bims-meract 2025-10-05 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–10–05
sixteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

Targeting inosine metabolism to enhance EGFR-targeted therapy in lung adenocarcinoma.
Metabolic reprogramming represents a targetable mechanism to overcome acquired resistance to venetoclax in acute myeloid leukemia.
DUSP14 suppresses ferroptosis and promotes tumor progression of triple-negative breast cancer.
PARK7-driven IGF2BP3-K76 lactylation mediates ferroptosis and HAIC resistance in hepatocellular carcinoma.
PARG inhibition halts cholangiocarcinoma progression via the Hippo pathway and enhances response to chemotherapy and immunotherapy.
Lipid reprogramming and ferroptosis crosstalk in clear cell renal cell carcinoma: metabolic vulnerabilities and therapeutic targeting.
Targeting JMJD6/PPARγ/GPX4 axis overcomes ferroptosis resistance and enhances therapeutic efficacy in hepatocellular carcinoma.
STAT3 induced BRD9 activation promotes intrahepatic cholangiocarcinoma progression by enhancing CD36 controlled fatty acid metabolism.
Targeting immunosuppressive macrophages by CSRP2-regulated CCL28 signaling sensitizes hepatocellular carcinoma to lenvatinib.
Deacetylation of ACLY Mediates RNA M6A-Modification of NOXA and Promotes Chemoresistance of Colorectal Cancer.
Serine-arginine protein kinase 1 (SRPK1) is under-expressed in mucinous colorectal cancer, and may mediate resistance to oxaliplatin.
FSTL3 is a biomarker of poor prognosis and associated with immunotherapy resistance in ovarian cancer.
A histone-centric multi-omics study shows that increased H3K4 methylation sustains triple-negative breast cancer phenotypes.
O-GlcNAcylation of UBAP2L regulates stress granule formation and sunitinib resistance in clear cell renal cell carcinoma.
Dual targeting of lipid metabolic reprogramming and immunosuppressive sentinel lymph nodes potentiates anti-metastatic therapy for triple negative breast cancer.
SOX9 drives a stem-like transcriptional state and platinum resistance in high-grade serous ovarian cancer.

Cancer Lett. 2025 Sep 29. pii: S0304-3835(25)00641-X. [Epub ahead of print] 218069

Targeting inosine metabolism to enhance EGFR-targeted therapy in lung adenocarcinoma.

Xiaolong Huang, Jiaqi Liang, Yanjun Yi, Junkan Zhu, Han Lin, Shencheng Ren, Tao Cheng, Guoshu Bi, Guangyao Shan, Dejun Zeng, Fengkai Xu, Di Ge, Cheng Zhan.

  Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for treating EGFR-mutant lung adenocarcinoma (LUAD), resistance significantly impairs their therapeutic effect. In this study, we explored the metabolic features associated with EGFR-TKI resistance and identified the nucleoside inosine as being significantly accumulated in TKI-resistant cells, drug-tolerant persister (DTP) cells, and clinical TKI-residual tumors. Mechanically, accumulated inosine activated the adenosine A2A receptor (A2aR) and the cAMP-PKA-CREB signaling pathway, thereby enhancing oxidative phosphorylation and TKI resistance. Additionally, we identified that inosine secreted by TKI-resistant cells also induced M2-like reprogramming of macrophages. Downregulated purine nucleotide phosphorylase (PNP) was identified as the pivotal factor for the accumulation of inosine. Overexpression of PNP in TKI-resistant cells not only increased sensitivity of TKI-resistant cells to EGFR-TKIs, but also induced cell death by elevating toxic xanthine, uric acid, and ROS production. Furthermore, overexpression of PNP or using taminadenant, a A2aR-targeting inhibitor used in clinical trials, significantly enhances the EGFR-targeted therapeutic response in vitro, as well as in patient-derived organoids, cell-derived xenografts and mouse models bearing human EGFR-driven spontaneous lung tumor. Overall, our findings clarify the role of inosine metabolism in TKI resistance, highlighting a potential therapeutic strategy-targeting the inosine/A2aR axis-to counteract EGFR-TKI tolerance in LUAD treatment.

Keywords:  Inosine; Lung adenocarcinoma; Macrophage; Metabolic reprogramming

DOI:  https://doi.org/10.1016/j.canlet.2025.218069
Biochim Biophys Acta Mol Basis Dis. 2025 Oct 01. pii: S0925-4439(25)00413-2. [Epub ahead of print] 168065

Metabolic reprogramming represents a targetable mechanism to overcome acquired resistance to venetoclax in acute myeloid leukemia.

Gustavo Nery de Queiroz, Keli Lima, Marcella Cipelli, Victoria Tomaz, Luiz Gustavo Ferreira Cortez, Marina de Franca Basto Silva, Rafael Lucas Muniz Guedes, Paulo Vidal Campregher, Eduardo Magalhães Rego, Niels Olsen Saraiva Câmara, Leticia Veras Costa-Lotufo, João Agostinho Machado-Neto.

