bims-meract 2025-07-13 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–07–13
24 papers selected by
Andrea Morandi, Università degli Studi di Firenze

Fatty acid synthase-derived lipid stores support breast cancer metastasis.
Precise metabolic dependencies of cancer through deep learning and validations.
THEM6 modulates carboplatin sensitivity by regulating ferroptosis through FDFT1 in triple-negative breast cancer.
Antibody-functionalized iron-based nanoplatform for ferroptosis-augmented targeted therapy of HER2-positive breast cancer.
Hippo pathway controls biopterin metabolism to shield adjacent cells from ferroptosis in lung cancer.
TTK activates ATR through RPA2 phosphorylation to promote olaparib resistance in ovarian cancer.
NF-κB-mediated cytokine secretion and glutamate metabolic reprogramming converge in breast cancer brain tropism.
The WWP1-JARID1B axis sustains acute myeloid leukemia chemoresistance.
USP44 promotes chemotherapeutic drug resistance of triple negative breast cancer through EZH2 protein stability.
SPP1 promotes malignant characteristics and drug resistance in hepatocellular carcinoma by activating fatty acid metabolic pathway.
NCOA5 suppresses tumor progression and cisplatin resistance in non-small cell lung cancer by interfering with PRDX6 transcription.
Colon cancer cells evade drug action by enhancing drug metabolism.
High fructose promotes MYCN-amplified neuroblastoma progression through NgBR-ACSS2-mediated biosynthesis of acetyl-CoA.
Metabolic hallmarks of trastuzumab resistance.
CDKN1B (p27/kip1) enhances drug-tolerant persister CTCs by restricting polyploidy following mitotic inhibitors.
Metabolic gatekeeper ACAD9 coordinates linoleic acid metabolism and redox homeostasis via mitochondrial complex I to drive ovarian cancer progression.
Metabolic reprogramming in melanoma therapy.
YY1 enhances HIF-1α stability in tumor-associated macrophages to suppress anti-tumor immunity of prostate cancer in mice.
AREG and EREG Are Predictive Biomarkers of Response to EGFR Inhibition in Gastroesophageal Cancer.
Targeting WEE1 and asciminib suppresses ABL-tyrosine kinase inhibitor-resistant chronic myeloid leukemia cells.
DNA2 protein destruction dictates DNA hyperexcision, cGAS-STING activation, and innate immune response in CDK12-deregulated cancers.
Tet Transgene Activation is Disrupted in Lipogenic Triple Negative Breast Cancer Cells.
Cascade-Targeted Nanoparticles for Enhanced Gemcitabine Delivery and Adenosine Metabolism Modulation to Overcome Treatment Resistance in Pancreatic Cancer.
Targeting Cystine Metabolism in the Lung Cancer Environment Enhances the Efficacy of Immune Checkpoint Inhibition.

Cancer Metab. 2025 Jul 10. 13(1): 35

Fatty acid synthase-derived lipid stores support breast cancer metastasis.

Chaylen Andolino, Eylem Kulkoyluoglu Cotul, Zilin Xianyu, Yun Li, Divya Bhat, Mitchell Ayers, Kimberly K Buhman, Stephen D Hursting, Michael K Wendt, Dorothy Teegarden.

  Lipid accumulation is associated with breast cancer metastasis. However, the mechanisms underlying how breast cancer cells increase lipid stores and their functional role in disease progression remain incompletely understood. Herein we quantified changes in lipid metabolism and characterized cytoplasmic lipid droplets in metastatic versus non-metastatic breast cancer cells. 14C-labeled palmitate was used to determine differences in fatty acid (FA) uptake and oxidation. Despite similar levels of palmitate uptake, metastatic cells increase lipid accumulation and oxidation of endogenous FAs compared to non-metastatic cells. Isotope tracing also demonstrated that metastatic cells support increased de novo lipogenesis by converting higher levels of glutamine and glucose into the FA precursor, citrate. Consistent with this, metastatic cells displayed increased levels of fatty acid synthase (FASN) and de novo lipogenesis. Genetic depletion or pharmacologic inhibition of FASN reduced cell migration, survival in anoikis assays, and in vivo metastasis. Finally, global proteomic analysis indicated that proteins involved in proteasome function, mitotic cell cycle, and intracellular protein transport were reduced following FASN inhibition of metastatic cells. Overall, these studies demonstrate that breast cancer metastases accumulate FAs by increasingde novo lipogenesis, storing TAG as cytoplasmic lipid droplets, and catabolizing these stores to drive several FAO-dependent steps in metastasis.

Keywords:  Breast cancer; FASN; Fatty acid synthase; Fatty acids; Lipid droplet; Lipid metabolism; Lipid storage; Mass spectrometry; Metastasis; TNBC

DOI:  https://doi.org/10.1186/s40170-025-00404-3
Cell Rep. 2025 Jul 03. pii: S2211-1247(25)00716-8. [Epub ahead of print]44(7): 115945

Precise metabolic dependencies of cancer through deep learning and validations.

Tao Wu, Xiangyu Zhao, Yu Zhang, Die Qiu, Kaixuan Diao, Dongliang Xu, Weiliang Wang, Xiaopeng Xiong, Xinxiang Li, Xue-Song Liu.

  Cancer cells exhibit metabolic reprogramming to sustain proliferation, creating metabolic vulnerabilities absent in normal cells. While prior studies identified specific metabolic dependencies, systematic insights remain limited. Here, we build a graph deep learning-based metabolic vulnerability prediction model, "DeepMeta," which can accurately predict the dependent metabolic genes for cancer samples based on transcriptome and metabolic network information. The performance of DeepMeta has been extensively validated with independent datasets. The metabolic vulnerability of "undruggable" cancer-driving alterations has been systematically explored using The Cancer Genome Atlas (TCGA) dataset. Notably, CTNNB1 T41A-activating mutations showed experimentally confirmed vulnerability to purine/pyrimidine metabolism inhibition. TCGA patients with the predicted pyrimidine metabolism dependency show a dramatically improved clinical response to chemotherapeutic drugs that block this pyrimidine metabolism pathway. This study systematically uncovers the metabolic dependency of cancer cells and provides metabolic targets for cancers driven by genetic alterations that are originally undruggable on their own.

