bims-merabr 2026-05-24 papers

bioRxiv. 2026 May 05. pii: 2026.05.01.722261. [Epub ahead of print]

CPT1A loss promotes lung metastasis in immune-competent mice via a mechanism of mtDNA release and chronic activation of STING pathway.

Xiaoyong Wang, Shu-Ting Chou, Yoonha Hwang, Jin Chen, Deanna N Edwards.

The metastatic progression of breast cancer involves complex interactions between tumor cells and immune cells, including T cells that exert cytotoxic pressure to limit metastasis. Tumor cells reprogram their metabolism to evade immune surveillance, a critical step to achieving metastatic outgrowth. Using an unbiased CRISPR screen targeting metabolism-related genes and a clinically relevant spontaneous metastasis mouse model, we identified CPT1A, the rate-limiting enzyme in fatty acid β-oxidation, as a suppressor of immune-dependent metastasis. Loss of CPT1A enhances lung metastasis in immunocompetent mice, but not Rag1 KO mice that lack mature lymphocytes. Loss of CPT1A triggers cytosolic mitochondrial DNA (mtDNA) release via the mPTP pore. Cytosolic mtDNA release triggers a STING-dependent inflammatory response, creating an environment that impairs CD8+ T cell function, promoting metastatic outgrowth. Among breast cancer patients, low CPT1A expression correlates with poor survival when CD8+ T cell infiltration is high. These findings reveal an extrinsic role for CPT1A in immune-tumor dynamics and suggest therapeutic opportunities targeting inflammation in metastatic breast cancer.

DOI: https://doi.org/10.64898/2026.05.01.722261

Neuro Oncol. 2026 May 21. pii: noag114. [Epub ahead of print]

LDHA-mediated CREB1 Lactylation Promotes Breast Cancer Brain Metastasis by Transcriptionally Activating Cytoskeletal Remodeling.

Siqi Liu, Zhirui Bai, Yifan Qiao, Yihan Ge, Fengyi Qu, Meihan Li, Jizhao Wang, Xiaobo Shi, Yuan Ma, Jing Li, Xuhuan Cao, Feng Guo, Xiaozhi Zhang, Yuchen Sun.

BACKGROUND: Brain metastasis (BM) is a leading cause of mortality in breast cancer patients. This study utilizes single-cell RNA sequencing (scRNA-seq) to identify high-risk malignant sub-clusters and uncover potential therapeutic targets driving BM.
METHODS: Five pairs of scRNA-seq data of primary breast tumors (PT) and brain metastases (BM) were retrieved from the Gene Expression Omnibus (GEO) database. Following unsupervised clustering and cell-type annotation, specialized bioinformatic pipelines-including inferCNV and pseudotime trajectory analysis-were implemented to delineate malignant subpopulations and evolutionary states associated with high brain metastatic potential. Molecular mechanisms were investigated using ChIP-qPCR, nascent RNA labeling assay, and dual-luciferase assays. Clinical significance was evaluated in a 124 paired-patient cohort using propensity score matching (PSM), while in vivo metastatic potential was assessed via a murine carotid artery injection model.
RESULTS: We identified a specific malignant epithelial sub-cluster (Cluster 3) characterized by high lactate levels and superior BM potential, and subsequently establishing CREB1 lactylation as a biomarker of this cluster. Mechanistically, LDHA-mediated lactylation of CREB1 at Lysine 136 (K136) enhances its transcriptional activity, upregulating cytoskeletal genes including CALML5, CNN2, and PDLIM1. This axis facilitates pseudopodia formation, cellular migration. In vivo, LDHA knockdown significantly reduced intracranial tumor burden. Clinically, high lactylation scores and high CALML5 expression are independent predictors of brain metastasis and overall survival.
CONCLUSIONS: The LDHA-lactylation-CREB1-cytoskeleton axis is a novel driver of brain metastasis, serving as a promising therapeutic target and prognostic biomarker for breast cancer.

Keywords: brain metastasis; breast cancer; cytoskeletal remodeling; lactylation; scRNA-seq

DOI: https://doi.org/10.1093/neuonc/noag114

Cancer Treat Res. 2026 ;195 155-174

Metabolic Reprogramming in Cancer Stem Cells.