  Acute myeloid leukemia (AML) often develops resistance to the BCL2 inhibitor venetoclax through metabolic reprogramming. This study established acquired venetoclax-resistant AML models (MV4-11VR and MOLM-13VR) to explore resistance mechanisms and therapeutic strategies. Cell viability and apoptosis assays revealed robust acquired resistance to venetoclax upon intermittent drug exposure. Metabolic profiling revealed distinct adaptations: MV4-11VR cells favored glycolysis, while MOLM-13VR cells increased oxidative phosphorylation. Proteomic analysis supported these findings, showing pathway enrichment for carbohydrate metabolism in MV4-11VR and aerobic energy production in MOLM-13VR. Despite these differences, both models shared hyperactivation of the PI3K/AKT/mTOR pathway, as shown by RPS6 hyperphosphorylation. Apoptotic regulation also diverged between the cellular models in relation to modulated BCL2-related genes and activation of the MAPK signaling pathway. Targeting these metabolic changes with metformin (a mitochondrial complex I inhibitor) or KPT-9274 (a NAMPT inhibitor) re-sensitized resistant cells to venetoclax. Combination treatments showed strong synergy and near-complete cell elimination. These results highlight metabolic reprogramming as a heterogeneous but targetable resistance mechanism and support combining metabolic inhibitors with BCL2 blockade to treat refractory AML.

Keywords:  Acute myeloid leukemia; Glycolysis; Metabolic reprogramming; OXPHOS; Targeted therapy; Venetoclax resistance

DOI:  https://doi.org/10.1016/j.bbadis.2025.168065
Cell Rep. 2025 Sep 30. pii: S2211-1247(25)01136-2. [Epub ahead of print]44(10): 116365

DUSP14 suppresses ferroptosis and promotes tumor progression of triple-negative breast cancer.

Yueyue Cao, Yitian Zheng, Ruiqi Niu, Tingting Wang, Haiyang Yu, Yicheng Tong, Yi-Da Tang, Yueyin Pan.

  Triple-negative breast cancer (TNBC) treatment remains challenging. Here, we found that dual-specificity phosphatase 14 (DUSP14) is highly expressed in TNBC and is associated with shorter relapse-free survival in patients. DUSP14 knockdown effectively inhibited the proliferation, migration, and invasion of TNBC cells in vitro and significantly suppressed tumor growth in vivo. Mechanistically, DUSP14 knockdown increased phosphorylation of protein tyrosine phosphatase non-receptor type 12 (PTPN12), thereby inhibiting the transcriptional activity of peroxisome proliferator-activated receptor alpha (PPARα) and ultimately downregulating the expression of stearoyl-coenzyme A (CoA) desaturase (SCD), a target gene involved in tumor progression and chemoresistance. This mechanism promoted lipid peroxidation in breast cancer cells, triggering ferroptotic cell death. In clinical analyses, DUSP14 and SCD protein levels in TNBC were strongly correlated. Targeting the DUSP14-PTPN12-PPARα/SCD axis with a small-molecule drug effectively restricted the malignant phenotype of TNBC cells. These findings reveal the role of DUSP14 in regulating ferroptosis. Targeting DUSP14 represents a promising strategy for TNBC treatment.

Keywords:  CP: Cancer; DUSP14; PTPN12; ferroptosis; peroxisome proliferator-activated receptors; triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.celrep.2025.116365
Redox Biol. 2025 Sep 26. pii: S2213-2317(25)00382-9. [Epub ahead of print]87 103869

PARK7-driven IGF2BP3-K76 lactylation mediates ferroptosis and HAIC resistance in hepatocellular carcinoma.

Zhiwen Zhu, Xinyu Xia, Yuanxiang Lu, Danfeng Li, Xincheng He, Baohua Zhang, Ge Xiong, Wanguang Zhang, Huifang Liang, Hong Zhu.

  Oxaliplatin/5-fluorouracil (OXA/5-FU)-based hepatic artery infusion chemotherapy (HAIC) represents a promising strategy against advanced hepatocellular carcinoma (HCC), yet acquired resistance frequently impedes its efficacy. Here, we identify lactylation of IGF2BP3 at lysine 76 (IGF2BP3-K76lac) as a key driver of HAIC resistance. IGF2BP3-K76lac overexpression enhances chemoresistance in vitro and in vivo. Mechanistically, lactylation at IGF2BP3 K76 strengthens its affinity for m6A-modified FSP1 mRNA, upregulating FSP1 and conferring ferroptosis resistance. Blocking of IGF2BP3-K76lac bolsters OXA/5-FU-induced ferroptosis, disrupts antioxidant defenses, and curbs tumor growth. Moreover, PARK7 functions as a lactyltransferase to facilitate IGF2BP3-K76lac via increasing the binding of lactate at IGF2BP3-K76 site. Finally, blocking antibody targeting IGF2BP3-K76lac was shown to work synergistically with OXA/5-FU to restore chemosensitivity. Taken together, our findings reveal a critical role for the PARK7-IGF2BP3-K76lac-FSP1 axis in HAIC resistance, highlighting IGF2BP3-K76lac as a potential therapeutic target in HCC.