Keywords:  CP: Cancer; CP: Metabolism; CTNNB1; GAT; cancer metabolism; drug target; graph attention network; metabolic dependency; nucleotide metabolism; undruggable

DOI:  https://doi.org/10.1016/j.celrep.2025.115945
Breast Cancer Res. 2025 Jul 06. 27(1): 124

THEM6 modulates carboplatin sensitivity by regulating ferroptosis through FDFT1 in triple-negative breast cancer.

Yuexiang Zeng, Zhijie Xu, Juan Huang, Qiaoli Yi, Xi Chen, Jiayu Wang, Zhihao Du, Jian Tian, Yuanliang Yan.

   BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis, as chemotherapy resistance leads to relapse in many patients. Carboplatin addition improves treatment response, but challenges persist.
METHODS: To identify novel targets for TNBC, we analyzed differentially expressed proteins in patients treated with neoadjuvant chemotherapy. Cell viability was assessed using CCK-8 and colony formation assays. In vivo effects were studied in an orthotopic xenograft model using THEM6 overexpression cells. ROS, iron levels, MDA, and mitochondrial ultrastructure were assessed. Protein expression was analyzed by Western blotting and RT-PCR, and FDFT1 ubiquitination was evaluated.
RESULTS: We identified THEM6 (co-downregulated) and PGRMC1 (co-upregulated) as survival-associated proteins. THEM6 overexpression enhanced carboplatin sensitivity in vitro and in vivo, reducing tumor weight and volume. THEM6-induced sensitivity was linked to ferroptosis, as the ferroptosis inhibitor Fer-1 reversed the effect, while apoptosis, necrosis, and autophagy inhibitors had no impact. THEM6 overexpression reduced GPX4 and SLC7A11, while increasing ACSL4. TEM revealed mitochondrial damage, and iron, MDA, and ROS levels were elevated in treated cells. Mechanistically, THEM6 stabilized FDFT1 by inhibiting its K48-linked ubiquitination, prolonging its protein half-life, and promoting ferroptosis. FDFT1 knockdown reversed THEM6-induced sensitivity to carboplatin.
CONCLUSIONS: Our findings suggest that THEM6 enhances carboplatin sensitivity in TNBC by promoting ferroptosis through regulation of FDFT1. THEM6 may serve as a novel therapeutic target to improve TNBC treatment outcomes.

Keywords:  Carboplatin; FDFT1; Ferroptosis; THEM6; Triple-negative breast cancer

DOI:  https://doi.org/10.1186/s13058-025-02078-7
Bioact Mater. 2025 Oct;52 702-718

Antibody-functionalized iron-based nanoplatform for ferroptosis-augmented targeted therapy of HER2-positive breast cancer.

Jingchao Gao, Tong Ye, Hongkun Miao, Mingjiang Liu, Li Wen, Yi Tian, Zhiguang Fu, Li Sun, Lihong Wang, Yu Wang.

  Human epidermal growth factor receptor 2 positive (HER2+) breast cancer, as a subtype with high invasiveness and poor prognosis, faces issues of intertumoral heterogeneity and signaling pathway dysregulation leading to trastuzumab resistance in clinical treatment. Therefore, innovative therapeutic strategies are urgently needed to enhance treatment efficacy and improve patient prognosis. In this study, we proposed an antibody-targeted nanoplatform responsive to the tumor microenvironment, aiming to induce ferroptosis in HER2+ breast cancer cells and thereby enhance the sensitivity to HER2-targeted drugs. Fe-MOF@Erastin@Herceptin (FEH) was prepared by loading Erastin onto mesoporous Fe-MOF and modifying it with trastuzumab (a HER2+ breast cancer cell-specific antibody). This platform gradually releases trastuzumab, Erastin, and Fe3+ in the tumor microenvironment. The modification of trastuzumab enhances tumor cell targeting while reducing toxicity to non-target cells and tissues. Erastin inhibits system XC - to reduce glutathione (GSH) synthesis. Fe3+ consumes glutathione and reduces itself to Fe2+ via a reduction reaction, which further enhances the catalytic effect of H2O2 and triggers the Fenton reaction to generate large amounts of reactive oxygen species (ROS). In the antibody-targeted cascade reaction, decreased intracellular GSH content and increased Fe2+ and ROS can further promote lipid peroxidation and down-regulation of glutathione peroxidase 4 (GPX4) in breast cancer cells, inducing ferroptosis. The experimental results indicate that FEH can significantly improve the tumor microenvironment by enhancing ferroptosis effects, providing a potential new strategy for precision therapy of HER2+ breast cancer cells.

Keywords:  Ferroptosis; GPX4; HER2-positive breast cancer; Nano-materials; SLC7A11

DOI:  https://doi.org/10.1016/j.bioactmat.2025.06.034
EMBO Rep. 2025 Jul 07.

Hippo pathway controls biopterin metabolism to shield adjacent cells from ferroptosis in lung cancer.

Hao Li, Yohei Kanamori, Akihiro Nita, Ayato Maeda, Tianli Zhang, Kenta Kikuchi, Hiroyuki Yamada, Touya Toyomoto, Mohamed Fathi Saleh, Mayumi Niimura, Hironori Hinokuma, Mayuko Shimoda, Koei Ikeda, Makoto Suzuki, Yoshihiro Komohara, Daisuke Kurotaki, Tomohiro Sawa, Toshiro Moroishi.

  Recent advances in single-cell technologies have uncovered significant cellular diversity in tumors, influencing cancer progression and treatment outcomes. The Hippo pathway controls cell proliferation through its downstream effectors: yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). Our analysis of human lung adenocarcinoma and murine models revealed that cancer cells display heterogeneous YAP/TAZ activation levels within tumors. Murine lung cancer cells with high YAP/TAZ activity grow rapidly but are sensitive to ferroptosis, a cell death induced by lipid peroxidation. In contrast, cells with low YAP/TAZ activity grow slowly but resist ferroptosis. Moreover, they protect neighbouring cells from ferroptosis, creating a protective microenvironment that enhances the tumor's resistance to ferroptosis. Mechanistically, inhibiting YAP/TAZ upregulates GTP cyclohydrolase 1 (GCH1), an enzyme critical for the biosynthesis of tetrahydrobiopterin (BH4), which functions as a secretory antioxidant to prevent lipid peroxidation. Pharmacological inhibition of GCH1 sensitizes lung cancer cells to ferroptosis inducers, suggesting a potential therapeutic approach. Our data highlights the non-cell-autonomous roles of the Hippo pathway in creating a ferroptosis-resistant tumor microenvironment.

