BC cells. The results revealed an intriguing positive feedback loop formed by glycolysis/H4K79la/H4K91la/glycolytic genes in BC, highlighting the relationship between metabolic reprogramming and epigenetic regulation. These findings provide new therapeutic targets for patients with BC.
    Keywords:  Breast cancer; Epigenetic modification; Glycolysis; Lactylation; Post-translational modifications
    DOI:  https://doi.org/10.1186/s13046-025-03512-6
  6. Nat Commun. 2025 Aug 20. 16(1): 7438
    Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis.
    Jeremy Williams, Roman Camarda, Serghei Malkov, Lisa J Zimmerman, Suzanne Manning, Dvir Aran, Andrew Beardsley, Daniel Van de Mark, Rachel Nakagawa, Yong Chen, Charles Berdan, Sharon M Louie, Celine Mahieu, Daphne Superville, Juliane Winkler, Elizabeth Willey, Erica J Hutchins, John D Gagnon, Seda Kilinc Avsaroglu, Kosaku Shinoda, Matthew Gruner, Hiroshi Nishida, K Mark Ansel, Zena Werb, Daniel K Nomura, Shingo Kajimura, Atul J Butte, Melinda E Sanders, Daniel C Liebler, Hope S Rugo, Gregor Krings, John A Shepherd, Andrei Goga.
      A pro-tumorigenic role for adipocytes has been identified in breast cancer, and reliance on fatty acid catabolism found in aggressive tumors. The molecular mechanisms by which tumor cells coopt neighboring adipocytes, however, remain incompletely understood. Here, we describe a direct interaction linking tumorigenesis to adjacent adipocytes. We examine breast tumors and their normal adjacent tissue from several patient cohorts, patient-derived xenografts, and mouse models, and find that lipolysis and lipolytic signaling are activated in neighboring adipose tissue. We find that functional gap junctions form between breast cancer cells and adipocytes. As a result, cAMP is transferred from breast cancer cells to adipocytes and activates lipolysis in a gap junction-dependent manner. We find that connexin 31 (GJB3) promotes receptor triple negative breast cancer growth and activation of lipolysis in vivo. Thus, direct tumor cell-adipocyte interaction contributes to tumorigenesis and may serve as a new therapeutic target in breast cancer.
    DOI:  https://doi.org/10.1038/s41467-025-62486-3
  7. Sci Rep. 2025 Aug 26. 15(1): 31501
    LRRC75A-AS1 facilitates breast cancer cell proliferation and invasion via functioning as a CeRNA to modulate miR489-3p/ARD1.
    Chunjiao Yu, Zhiyuan Wang, Xi Zhang, Ming Yu, Xue Cao, Hongbo Zhao, Shan Yan.
      This study aimed to elucidate the molecular mechanism through which ARD1 regulates breast cancer (BC) progression via the LRRC75A-AS1/miR-489-3p axis. The expression levels of ARD1, miR-489-3p, and LRRC75A-AS1 in BC cells were quantified using reverse transcription-polymerase chain reaction (RT-PCR). The interaction between miR-489-3p and ARD1 was validated through dual-luciferase reporter assays and RNA-binding protein immunoprecipitation (RIP). The sponge effect of LRRC75A-AS1 on miR-489-3p was confirmed by RNA pull-down assays. Functional roles of LRRC75A-AS1, miR-489-3p, and ARD1 in cell proliferation, invasion, and epithelial-to-mesenchymal transition (EMT) were evaluated using colony formation, Transwell, and western blot assays. Moreover, in vivo tumor xenograft experiments were conducted in BALB/c nude mice to assess the effect of LRRC75A-AS1 knockdown and its interaction with miR-489-3p and ARD1 on tumor growth. ARD1 promoted BC cell proliferation, invasion, and EMT. miR-489-3p was identified as a negative regulator of ARD1, while LRRC75A-AS1 acted as a competing endogenous RNA (ceRNA) that sponged miR-489-3p, thereby restoring ARD1 expression. Rescue experiments confirmed that LRRC75A-AS1 facilitated BC cell malignancy via the miR-489-3p/ARD1 axis. Importantly, in vivo studies demonstrated that silencing LRRC75A-AS1 significantly inhibited tumor growth in nude mice, accompanied by reduced ARD1 expression and increased miR-489-3p levels. The inhibitory effect on tumor growth was reversed by miR-489-3p inhibition and further restored by ARD1 knockdown, validating the functional relevance of this regulatory axis in vivo. Both in vitro and in vivo findings reveal that LRRC75A-AS1 promotes breast cancer progression by sponging miR-489-3p and upregulating ARD1. The LRRC75A-AS1/miR-489-3p/ARD1 ceRNA axis represents a novel regulatory pathway and a promising therapeutic target in BC.
    Keywords:  Arrest defective 1; Breast cancer; LRRC75A-AS1; MiR-489-3p
    DOI:  https://doi.org/10.1038/s41598-025-17372-9
  8. Front Oncol. 2025 ;15 1619171
    SPOCK1 promotes the progression of breast cancer by modulating cancer-associated fibroblasts and exerts a synergistic effect with ANXA2.
    Yuan Jie, Xin Fei, Meng Fan.
       Background: SPOCK1, a matricellular glycoprotein, has been implicated in tumor progression, metastasis, and the tumor immune microenvironment, yet its specific roles in breast cancer (BRCA) remain unclear. This study aimed to systematically explore the expression pattern, prognostic significance, mutation landscape, immune association, and spatial localization of SPOCK1 in breast cancer through integrated multi-omics analyses.