Gaurav Ranjan, Srijani Dasgupta, Uttam Kumar Mishra, Priyashree Sunita, Shakti Prasad Pattanayak.

Cancer stem cells (CSCs) are a subset of tumor cells that exhibit self-renewal, differentiation potential, and resistance to conventional therapies. One of the characteristic traits of CSCs is their metabolic flexibility, with the ability to adapt energy production and biosynthesis in the context of low oxygen, limited nutrients, and therapy-driven stress. This adaptability allows them to survive, advances tumor development, and results in relapse after treatment.CSCs can switch between glycolysis and oxidative phosphorylation (OXPHOS) dynamically in different biological contexts. CSCs mainly produce ATP and synthesize nucleotides, amino acids, and lipids through glycolysis in hypoxia. OXPHOS is important for the maintenance of quiescent cells, for reducing reactive oxygen species (ROS) production, and supports long-term survival and tumor initiation. In addition to glucose, CSCs utilize lipid and amino acid metabolism. Fatty acid oxidation provides energy during stress, while glutamine, serine, and glycine support biosynthesis, redox homeostasis, and epigenetic control, collectively enhancing survival and therapy resistance. CSCs also rely on lipid and amino acid metabolism, in addition to glucose. Fatty acid oxidation is a source of energy during stress, and glutamine-, serine-, and glycine-derived metabolic products contribute to promoting biosynthesis for redox homeostasis, epigenetic regulation, and survival/therapy resistance. The tumor microenvironment (TME) dictates CSCs' metabolism through cross talk with fibroblasts, immune cells, and components of the extracellular matrix. Metabolic interplay, e.g., reverse Warburg effect, allows CSC to consume stromal metabolites, facilitating the promotion of tumor and resistance to therapy. Targeting of CSC metabolism, via glycolytic and mitochondrial inhibitors, lipid metabolism originated blockers, or amino acids modulators can perturb the survival of CSCs and increase tumor sensitivity to classical therapies. In this aspect, the application of combinatorial therapy was able to provide additional benefit by addressing both proliferative and quiescent CSC.In conclusion, metabolic reprogramming underpins CSC survival, drives therapy resistance, and promotes tumor progression. Exploiting these metabolic adaptations provides a promising strategy for achieving long-lasting and effective cancer therapies.

Keywords: Cancer stem cells; Glycolysis; Metabolic reprogramming; Metabolic targeting; Reverse Warburg effect; Tumor microenvironment

DOI: https://doi.org/10.1007/978-3-032-21861-2_8

Pathol Res Pract. 2026 May 16. pii: S0344-0338(26)00168-8. [Epub ahead of print]284 156515

Transcriptomic analysis reveals the regulatory role of LIPE in lipid metabolism and tumor-associated macrophage polarization in breast cancer.

Xuqin Feng, Qinghua Jiang, Yongpeng He, Tingting Li, Silin Chen, Xin Hu, Xianjun Pan, Wei Yang.

BACKGROUND: Breast cancer (BC) is one of the most common malignancies in women. Lipase E, hormone-sensitive type (LIPE), is a key lipase with potential regulatory roles in tumor lipid metabolism and the immune microenvironment. However, the molecular mechanisms by which LIPE regulates BC progression remain unclear.
METHODS: The Gene Expression Omnibus (GEO) database was used to download BC-related transcriptomic data. The Weishengxin platform was used for gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses. TNMplot and gene expression profiling interactive analysis (GEPIA) platforms were used to obtain LIPE expression in BC tissues and at different clinical stages. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot were used to detect messenger RNA (mRNA) and protein expression. Cell transfection, 5-ethynyl-2'-deoxyuridine (EdU), transwell, and wound healing assays were used to evaluate gene overexpression, cell proliferation, invasion, and migration. Commercial kits were used to measure free fatty acid (FFA) and lipoprotein lipase (LPL). Flow cytometry was used to analyze the proportion of cluster of differentiation 206 (CD206)-positive cells. In vivo experiments were conducted to validate the effects of LIPE on BC lipid metabolism and macrophage polarization. Immunohistochemistry (IHC) was used to detect CD206 and Ki-67 levels.
RESULTS: BC transcriptomic analysis identified c-x-c motif chemokine receptor 4 (CXCR4), LIPE, and cyclin-dependent kinase inhibitor 1c (CDKN1C) as potential key regulators of BC progression. GO and KEGG enrichment analyses showed that lipid droplet, acylglycerol lipase activity, regulation of lipolysis in adipocytes, and leukocyte transendothelial migration were significantly enriched. LIPE was significantly downregulated in BC-related transcriptomic datasets, BC tissues, and cells. LIPE overexpression reduced BC cell proliferation, invasion, and migration, increased FFA and LPL levels and activity, and decreased fatty acid synthase (FASN) and atp-citrate lyase (ACLY) expression. It also reduced the proportion of CD206-positive cells and the levels of interleukin-10 (IL-10) and transforming growth factor beta 1 (TGF-β1), while increasing the level of IL-1β. In vivo, LIPE overexpression decreased tumor volume and weight, and reduced FASN, ACLY, CD206, and Ki-67 levels in BC tissues.
CONCLUSION: LIPE regulates lipid metabolism and thereby influences macrophage polarization, affecting BC progression and providing new insights and targets for its mechanistic research and therapy.