Keywords:  Biopterin; Cell Communication; Ferroptosis; Hippo Pathway; Lung Cancer

DOI:  https://doi.org/10.1038/s44319-025-00515-4
Commun Biol. 2025 Jul 05. 8(1): 1011

TTK activates ATR through RPA2 phosphorylation to promote olaparib resistance in ovarian cancer.

Gonghua Qi, Hanlin Ma, Jingying Chen, Panpan Gai, Kai Teng.

Resistance to poly(ADP‒ribose) polymerase inhibitors (PARPis) remains a significant challenge in ovarian cancer (OC) treatment. TTK protein kinase (TTK) has been implicated in cisplatin resistance in OC, but its role in PARPi resistance remains unclear. In this research, we found that TTK inhibition overcome olaparib resistance in HR-proficient OC cells, whereas TTK promotes olaparib resistance in HR-deficient OC cells. Mechanistically, TTK directly interacts with RPA2, facilitating phosphorylation of its S33 residue to activate the ATR signaling pathway. Knocking down RPA2 increased olaparib sensitivity in OC cells. Additionally, TTK-mediated resistance to olaparib through the RPA2/ATR signaling pathway was confirmed via both in vitro and in vivo models. In conclusion, TTK inhibition overcomes olaparib resistance in HR-proficient OC cells, in part by suppressing RPA2-S33 phosphorylation and attenuating ATR signaling. TTK inhibitors offer a promising strategy to increase the therapeutic efficacy of PARPis in OC patients.

DOI: https://doi.org/10.1038/s42003-025-08444-7
Cancer Lett. 2025 Jul 08. pii: S0304-3835(25)00475-6. [Epub ahead of print] 217907

NF-κB-mediated cytokine secretion and glutamate metabolic reprogramming converge in breast cancer brain tropism.

Sara Di Russo, Giulia Elizabeth Borsatti, Amani Bouzidi, Francesca Romana Liberati, Agnese Riva, Farida Tripodi, Lucrezia Romana Rolfi, Sharon Spizzichino, Antonella Tramutola, Marzia Perluigi, Daniela Trisciuoglio, Giorgio Giardina, Alessandro Paiardini, Paola Coccetti, Serena Rinaldo, Francesca Cutruzzolà, Alessio Paone.

  Brain metastases are an increasingly common and life-threatening complication of breast cancer. Here, we report that breast cancer cells with a propensity for cerebral colonization (BrM cells) display a distinct imbalance in the NF-κB pathway characterized by elevated IKKβ and reduced IKKα levels. This imbalance reduces the levels of the downstream NF-κB modulators IκBα and TAX1BP1, fostering a chronically active pro-inflammatory program. Such BrM cells secrete high concentrations of IL-8 and GRO chemokines, enhancing blood-brain barrier permeability in vitro and triggering astrocyte activation in vivo. In parallel, we observed that the altered NF-κB signaling increases the expression of glutamate transporters EAAT1 and EAAT2, which allows BrM cells to uptake and utilize glutamate, a neurotransmitter readily available in the brain, as a key energy source. Analysis of energy metabolism confirms a pronounced reliance on glutamate for both oxidative phosphorylation and glycolysis, which correlates with an increased migratory and invasive capacity. Importantly, pharmacological inhibition of glutamate import curtails in vitro migratory ability and reduces the formation of brain lesions in a murine model. Our study thus highlights a dual strategy employed by BrM cells, whereby they orchestrate a pro-inflammatory milieu to breach the BBB and simultaneously exploit glutamate metabolism to sustain invasiveness. These findings highlight the inflammatory-metabolic axis as a promising target for therapeutic or preventive strategies against breast cancer progression to the brain.

Keywords:  Breast cancer; NF-κB signaling; blood-brain barrier; brain metastasis; glutamate; inflammation

DOI:  https://doi.org/10.1016/j.canlet.2025.217907
Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2421159122

The WWP1-JARID1B axis sustains acute myeloid leukemia chemoresistance.

Claudia Fierro, Sara Giovannini, Valeria Moriconi, Claudia Fiorilli, Emanuele Panatta, Valentina Frezza, Federica Corigliano, Rosalba Pecorari, Yanan Li, Ji Zhou, Vincenza Simona Delvecchio, Artem Smirnov, Jose Manuel Garcia Manteiga, Andrea Brendolan, Jinping Zhang, Yufang Shi, Ivano Amelio, Eleonora Candi, Gerry Melino, Francesca Bernassola.

  To uncover substrates mediating the oncogenic activity of WWP1 in acute myeloid leukemia (AML), we performed a proteomic analysis that identified the histone demethylase KDM5B/JARID1B as a candidate target. Of note, JARID1B is indispensable for efficient recruitment of several DNA damage repair factors and for damage resolution, thus negatively influencing the sensitivity of cancer cells to chemo- and radiation therapies. Validation of JARID1B as a substrate of WWP1 revealed a positive regulation of JARID1B half-life by WWP1 through the establishment of K63-linked polyubiquitin chains. As a result, downregulation of JARID1B rising from WWP1 inactivation was associated with higher H3K4me3 enrichment at JARID1B target genes in WWP1-depleted relatively to control AML cells. Integration of RNA-seq and H3K4me3 ChIP-seq data uncovered a highly significant overlap between upregulated gene expression and enriched H3K4me3 peaks after shWWP1 inactivation. We confirmed transcriptional activation of JARID1B targets in WWP1-depleted cells, supporting a role for WWP1 in regulating JARID1B activity. Coherently, upon WWP1 inactivation, we observed a defective recruitment of repair proteins after DNA damage, with subsequent reduced DNA damage repair efficiency and enhanced sensitization of AML cells to the cytotoxic activity of chemotherapeutic drugs. All together, these data identify JARID1B as a bona fide target of WWP1 and imply that WWP1-mediated regulation of JARID1B impacts its ability to modify chromatin and to recruit DNA damage repair factors, thus ultimately affecting chemosensitivity of AML cells.

