bims-merabr 2026-05-03 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2026–05–03
six papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

FABP4 Couples Lipid Metabolism to PD-L1 Stabilization in Immunosuppressive Macrophages.
Metabolic maintenance of breast cancer cells and metastases through E-cadherin/YAP-dependent pyruvate carboxylase expression.
CTDSPL2 facilitates resistance to paclitaxel in breast cancer cells by suppressing SCYL1 phosphorylation.
Ferroptosis in Breast Cancer: Molecular Insights and Therapeutic Strategies.
Significance of Lipid Metabolism Reprogramming in Tumor Microenvironment and Development of Novel Therapeutic Intervention.
Metabolic adaptation to IMMT deficiency through the ATF6-PPARγ axis is contingent on TP53 mutation status in breast cancer.

bioRxiv. 2026 Apr 13. pii: 2026.04.09.717546. [Epub ahead of print]

FABP4 Couples Lipid Metabolism to PD-L1 Stabilization in Immunosuppressive Macrophages.

Jianyu Yu, Jonathan Shilyansky, Jiaqing Hao, Anthony Avellino, Yanwen Sun, Xingshan Jiang, Zhaohua Wang, Xiaochun Han, Melissa A Curry, Sonia L Sugg, Bing Li.

Metabolic dysregulation in obesity reshapes immune function, but how lipid signals drive immune suppression remains unclear. Here, we identify a FABP4-PD-L1 axis that links lipid metabolism to immune checkpoint regulation in monocytes and macrophages. Single-cell transcriptomics revealed a distinct FABP4 high immunosuppressive macrophage subset enriched under high-fat diet (HFD) conditions, characterized by impaired antigen presentation and elevated PD-L1 expression. Mechanistically, palmitic acid (PA) induces FABP4 and promotes PD-L1 palmitoylation, leading to its stabilization on the cell surface independent of transcriptional regulation. FABP4 is essential for this process, which enables PD-L1 surface stabilization, immunosuppression and mammary tumor progression. In humans, a conserved CD14 int CD16⁺ monocyte population exhibits elevated FABP4-PD-L1 signaling and correlates with obesity and invasive breast cancer. These findings establish PD-L1 as a metabolically regulated protein and reveal a mechanism by which lipid excess drives immune evasion, suggesting that targeting FABP4 may enhance responses to immune checkpoint blockade.
Highlights: FABP4 defines a lipid-responsive, immunosuppressive monocyte/macrophage subsetFABP4 links lipid sensing to PD-L1 expression in macrophagesFABP4 enables palmitic acid-dependent PD-L1 palmitoylation and stabilizationFABP4-PD-L1 signaling correlates with obesity and invasive breast cancer in humans.

DOI: https://doi.org/10.64898/2026.04.09.717546
bioRxiv. 2026 Apr 16. pii: 2026.04.13.718309. [Epub ahead of print]

Metabolic maintenance of breast cancer cells and metastases through E-cadherin/YAP-dependent pyruvate carboxylase expression.

Kuppusamy Balamurugan, Jonathan M Weiss, Lois McKennett, Shikha Sharan, Duncan Donohue, Daniel W McVicar, Esta Sterneck.

Epithelial-mesenchymal transition (EMT) and glycolytic metabolism are well-characterized drivers of cancer progression and metastasis. However, most primary breast tumors and metastases express E-cadherin and the epithelial phenotype is associated with mitochondrial oxidative metabolism, yet the causality and relevance of these relationships and their underlying mechanisms remain poorly understood. Using a 3D culture model with mechano-stimulation, we found that E-cadherin promotes mitochondrial oxidative phosphorylation (OXPHOS) while reducing oxidative stress. Through pharmacological and genetic manipulations of inflammatory breast cancer (IBC) and/or triple negative breast cancer (TNBC) cell lines, we identified pyruvate carboxylase (PC) as an E-cadherin effector. Critically, restoring PC in E-cadherin-silenced cells rescued mitochondrial oxygen consumption and protection from oxidative stress. Co-expression of E-cadherin and PC was confirmed in breast cancer tissues and experimental lung metastases. Mechanistically, E-cadherin induced PC expression and OXPHOS via AKT-mediated activation of YAP/ /TEAD transcription factors, which are better known as supporting EMT. Clinically relevant AKT and TEAD inhibitors reduced both PC expression and oxidative respiration. Importantly, PC inhibition as monotherapy attenuated or reduced established experimental lung metastasis burden in mice. These findings reveal that E-cadherin-mediated cell-cell adhesions directly support mitochondrial metabolism through AKT-YAP/TEAD-PC signaling, identifying a therapeutic vulnerability in metastatic epithelial TNBC.