Keywords: Breast cancer; LIPE; Tumor lipid metabolism; Tumor-associated macrophage M2 polarization

DOI: https://doi.org/10.1016/j.prp.2026.156515

Neoplasia. 2026 May 19. pii: S1476-5586(26)00048-5. [Epub ahead of print]78 101318

Cancer-associated fibroblast-derived protein S100-A11 influences the response to anti-HER2 therapies in HER2-positive breast cancer.

Melani Luque, Miriam Morales-Gallego, Marta Sanz-Álvarez, Claudia Arguiñano, Yamileth Rangel, Natalia Ramírez-Merino, Mengjuan Qin, Ana Rovira, Joan Albanell, Juan Madoz-Gúrpide, Federico Rojo.

Breast cancer is the most commonly diagnosed cancer worldwide and includes the HER2-positive (HER2+) subtype, characterised by HER2 overexpression. HER2+ breast cancer is treated with neoadjuvant anti-HER2 therapy combined with taxane-based chemotherapy, yet a substantial proportion of patients fail to achieve pathological complete response. Increasing evidence indicates that the tumour microenvironment (TME), particularly cancer-associated fibroblasts (CAFs), contributes to therapy resistance through paracrine signalling. In this study, we investigated the role of stromal/CAF-derived S100-A11 in the response to trastuzumab, pertuzumab, and docetaxel (TPD) therapy. Proteomic analysis and ELISA confirmed increased S100-A11 secretion by TPD-treated CAF-200 fibroblasts. Recombinant S100-A11 reduced sensitivity to TPD in multiple HER2+ breast cancer cell lines, whereas S100A11 silencing in CAF-200 attenuated the resistance-promoting effect of CAF-conditioned medium in BT-474 and EFM-192A cells. Mechanistically, S100-A11 exposure was associated with increased STAT3 phosphorylation, and pharmacological inhibition of STAT3 or RAGE partially reversed the S100-A11-associated resistance phenotype. In a reductionist xenograft model, RAGE inhibition with azeliragon attenuated the effect of exogenous S100-A11 on tumour response to TPD. In a retrospective cohort of early-stage HER2+ breast cancer, high stromal S100-A11 expression was associated with residual disease after neoadjuvant therapy and with increased tumour p-STAT3 levels. Dual staining for S100-A11 and α-SMA further supported the presence of S100-A11-expressing CAFs in patient tumours. Together, these findings support a role for stromal S100-A11 in modulating response to anti-HER2 therapy and suggest that the S100-A11/RAGE/STAT3 axis may represent a therapeutically relevant stromal signalling pathway. Further validation in independent clinical cohorts and more physiologically representative models is required. TRANSLATIONAL RELEVANCE: Resistance to anti-HER2 therapies remains a major clinical challenge in the treatment of HER2+ breast cancer. This study identifies the stromal protein S100-A11, secreted by CAFs, as a candidate mediator associated with reduced sensitivity to TPD therapy. We show that extracellular S100-A11 promotes tumour cell proliferation and is associated with activation of the RAGE/STAT3 signalling axis. Pharmacological inhibition of this pathway using azeliragon (a RAGE antagonist) or stattic (a STAT3 inhibitor) partially reverses the S100-A11-associated resistance phenotype in vitro and in a reductionist xenograft model. In parallel, high stromal S100-A11 expression is associated with poorer pathological response in a retrospective cohort of early-stage HER2+ breast cancer patients. While these findings are exploratory, they support the potential relevance of stromal S100-A11 as a component of the TME linked to therapy response. Overall, this work provides a rationale for further investigation of the S100-A11/RAGE/STAT3 axis as a potential target in stromal-mediated resistance to anti-HER2 therapy. CONCEPTUAL ADVANCE: This study provides further insight into the mechanisms underlying resistance to anti-HER2 therapy by identifying a therapy-associated, stroma-related adaptive response that may contribute to reduced treatment sensitivity beyond tumour-intrinsic alterations. While resistance in HER2+ breast cancer has traditionally been attributed to oncogenic signalling rewiring within tumour cells, our findings suggest that anti-HER2 therapy may also influence CAFs, promoting the secretion of factors that support tumour cell survival under therapeutic pressure. In this context, we describe a paracrine signalling interaction in which CAF-associated S100-A11 is linked to activation of the RAGE/STAT3 axis in tumour cells, accompanied by increased proliferation and reduced sensitivity to treatment. These observations support a model in which the TME acts as an active contributor to adaptive resistance, rather than a passive component. Moreover, the partial reversibility of this phenotype through pharmacological inhibition of RAGE or STAT3 suggests that stromal signalling pathways may represent potential targets for therapeutic intervention. Overall, these findings expand current perspectives on resistance by incorporating the contribution of therapy-associated stromal responses and support further investigation into combinatorial strategies targeting both tumour cells and their TME.