Keywords:  DNA repair; acute myeloid leukemia; protein degradation; protein ubiquitination

DOI:  https://doi.org/10.1073/pnas.2421159122
Cancer Biol Ther. 2025 Dec;26(1): 2529652

USP44 promotes chemotherapeutic drug resistance of triple negative breast cancer through EZH2 protein stability.

Pu Wu, Wanting Xiao, Junjie Ni, Yuming Lou, Chaoyang Xu.

  Triple negative breast cancer (TNBC), a highly invasive breast cancer, is one of the leading causes of cancer-related mortality worldwide. Although chemotherapy remains the standard of care for TNBC, the development of chemotherapy resistance significantly limits its clinical efficacy. In this study, we identified the deubiquitinating enzyme USP44 as a contributor to chemoresistance in TNBC and investigated the potential regulatory feedback mechanisms involved. In this experimental study, we investigated the sensitivity of TNBC cells MDA-MB-231 and BT-549 to chemotherapy drugs after overexpression and knockdown of USP44 using CCK-8 reagent kit and flow cytometry analysis, respectively. Western blot was performed to evaluate the expression levels of relevant proteins. In vivo xenograft models were established to examine the effects of USP44 and its downstream targets on chemosensitivity. Co-immunoprecipitation assay and ubiquitination assay were conducted to identify interacting proteins and elucidate the underlying molecular mechanisms. Knockdown of USP44 increased the sensitivity of MDA-MB-231 and BT-549 cells to chemotherapeutic agents, accompanied by elevated levels of Cleaved PARP. In contrast, USP44 overexpression reduced drug sensitivity. Mechanistically, USP44 was found to interact with EZH2, preventing its ubiquitination and subsequent proteasomal degradation. Notably, treatment with GSK126, a specific EZH2 inhibitor, reversed the chemoresistance induced by USP44 overexpression. USP44/EZH2 signaling pathway is one of the key to causing the drug resistance of TNBC, warranting further clinical investigation.

Keywords:  EZH2; Triple-negative breast cancer; USP44; drug resistance

DOI:  https://doi.org/10.1080/15384047.2025.2529652
Funct Integr Genomics. 2025 Jul 11. 25(1): 151

SPP1 promotes malignant characteristics and drug resistance in hepatocellular carcinoma by activating fatty acid metabolic pathway.

Zhijiang Wang, Chengfang Wang.

  Hepatocellular carcinoma (HCC) progression and prognosis are influenced by various molecular markers. This study aimed to identify the hub gene associated with HCC clinical characteristics and its role in HCC progression. Differentially expressed genes (DEGs) between HCC tumor and normal tissues, as well as between stage I/II and stage III/IV, were analyzed. Machine learning algorithms were used to pinpoint three critical hub genes (SPP1, ADH4, and ANXA10). A prognostic risk model was constructed and evaluated using Kaplan-Meier curves, COX regression, and decision curve analysis, which could effectively predict HCC survival. Among the three hub genes, SPP1 was significantly associated with the overall survival (OS) of HCC patients and effectively predicted prognosis. More importantly, SPP1 was upregulated in HCC tumor tissues and cells, and its overexpression enhanced HCC cell proliferation, migration, invasion, and drug resistance. It also promoted fatty acid metabolism in HCC cells, with malignant characteristics and drug resistance induced by SPP1 being mitigated by fatty acid oxidation inhibition. In vivo experiments showed that SPP1 knockdown inhibited tumor growth and fatty acid metabolism of HCC mice. In conclusion, SPP1 is a pivotal gene that influences HCC prognosis by enhancing malignancy and drug resistance through fatty acid metabolism.

Keywords:  Drug resistance; Hepatocellular carcinoma; Malignant characteristic; Metabolic pathway; Prognosis

DOI:  https://doi.org/10.1007/s10142-025-01664-4
Biochem Pharmacol. 2025 Jul 05. pii: S0006-2952(25)00367-3. [Epub ahead of print]240 117102

NCOA5 suppresses tumor progression and cisplatin resistance in non-small cell lung cancer by interfering with PRDX6 transcription.

Dan-Ni Wu, Ping Huang, Kang-Liang Zhang, Rui-Heng Chen, Ri-Sheng Huang.

  Cisplatin (CDDP)-based chemotherapy is an important treatment modality for non-small cell lung cancer (NSCLC), yet its efficacy is limited by the development of drug resistance. Chemoresistance is associated with aberrant lipid metabolism. We analyzed differentially expressed lipid metabolism-related genes based on public data and searched for a novel regulator of NSCLC chemoresistance. NCOA5, a regulator of cholesterol efflux, was found to be downregulated in CDDP-resistant NSCLC cells and surgically resected NSCLC tissues. Low NCOA5 expression was significantly associated with lymph node metastasis, TNM stage, and prognosis in NSCLC. NCOA5 knockdown increased the proliferation, invasion, and tumorigenesis of NSCLC cells. Overexpression of NCOA5 reversed the CDDP resistance of NSCLC cells both in vitro and in vivo. The chemosensitive effect of NCOA5 on CDDP-resistant NSCLC cells was impaired by N-acetylcysteine, an inhibitor of reactive oxygen species (ROS). Mechanistic investigations revealed that NCOA5 repressed PRDX6 expression by interfering with NRF2-mediated transactivation. Depletion of PRDX6 phenocopied the NCOA5-overexpressing cells and resulted in increased ROS generation and CDDP sensitivity. Furthermore, enforced expression of PRDX6 blunted the effects of NCOA5 on ROS production and CDDP sensitivity in NSCLC cells. Our data reveal a crucial role for NCOA5 in NSCLC progression and CDDP resistance. Thus, targeting the NCOA5/PRDX6 axis may be a promising strategy to overcome CDDP resistance in NSCLC.