DOI: https://doi.org/10.64898/2026.04.13.718309
Cell Cycle. 2026 Dec;25(1): 1-18

CTDSPL2 facilitates resistance to paclitaxel in breast cancer cells by suppressing SCYL1 phosphorylation.

Jing Zhao, Wei Zhao, Zhimin Wei, Feng Hou, Lingling Sun, Xia Li, Xianning Dong.

  Breast cancer (BC) exhibits significant heterogeneity and complexity and is leading causes of mortality in women globally. Paclitaxel (PTX) is commonly utilized as the primary medication for BC. However, the resistance of BC to PTX poses a significant challenge in clinical treatment. This study aimed at to explore whether carboxy-terminal domain small phosphatase like 2 (CTDSPL2) affected PTX resistance in BC cells. PTX resistant BC cell lines, including MCF-7/PTX and MDA-MB-231/PTX, were developed by continuously increasing PTX concentration, and we found that CTDSPL2 was upregulated in BC cells with PTX resistance. Loss-of-function studies showed that CTDSPL2 knockdown caused a decrease in cytotoxicity and proliferative ability in PTX-resistant BC cells, as well as enhanced cell apoptotic rate and DNA damage. The results from nanoparticle tracking analysis (NTA) indicated that CTDSPL2 knockdown also suppressed the secretion of extracellular vesicles. In vivo tumorigenesis assays showed that CTDSPL2 downregulation inhibited tumorigenicity of nude mice injecting with PTX-resistant BC cells. Co-immunoprecipitation (Co-IP) assay demonstrated the binding between CTDSPL2 and SCY1-like pseudokinase 1 (SCYL1). The increased level of SCYL1 phosphorylation evoked by CTDSPL2 knockdown in PTX-resistant cancer cells was blocked after mutating the serine 754 site of SCYL1 to alanine. In conclusion, the present study identifies CTDSPL2 as a new factor in BC that plays an essential role in PTX-resistant BC cells through the regulation of SCYL1 phosphorylation.

Keywords:  Breast cancer; CTDSPL2; extracellular vesicles; paclitaxel; paclitaxel resistance

DOI:  https://doi.org/10.1080/15384101.2026.2663187
Front Biosci (Landmark Ed). 2026 Apr 17. 31(4): 50950

Ferroptosis in Breast Cancer: Molecular Insights and Therapeutic Strategies.

Nahid Iftikhar, Suryavathi Viswanadhapalli, Uday P Pratap, Ratna K Vadlamudi.

  Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation and insufficient antioxidant defenses and is mechanistically distinct from apoptosis, necroptosis, and other cell death mechanisms. Over the past decade, ferroptosis has emerged as a significant determinant of cancer cell fate. An increasing body of research indicates that it may serve as a vulnerability in breast cancer treatment. Breast cancers undergo significant metabolic and redox reprogramming that directly influences ferroptosis regulation, including alterations in iron homeostasis, polyunsaturated lipid metabolism, and antioxidant networks. Sensitivity to ferroptosis varies among breast cancer subtypes, underscoring subtype-specific metabolic requirements and stress-response mechanisms. Ferroptosis plays a critical role in breast cancer stem cells (BCSCs), therapeutic resistance, and tumor recurrence. Targeting ferroptosis provides a promising therapeutic strategy to eradicate drug-resistant, stem-like populations. Ferroptosis also profoundly influences the tumor microenvironment (TME) by altering immune cell function, reshaping stromal cell interactions, and modulating cellular responses to hypoxia and metabolic stress. This review summarizes the current mechanistic insights into ferroptosis regulation in breast cancer and discusses therapeutic avenues targeting breast cancer cells, stem cells, and the tumor microenvironment. Understanding ferroptosis mechanisms in breast cancer subtypes may enable rational, biomarker-guided strategies to overcome therapeutic resistance and improve clinical outcomes for patients with breast cancer.