Keywords: Azeliragon; Biomarkers; Breast cancer; Cancer-associated fibroblasts; HER2-positive; Pertuzumab; Preclinical models; RAGE receptor; Resistance; S100-A11; STAT3 signalling; Stattic; Therapy-response biomarker potential; Trastuzumab; Tumour microenvironment

DOI: https://doi.org/10.1016/j.neo.2026.101318

Sci Rep. 2026 May 18. pii: 15281. [Epub ahead of print]16(1):

Effect of obesity and endocrine therapy on the prognosis of premenopausal women with HR+HER2-breast cancer: a multi-center retrospective study.

Weibin Lian, Chengye Hong, Chuan Wang, Debo Chen.

Obesity's impact on breast cancer prognosis may depend on molecular subtype, yet there is limited research on premenopausal women with HR+HER2- breast cancer. In this study, we included 5,094 premenopausal women with HR+HER2- early-stage breast cancer who underwent radical surgery at 42 breast centers across China between 2016 and 2021. Patients were categorized into four BMI groups: underweight (UW), normal weight (NW), overweight (OW), and obese (OB). Using propensity score matching (PSM) to adjust for confounding factors, we compared disease-free survival (DFS) across BMI groups with Kaplan-Meier curves and performed multivariate Cox regression analysis to evaluate the effect of obesity on prognosis. Our results showed that obese patients had significantly worse DFS compared to those who were UW, NW, or OW (p = 0.013). After adjusting for clinicopathologic factors and treatment, obesity remained an independent prognostic factor for DFS in premenopausal HR+/HER2- patients (p = 0.043). After 1:1 PSM, OW/OB patients receiving selective estrogen receptor modulators (SERMs) alone had significantly worse DFS compared to UW/NW patients (p = 0.022), whereas OW/OB patients treated with SERMs or aromatase inhibitors (AIs) in combination with ovarian function suppression (OFS) showed no significant difference in DFS from UW/NW patients. In addition, Restricted Cubic Splines (RCS) analysis demonstrated that the risk of recurrence increases with BMI in OW/OB patients. Collectively, these findings indicate that obesity may act as an independent adverse prognostic factor for DFS in premenopausal women with HR+/HER2- breast cancer. Importantly, our results also suggest that OFS may attenuate the detrimental effect of obesity in patients treated with SERMs.

Keywords: Breast cancer; Obesity; Premenopausal; Prognosis

DOI: https://doi.org/10.1038/s41598-026-45742-4