Keywords:  Chemotherapy; Lung cancer; NCOA5; Oxidative stress

DOI:  https://doi.org/10.1016/j.bcp.2025.117102
Oncogene. 2025 Jul 10.

Colon cancer cells evade drug action by enhancing drug metabolism.

Bojie Cong, Teena Thakur, Alejandro Huerta Uribe, Evangelia Stamou, Sindhura Gopinath, Owen Sansom, Oliver Maddocks, Ross Cagan.

Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide. One key reason is the lack of durable therapies that target KRAS-dependent disease, which represents approximately 40% of CRC cases. Here, we use liquid chromatography/mass spectrometry (LC/MS) analyses on Drosophila CRC tumour models to identify multiple metabolites in the glucuronidation pathway-a toxin clearance pathway that impacts most drugs-as upregulated in trametinib-resistant RAS/APC/P53 ("RAP") tumours compared to trametinib-sensitive RasG12V single mutant tumours. Genetic inhibition of different steps along the glucuronidation pathway strongly reversed RAP resistance to trametinib; conversely, elevating glucuronidation pathway activity was sufficient to direct trametinib resistance in RasG12V animals. Mechanistically, pairing oncogenic RAS with hyperactive WNT activity strongly elevated PI3K/AKT/GLUT signalling, which in turn directed elevated glucose uptake and glucuronidation; our data also implicate the pentose phosphate pathway in this process. We provide evidence that this mechanism of trametinib resistance is conserved in a KRAS/APC/TP53 mouse CRC tumour organoid model. Finally, we identify two clinically accessible approaches to inhibiting drug glucuronidation: (i) blocking an initial HDAC1-mediated deacetylation step of trametinib with the FDA-approved drug vorinostat; (ii) reducing blood glucose by the alpha-glucosidase inhibitor acarbose. Overall, our observations demonstrate a key mechanism by which oncogenic RAS/WNT activity promotes increased drug clearance in CRC and provides a practical path towards abrogating drug resistance in CRC tumours.

DOI: https://doi.org/10.1038/s41388-025-03472-3
Cell Rep. 2025 Jul 03. pii: S2211-1247(25)00718-1. [Epub ahead of print]44(7): 115947

High fructose promotes MYCN-amplified neuroblastoma progression through NgBR-ACSS2-mediated biosynthesis of acetyl-CoA.

Wenquan Hu, Xiang Wang, Zhi Fang, Jing Zhang, Munichandra Babu Tirumalasetty, Qing Robert Miao.

  MYCN amplification, a characteristic of aggressive neuroblastoma, presents therapeutic challenges. This study uncovered the potential effects of a fructose metabolite, acetate, on the transcriptional regulation of MYCN expression, which is still largely unexplored. We elucidated the pivotal role of acyl-coenzyme A (acyl-CoA) synthetase short-chain family member 2 (ACSS2), found to be heightened in MYCN-amplified neuroblastoma. We demonstrated that ACSS2 enhanced MYCN gene transcription and growth of MYCN-amplified neuroblastoma. Our results revealed a new mechanism wherein ACSS2 orchestrates MYCN transcription by escalating acetyl-CoA levels and histone acetylation, hinting at a metabolic participation in forcibly dictating MYCN regulation. We further demonstrated that fructose or acetate exacerbated neuroblastoma growth, which can be halted by the ACSS2 inhibitor. We further identified the Nogo-B receptor (NgBR) as the trigger for ACSS2 induction through the Akt-SREBP-1 pathway. Our findings propose NgBR as a novel therapeutic target, emphasizing the promising potential of metabolic therapies for managing aggressive MYCN-amplified neuroblastoma.

Keywords:  ACSS2; Acyl-CoA synthetase short-chain family member 2; CP: Cancer; CP: Metabolism; MYCN; Nogo-B receptor; acetate; acetyl-CoA; acetylation; fructose; histone; neuroblastoma

DOI:  https://doi.org/10.1016/j.celrep.2025.115947
Expert Opin Ther Targets. 2025 Jul 11.

Metabolic hallmarks of trastuzumab resistance.

Begoña Martin-Castillo, Sara Verdura, Àngela Llop-Hernández, Ruth Lupu, Elisabet Cuyàs, Javier A Menendez.

   INTRODUCTION: The HER2-targeted monoclonal antibody trastuzumab has significantly improved the survival of patients with HER2-positive breast cancer (HER2+ BC) in both early and metastatic disease. Therapeutic resistance remains an inevitable challenge in the advanced setting, ultimately limiting the long-term efficacy of trastuzumab. Numerous mechanisms of trastuzumab resistance and response heterogeneity have been described, most involving alterations in HER2 receptor levels and reactivation of HER2 downstream signaling. However, the growing number of metabolic escape routes that allow HER2+ BC cells to evade HER2 inhibition have received little attention.
AREAS COVERED: We comprehensively review the metabolic strategies that HER2+ BC cells adopt to enable trastuzumab resistance, grouping them into a structured classification that takes into account their functional nature, namely: (1) metabolic reprogramming - how cells maintain an adequate supply of energy and biosynthetic precursors to survive, grow and proliferate despite HER2 inhibition; (2) adaptive stress response - how cells increase their resilience to survive trastuzumab-induced stress and damage; and (3) metabolic-signaling crosstalk - how key survival pathways redirect metabolism to reinforce trastuzumab resistance feedback loops.
EXPERT OPINION: The metabolic hallmarks of trastuzumab resistance may help to identify high-quality predictive biomarkers and to rationally develop optimized therapeutic strategies to counteract trastuzumab resistance metabolically.

Keywords:  HER2 therapies; autophagy; bioenergetics; metabolism; therapy resistance

DOI:  https://doi.org/10.1080/14728222.2025.2532394
Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2507203122

CDKN1B (p27/kip1) enhances drug-tolerant persister CTCs by restricting polyploidy following mitotic inhibitors.

Elad Horwitz, Taronish D Dubash, Annamaria Szabolcs, Ben S Wittner, Johannes Kreuzer, Robert Morris, Aditya Bardia, Brian Chirn, Devon Wiley, Dante Che, Hunter C Russell, Xcanda Ixchel Herrera Lopez, Douglas B Fox, Ezgi Antmen, Risa Burr, David T Ting, Wilhelm Haas, Moshe Sade-Feldman, Shyamala Maheswaran, Daniel A Haber.