    Methods: Transcriptomic, genomic, and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were utilized. Bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) analyses were conducted, including functional enrichment, immune infiltration assessments, mutation profiling, and transcription factor activity analysis. Multiplex immunohistochemistry (mIHC) was performed to validate the spatial distribution of SPOCK1+ cancer-associated fibroblasts (CAFs) within the tumor microenvironment. Statistical analyses were performed using R and GraphPad Prism.
    Results: SPOCK1 was broadly overexpressed in multiple cancer types and significantly associated with poor prognosis in BRCA. High SPOCK1 expression correlated with immune checkpoint activation, enhanced immune infiltration, and enriched metastasis-related pathways such as epithelial-mesenchymal transition (EMT) and TGF-β signaling. Single-cell analysis identified CAFs as the primary cell population expressing SPOCK1, with spatial mIHC confirming their close proximity to tumor cells. Furthermore, SPOCK1-high CAFs exhibited stronger intercellular communications with malignant cells via collagen, fibronectin, and IGFBP signaling pathways, alongside distinct transcription factor and metabolic profiles. In breast cancer CAF cell lines with knockdown of ANXA2 we found that the expression of both SPOCK1 and IGF1 was reduced.
    Conclusion: SPOCK1 serves as a critical regulator of breast cancer progression, influencing tumor metastasis and reshaping the immune microenvironment via CAF-mediated mechanisms. These findings suggest that targeting SPOCK1+ CAFs could offer new therapeutic opportunities for breast cancer treatment.
    Keywords:  AnxA2; SPOCK1; breast cancer; cancer-associated fibroblasts; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2025.1619171
  9. Cell Death Discov. 2025 Aug 21. 11(1): 395
    Adipocyte-derived IL6 and triple-negative breast cancer cell-derived CXCL1 co-activate STAT3/NF-κB pathway to mediate the crosstalk between adipocytes and triple-negative breast cancer cells.
    Guo-Tian Ruan, Li-Chen Zhu, Hai-Lun Xie, He-Yang Zhang, Meng-Meng Song, Li Deng, Han-Ping Shi.
      Triple-negative breast cancer (TNBC) is correlated to a poor prognosis, especially in the context of obesity. The interaction between adipocytes and TNBC cellsplay a key role in the progression of TNBC. This study aims to investigate the mechanisms underlying the cross-talk and progression between adipocytes and TNBC cells. We established a co-culture model involving mature adipose cells (hADSC and 3T3-L1) and TNBC cells. Cell invasion abilities were assessed using wound healing and Transwell assays. Gene and protein expression levels were examined using RT-PCR, western blotting, and immunostaining. Adipocytokine and chemokine levels were measured using ELISA. Additionally, we developed a fat mouse model induced by a high-fat diet and a tumor-bearing model of TNBC cells in vivo. The results indicated a significant enhancement in the invasion abilities of TNBC cells after co-culture. Mature adipose tissue co-cultured with TNBC cells increased the expression and secretion of C-X-C motif chemokine ligand 1 (CXCL1) and upregulated matrix metalloproteinase 7 (MMP7) and MMP9 in TNBC cells by activating the signal transducer and activator of transcription 3 (STAT3) /nuclear factor-κB p65 (NF-κB p65) pathway. Additionally, co-culture activated the STAT3/NF-κB p65 pathway, increasing the expression and secretion of IL6 in adipocytes. Based on the mouse obesity model, our experiments on orthotopic breast fat pad xenoimplantation showed consistent results in vivo. Our findings suggest a cross-talk between TNBC cells and adipocytes, activating the STAT/NF-κB p65 pathway through the production and secretion of CXCL1 and IL6, respectively, thereby promoting TNBC progression. These results propose a potential strategy for developing individualized treatments for patients with TNBC in clinical practice.
    DOI:  https://doi.org/10.1038/s41420-025-02713-4
  10. Sci Rep. 2025 Aug 25. 15(1): 31247
    SLAMF1 expression in breast cancer cells delays tumor growth in vivo.
    Kyung-Hee Song, Seung-Youn Jung, Jeong-In Park, Dong-Hyeon Lee, Jiyeon Ahn, Sang-Gu Hwang, Jie-Young Song.
      Signaling lymphocytic activation molecule (SLAM) family receptors are widely expressed on immune cells, often acting as self-ligands and playing crucial roles in cellular communication and adhesion, thereby modulating immune responses. Several studies have demonstrated that SLAM family receptors are associated with potential immune checkpoints on T cells and play a role in tumor immunity in various cancers. However, the effect of SLAMF1 expression in tumors has been rarely investigated. Here, we confirmed SLAMF1 expression using tissue microarray analysis in breast cancer tissues with diverse pathological characteristics and subtypes. Additionally, SLAMF1 expression in triple-negative breast cancer (TNBC) cells was analyzed using flow cytometry and real-time PCR. Public clinical data analysis suggests that a positive correlation exists between SLAMF1 expression and overall survival and that SLAMF1 levels are slightly increased in patients with breast cancer who received radiation therapy. Similarly, when TNBC cells were irradiated, SLAMF1 expression specifically increased compared to that in non-irradiated cells. To study the biological function of SLAMF1 in mice, we established 4T1-SLAMF1 overexpressing a stable cell line. In the 4T1 syngenetic tumor model, SLAMF1 overexpression triggered strong infiltrating-CD8+ T cell responses and significantly reduced the tumor growth. Our results provide clear evidence for SLAMF1 expression in breast cancer and provide insights into the recent advances in SLAM-based targeted immunotherapies.
    Keywords:  Breast cancer; Cancer immunotherapy; Immune checkpoint; Signaling lymphocytic activation molecule (SLAM) family 1 (CD150)
    DOI:  https://doi.org/10.1038/s41598-025-17322-5
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