Keywords:  amino acid transport systems; breast neoplasms; drug resistance; ferroptosis; glutathione peroxidase 4; iron metabolism disorders; lipid peroxidation; neoplasm; triple negative breast neoplasms; tumor microenvironment

DOI:  https://doi.org/10.31083/FBL50950
Cell Biochem Funct. 2026 Apr;44(4): e70215

Significance of Lipid Metabolism Reprogramming in Tumor Microenvironment and Development of Novel Therapeutic Intervention.

Pallabi Mondal, Sankar Bhattacharyya.

  The metabolic reprogramming of cancer cell has recently gained heightened attention in the field of tumor metastasis. This metabolic reprogramming helps the cancer cells to meet increased energy and biosynthetic requirements. Beyond their structural role in membrane integrity, fatty aids are also crucial for the energy requirement of cancer cell which ultimately helps epithelial to mesenchymal transition and metastatic progression. There is urgent need for identifying the varied role of fatty acid metabolism in the tumor microenvironment (TME), that includes tumor cell, immune cells and stromal cells. Understanding how the tumor cells alter their lipid metabolism after their interaction with other cells in the TME can present a promising therapeutic strategy against cancer. This metabolic interaction between cancer cells and other cells of the TME (like immune cells and stromal cells) which supply fatty acids that helps in the formation of metastatic niche. In this review, we discussed in detail the role of exogenous fatty acid uptake and endogenous fatty acid synthesis in tumor cells and the mechanism through which cancer cells regulate lipid metabolism. Also, the involvement of immune and stromal cell in the metabolic reprogramming and the molecules or drugs that can affect the receptor or enzymes involved in lipid metabolism are identified. This review underscores the importance of further research focusing on targeting fatty acid metabolism to identify susceptibilities and enhance cancer therapy.

Keywords:  fatty acid synthesis; fatty acid uptake; lipid metabolism; metastasis; tumor; tumor microenvironment

DOI:  https://doi.org/10.1002/cbf.70215
Cell Death Dis. 2026 Apr 28.

Metabolic adaptation to IMMT deficiency through the ATF6-PPARγ axis is contingent on TP53 mutation status in breast cancer.

Li Liu, Dan Li, Zeyu Hou, Yi Huang, Jinjing Wang, Chaorui Pu, Qingqing Zhao, Yunyan Yu, Rui Chen.

Mitochondrial dysfunction and the corresponding metabolic reprogramming have been established as critical drivers of tumor progression; nevertheless, the specific molecular mechanisms have not yet been fully elucidated. In this study, we reveal that ablation of inner mitochondrial membrane protein (IMMT), a key architectural component of mitochondrial cristae, induces concurrent mitochondrial and endoplasmic reticulum stress (ERS), which selectively activates the ATF6-mediated unfolded protein response (UPR) to drive breast cancer (BC) cell proliferation. Mechanistically, IMMT loss promotes ATF6α-ATF6β heterodimer formation, whereby ATF6α stabilizes ATF6β protein, enabling ATF6β to engage PPARγ through direct physical interaction and orchestrate redox homeostasis remodeling that sustains tumor cell proliferation. Notably, we discovered that this compensatory stress adaptation is context-dependent, manifesting specifically in TP53-mutant tumors, but not in their wild-type counterparts, and targeted disruption of the ATF6β-PPARγ signaling axis effectively abrogates the oncogenic effects induced by IMMT-KO. Our work uncovers a previously unrecognized adaptive axis linking chronic mitochondrial dysfunction to redox control in BC and establishes ATF6β as a critical effector that partners with PPARγ under stress-a functional role distinct from its classical regulatory relationship with ATF6α. These findings provide a theoretical foundation for precision therapeutic strategies targeting vulnerabilities in the stress adaptation pathway of BC.

DOI: https://doi.org/10.1038/s41419-026-08813-y