  The mitotic inhibitor docetaxel (DTX) is often used to treat endocrine-refractory metastatic breast cancer, but initial responses are mitigated as patients develop disease progression. Using a cohort of ex vivo cultured circulating tumor cells (CTCs) from patients with heavily pretreated breast cancer (n=18), we find distinct patterns of response to DTX, which are intrinsic and independent of past clinical treatment with taxanes. In some CTC cultures, treatment with a single dose of DTX results in complete cell killing, associated with accumulation of nonviable polyploid (≥8 N) cells arising from endomitosis. In other CTC cultures, a transient viable drug-tolerant persister (DTP) population emerges, ultimately enabling renewed proliferation of CTCs with preserved parental cell ploidy and restored DTX sensitivity identical to that of the pretreated culture. In these CTCs, efficient cell cycle exit generates a ≤4 N drug-tolerant state dependent on CDKN1B (p27/kip1). Exposure to DTX triggers stabilization of CDKN1B through AKT-mediated phosphorylation at serine 10. Suppression of CDKN1B reduces the number of persister CTCs, increases ≥8 N mitotic cells and abrogates regrowth after DTX exposure. Thus, CDKN1B-mediated suppression of endomitosis contributes to the initiation of a reversible drug-tolerant persister state following mitotic inhibitors in advanced patient-derived breast cancer cells.

Keywords:  CDKN1B; breast cancer; circulating tumor cells; drug-tolerant persister cells; taxanes

DOI:  https://doi.org/10.1073/pnas.2507203122
Cancer Lett. 2025 Jul 05. pii: S0304-3835(25)00471-9. [Epub ahead of print]630 217903

Metabolic gatekeeper ACAD9 coordinates linoleic acid metabolism and redox homeostasis via mitochondrial complex I to drive ovarian cancer progression.

Jia Li, Jie Shi, Jixuan Ding, Weiao Qu, Jianying Lv, Yuting Bai, Shuo Wang, Rui Zhou, Yanan Chen, Yanhua Liu, Wei Ding, Yongjun Piao, Yan Fan, Longlong Wang, Shuang Yang, Tong Li, Yi Shi.

  Balancing high metabolic activity with redox homeostasis is crucial for cancer progression, particularly in high-grade serous ovarian cancer (HGSOC), which thrives in a lipid-rich environment abundance in free fatty acids, yet the key molecular regulators of this balance remain undefined. Through an in vivo genome-wide CRISPR/Cas9 knockout screen in an orthotopic ovarian cancer (OC) mouse model, we identify ACAD9 as a pivotal driver of OC progression, with its elevated expression correlating with poor patient prognosis. Multi-omics integration analysis and mechanism studies reveal ACAD9's dual role in maintaining OC metabolic homeostasis. ACAD9 preserves electron transport chain integrity and regulates linoleic acid (LA) metabolism to sustain energy production while mitigating oxidative stress. ACAD9 deficiency triggers mitochondrial respiratory collapse, inducing metabolic crisis marked by oxidative phosphorylation failure and reactive oxygen species (ROS) accumulation. Strikingly, under LA-enriched condition, ACAD9 loss redirects LA flux from β-oxidation toward membrane lipid biosynthesis, increasing polyunsaturated fatty acids incorporation. This membrane remodeling synergizes with ROS overload to create a "perfect storm" triggering ferroptosis. Our findings elucidate the dual metabolic guardianship of ACAD9 in OC, demonstrating its critical role in orchestrating mitochondrial respiration and lipid homeostasis to evade ferroptosis, which offer a potential target for the treatment of OC.

Keywords:  ACAD9; Ferroptosis; Linoleic acid; Mitochondrial complex I; Ovarian cancer; Redox

DOI:  https://doi.org/10.1016/j.canlet.2025.217903
Cell Death Discov. 2025 Jul 05. 11(1): 308

Metabolic reprogramming in melanoma therapy.

Dongliang Shen, Lu Zhang, Shun Li, Liling Tang.

Melanoma, a deadly and aggressive cancer, exhibits significant metabolic reprogramming that supports energy production, biosynthesis, and tumor progression. This metabolic adaptation drives melanoma growth, proliferation, metastasis, and therapy resistance, highlighting its potential as a promising target for therapeutic intervention. This review focuses on the latest studies elucidating metabolic pathways involved in melanoma progression, therapeutic response, and resistance. Additionally, the potential of targeting metabolic pathways-either alone or in combination with established therapeutic inhibitors-to block disease progression in melanoma is also discussed. Such insights might improve our understanding of metabolic pathways in melanoma development and foster advancements in melanoma therapy.

DOI: https://doi.org/10.1038/s41420-025-02617-3
Nat Commun. 2025 Jul 07. 16(1): 6261

YY1 enhances HIF-1α stability in tumor-associated macrophages to suppress anti-tumor immunity of prostate cancer in mice.

Wenchao Li, SaiSai Chen, Jian Lu, Weipu Mao, Shiya Zheng, Minhao Zhang, Tiange Wu, Yurui Chen, Kai Lu, Chunyan Chu, Chuanjun Shu, Yue Hou, Xue Yang, Naipeng Shi, Zhijun Chen, Lihua Zhang, Lei Zhang, Rong Na, Ming Chen, Shenghong Ju, Dingxiao Zhang, Yi Ma, Bin Xu.

Immune checkpoint therapy for prostate cancer (PCa), a classic 'immune-cold' tumor characterized by an immunosuppressive tumor microenvironment, failed previously in clinical trials, but the underlying causes remain elusive. Here we find that YY1+, immunosuppressive macrophages aggregate in the hypoxic areas of PCa. Mechanistically, hypoxia promotes the phase separation of YY1 in the nucleus, where YY1 binds to NUSAP1 and promotes the SUMOylation, phase separation and stabilization of HIF-1α. Either myeloid-specific conditional knockout of YY1 or a treatment with tenapanor for decreasing the YY1-NUSAP1-HIF-1α interaction impairs subcutaneous PCa tumor formation in mouse prostate tumor models. Lastly, a first-generation tetrahedral DNA nanostructure based on the proteolysis targeting chimera technique, termed YY1-DcTAC, allows targeting and degrading YY1 in tumor-associated macrophages for inducing antitumor effects and CD8+ T cell tumor infiltration in mouse tumor models. In summary, our findings underscore the pivotal role of YY1 in the hypoxia/HIF-1α pathway in tumor-associated macrophages and support the targeting of YY1 for treating PCa.

DOI: https://doi.org/10.1038/s41467-025-61560-0
Cancer Res. 2025 Jul 10. OF1-OF12

AREG and EREG Are Predictive Biomarkers of Response to EGFR Inhibition in Gastroesophageal Cancer.

Daniela Conticelli, Marco Volante, Filippo Pietrantonio, Claudia Orrù, Martina Olivero, Alessia Nottegar, Felice Borghi, Gian L Baiocchi, Giovanni Crotti, Uberto Fumagalli Romario, Giovanni De Manzoni, Rossella Reddavid, Roberta Porporato, Dinçer Kılıç, Rebecca Ghione, Erika Calabrò, Russell Petty, Simona Corso, Silvia Giordano, Cristina Migliore.

EGFR is a potential therapeutic target in gastroesophageal cancer. However, negative results from several phase II/III clinical trials have hindered the approval of EGFR inhibitors for treating gastroesophageal adenocarcinoma. Preclinical and clinical results have shown that EGFR targeting is effective in patients with gastroesophageal adenocarcinoma harboring EGFR amplification. Retrospective analyses also suggest that a subset of patients with gastroesophageal adenocarcinoma lacking EGFR amplification may benefit from the treatment, thus underscoring the need to identify reliable predictive biomarkers of response. Through the screening of 27 gastroesophageal adenocarcinoma primary cancer cell lines and 10 patient-derived xenograft models, we identified a subset of gastroesophageal adenocarcinoma lacking EGFR quantitative alterations but sensitive to EGFR targeting. Molecular characterization of the sensitive models revealed overexpression of the EGFR ligand amphiregulin (AREG) or epiregulin (EREG). Post hoc analysis of patients on the Cancer Esophagus Gefitinib trial treated with the EGFR inhibitor gefitinib demonstrated a significant correlation between overall survival and AREG/EREG expression level. No predictive power of EGFR ligand expression was observed in the presence of KRAS mutations. In conclusion, this study proposes the existence of a subgroup of patients with gastroesophageal adenocarcinoma with susceptibility to EGFR inhibition driven by overexpression of the EGFR ligands AREG and EREG.
SIGNIFICANCE: Elevated levels of AREG or EREG in gastroesophageal cancer confers sensitivity to EGFR inhibition, providing a low-toxicity treatment option for the subpopulation of patients overexpressing the EGFR ligands.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0073
Discov Oncol. 2025 Jul 08. 16(1): 1283

Targeting WEE1 and asciminib suppresses ABL-tyrosine kinase inhibitor-resistant chronic myeloid leukemia cells.

Seiichi Okabe, Mitsuru Moriyama, Akihiko Gotoh, Daigo Akahane.

   BACKGROUND: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the uncontrolled proliferation of white blood cells. Tyrosine kinase inhibitors (TKIs) are the standard treatment; however, resistance to BCR::ABL1 mutations remains challenging. WEE1, a checkpoint kinase involved in mitosis and DNA repair, is a potential therapeutic target for CML treatment.
METHODS: Ponatinib-resistant CML cells were screened to identify candidates for overcoming drug resistance. The efficacy of the ABL TKI asciminib and the WEE1 inhibitor MK-1775 was evaluated using proliferation and colony formation assays. Public database analysis (GSE100026) assessed WEE1/PKMYT1 expression in CML.
RESULTS: In vitro screening identified MK-1775 as a promising therapeutic candidate. WEE1/PKMYT1 expression was elevated in CML cells compared to healthy cells. Both asciminib and MK-1775 inhibited CML cell proliferation after 72 h, with enhanced cytotoxicity when combined. Co-treatment reduced colony formation and induced G2/M arrest, whereas an increase in the sub-G1 cell population indicated apoptosis. Furthermore, the combination treatment disrupted the mitochondrial membrane potential.
CONCLUSIONS: The combination of asciminib and WEE1 inhibition demonstrated greater efficacy than either drug alone, suggesting a novel therapeutic strategy for treating CML. These findings provide insights into overcoming TKI resistance and highlight a promising approach for future clinical applications.

Keywords:  ABL inhibitor resistance; Chronic myeloid leukemia; STAMP inhibitor; WEE1 inhibitor

DOI:  https://doi.org/10.1007/s12672-025-03036-7
Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2413732122

DNA2 protein destruction dictates DNA hyperexcision, cGAS-STING activation, and innate immune response in CDK12-deregulated cancers.

Rui Sun, Peng Jiang, Zhijun Wang, Binyuan Yan, Shouhai Zhu, Zhenlin Huang, Jianong Zhang, Donglin Ding, Xiang Li, Liguo Wang, Zhenkun Lou, Baiye Jin, Jun Pang, Haojie Huang, Dan Xia.

  CDK12 primarily functions as a transcription regulatory cyclin-dependent kinase (CDK) that controls mRNA elongation, splicing, and polyadenylation. The CDK12 gene is implicated in human cancers since it is frequently mutated and/or deleted in prostate and ovarian cancer but paradoxically amplified in breast cancer. Here, we demonstrate that CDK12 promotes serine-933 phosphorylation of DNA2, a nuclease/helicase critical for replication fork stress regulation, and the phosphorylation subsequently facilitates DNA2 polyubiquitination and degradation mediated by the APC/CCDC20 E3 ubiquitin ligase. CDK12 inactivation induces but amplification suppresses genome-wide expression of interferon response and antigen processing and presentation machinery genes in ovarian and breast cancer cells, respectively. Besides causing aberrant DNA2 stabilization, replication stress, genomic instability, and cytosolic double-stranded DNA (dsDNA) accumulation, CDK12 loss also triggers cGAS-STING activation and innate immune response, which can be reversed by forced expression of replication protein A (RPA) subunits or DNA2 depletion. Our findings identify DNA2 as a phosphorylation substrate of CDK12, connecting CDK12 to cell cycle regulation. These data also reveal DNA2 protein destruction as a critical mechanism that dictates genomic instability, cGAS-STING signaling activation, and innate immune response in CDK12-deregulated cancers.

Keywords:  DNA resection; cGAS-STING; innate immunity; prostate cancer; ubiquitination

DOI:  https://doi.org/10.1073/pnas.2413732122
ACS Synth Biol. 2025 Jul 08.

Tet Transgene Activation is Disrupted in Lipogenic Triple Negative Breast Cancer Cells.

Ashley Townsel, Yifei Wu, Maya Jaffe, Cara Shields, Karmella A Haynes.

  A critical challenge for mammalian cell engineering is the unexpected response of transgenes to native transcriptional regulation pathways. One transgene can show different levels of expression at different genomic sites, in different cell types, and under different growth conditions. Collisions between transcription and DNA replication, heterochromatin encroachment, and viral defense have been linked to transgene silencing. In this study, we identify fatty acid metabolism as another mediator of transgene behavior. Adipocyte secretome-induced lipogenesis in epithelial breast cancer cells was accompanied by the loss of expression from a Tet-TA regulated pCMV-AmCyan reporter transgene. Transcription profiling showed activation of lipid droplet biosynthesis, and repression of loci across the genome, consistent with the idea that lipogenesis affects the availability of substrates and cofactors for global chromatin remodeling. Preinduction of pCMV prevented full silencing during lipogenesis. Our results provide new insights into the influence of shifting metabolic states on transgene behavior.

Keywords:  breast cancer; cell line; epigenetics; lipogenesis; metabolism; transgene

DOI:  https://doi.org/10.1021/acssynbio.4c00851
Adv Sci (Weinh). 2025 Jul 08. e07118

Cascade-Targeted Nanoparticles for Enhanced Gemcitabine Delivery and Adenosine Metabolism Modulation to Overcome Treatment Resistance in Pancreatic Cancer.

Hongrui Fan, Hongyi Chen, Haolin Song, Chufeng Li, Yu Wang, Zhenhao Zhao, Qin Guo, Xuwen Li, Mingxuan Liu, Tao Sun, Chen Jiang.

  KRAS mutations are find in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases, making PDAC exhibit intrinsic resistance to chemotherapy and reshape the immunosuppressive tumor microenvironment (TME), disappointing the clinically preferred chemotherapy-immunotherapy combination. Standing on the cross point of therapeutic resistance, the aberrant adenosine metabolism contributes greatly to chemo- and immunotherapy tolerance. KRAS mutation-induced over-expression of key enzyme CD39 is believed to be involved in shaping the immunosuppressive TME, as it catalyzes the hydrolysis of extracellular ATP into immunosuppressive adenosine. Meanwhile, the loss of equilibrative nucleoside transporters (ENTs) leads to the accumulation of adenosine and the intracellular delivery difficulty of gemcitabine, further vanishing patients' hope of benefiting from either chemotherapy or immunotherapy. The key challenge is to modulate the aberrant metabolism, also enhance gemcitabine intracellular delivery. Therefore, ROS-responsive positively-charged polymer B-PDEA is prepared and assembled into polyplexes for loading CD39-down-regulating small interfering RNA. Gemcitabine-loaded albumin is coupled with the polyplexes through enzyme-cleavable peptide, forming the intact nanoparticles for the co-delivery of the first-line chemotherapeutic drug and CD39-regulating nucleic acid, showing enhanced gemcitabine intracellular delivery and adenosine metabolism regulating capacity. This approach activated antitumor immunity while achieving chemosensitization by changing the metabolic-immune crosstalk of TME, showcasing great potential for PDAC treatment.

Keywords:  Therapeutic resistance; adenosine metabolism; albumin‐nanoparticle conjugate; drug‐loaded albumin; pancreatic cancer

DOI:  https://doi.org/10.1002/advs.202507118
Adv Sci (Weinh). 2025 Jul 10. e13084

Targeting Cystine Metabolism in the Lung Cancer Environment Enhances the Efficacy of Immune Checkpoint Inhibition.

Yun Xu, Shumin Li, Jiaji Wu, Shumin Xu, Mo Shen, Chenyang Wang, Lundqvist Andreas, Jianghao Yu, Zhiyong Xu, Yueli Shi, Nana Liu, Yunke Yang, Jiangnan Zhao, Ying Yang, Pingli Wang, Peng Yi, Jin Cheng, Junhui Sun, Mengshu Li, Peng Xiao, Kai Wang.

  Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has shown promising therapeutic effects in the treatment of lung cancer, the overall efficacy of PD-1/PD-L1 inhibitors is only 20%-30%. Thus, more effective combination therapies are needed. This study finds that cystine and cysteine levels in tumor tissues of lung cancer patients are significantly higher than adjacent non-tumor tissues. Cystine deficiency polarizes macrophages toward an M1 phenotype, secreting more TNF-α, CXCL9, and CXCL10. However, using a cystine-free diet marginally reduces the development of lung cancer in vivo. A cystine-free diet slightly reduces lung cancer progression in vivo. Further studies show that cystine deprivation or erastin-mediated transport inhibition increased PD-L1 expression in macrophages both in vitro and in vivo. Combining a cystine-free diet or IKE injection with PD-L1 antibody treatment significantly inhibited subcutaneous tumor growth in mice. Mechanistic studies indicat that cystine deficiency-induced GSH depletion activates NF-κB in macrophages by reducing its glutathionylation. This effect can be reversed by replenishing GSH or using an NF-κB inhibitor. At the same time, lung cancer patients with better responses to immunotherapy are found to have lower serum GSH levels. These findings suggest that targeting cystine metabolism combined with PD-L1 inhibition is a promising therapeutic strategy.

Keywords:  PD‐L1; cystine; immunotherapy; lung cancer; macrophage polarization; tumor microenvironment

DOI:  https://doi.org/10.1002/advs.202413084