Keywords:  Chemoresistance; Ferroptosis; IGF2BP3; Lactylation; PARK7

DOI:  https://doi.org/10.1016/j.redox.2025.103869
J Hepatol. 2025 Sep 26. pii: S0168-8278(25)02500-0. [Epub ahead of print]

PARG inhibition halts cholangiocarcinoma progression via the Hippo pathway and enhances response to chemotherapy and immunotherapy.

Mincheng Yu, Peiyi Xie, Qiang Yu, Yufei Zhao, Wenxin Xu, Zhangfu Yang, Yujuan Wei, Binghai Zhou, Shuang Liu, Sanyuan Dong, Yongfeng Xu, Yongsheng Xiao, Bo Zhang, Lei Guo, Qinghai Ye, Hui Li.

   BACKGROUND & AIMS: Cholangiocarcinoma (CCA) is a fatal malignancy with limited therapeutic options. We sought to investigate the oncogenic role of poly(ADP-ribose) glycohydrolase (PARG) and test potential therapeutic strategies.
METHODS: A tissue microarray comprising 275 CCA patient samples was analyzed by immunohistochemistry. Liquid chromatography-tandem mass spectrometry was utilized to identify downstream targets of PARG. Transgenic mice (Pargf/f) were employed to establish spontaneous CCA model via hydrodynamic tail vein injection (HTVi) and biliary instillation (BI). The efficacy of PARG inhibition was tested in various CCA preclinical models, including patient derived organoids (PDOs), patient-derived xenograft (PDX), an immunocompetent syngeneic murine model, and orthotopic xenograft models. Cytometry by time of flight (CyTOF) analysis was utilized to profile the changes in tumor microenvironment following PARG inhibition and anti-PD-1 therapy.
RESULTS: PARG is highly expressed in CCA and predicts a dismal prognosis based on analysis of a large patient cohort. Genetic depletion of Parg in spontaneous CCA models induced by two methods, including HTVi and BI, significantly halted carcinogenesis. PARG inhibition alone showed impressive efficacy and potentiated Gem/Cis in PDOs, PDX, and orthotopic models. Mechanistically, PARG dePARylates and suppresses ITCH autoubiquitination, thus inhibiting the Hippo pathway, which promotes CCA proliferation and chemoresistance. Moreover, CyTOF analysis revealed the crosstalk between the tumor and stroma, which could be suppressed by PARG inhibitors via TEADs/CXCR4/CXCL12 axis. Combining PD-1 blockade and Gem/Cis with PARG inhibitors resulted in a significantly greater reduction in tumor burden, as well as a survival benefit.
CONCLUSIONS: Targeting PARG limits CCA progression, alleviates desmoplasia, and enhances response to both anti-PD-1 therapy and chemotherapy.
LAY SUMMARY: Little is known about the role of PARG in CCA development and progression. Herein, we show that PARG expression is upregulated and hyperactivated in CCA, promoting tumor cell proliferation, cancer-associated fibroblast recruitment, and resistance to therapy. Pharmacological inhibition of PARG suppresses CCA development and could be an effective therapeutic strategy when combined with chemotherapy and immunotherapy.

Keywords:  CAFs; CCA; Hippo pathway; PARG; chemotherapy; immunotherapy

DOI:  https://doi.org/10.1016/j.jhep.2025.09.018
Mol Cancer. 2025 Oct 02. 24(1): 236

Lipid reprogramming and ferroptosis crosstalk in clear cell renal cell carcinoma: metabolic vulnerabilities and therapeutic targeting.

Qing Deng, Yu Ji, Jian Liu, Tao Wen.

  Clear cell renal cell carcinoma (ccRCC) features metabolic dysregulation, with altered lipid metabolism and ferroptosis dysregulation driving malignancy. This review examines the interplay between lipid reprogramming and ferroptosis resistance in ccRCC pathogenesis and therapy. Tumor cells exploit lipid accumulation for growth and evade ferroptosis adaptively. Preclinical studies show targeting lipid metabolism or inducing ferroptosis synergizes with anti-angiogenic/immunotherapy, improving survival. This study provides a framework for dual therapeutic strategies.

Keywords:  CcRCC; Ferroptosis; Lipid reprogramming; Metabolic vulnerabilities; Therapeutic targeting

DOI:  https://doi.org/10.1186/s12943-025-02457-w
Oncogene. 2025 Sep 30.

Targeting JMJD6/PPARγ/GPX4 axis overcomes ferroptosis resistance and enhances therapeutic efficacy in hepatocellular carcinoma.

Jie Li, Shengwei Mao, Shiguang Yang, Yunwei Lou, Xuhui Zhao, Jiafeng Chen, Yichao Bu, Bei Lv, Qing Shi, Yunjie Zhang, Xingxing Zhang, Zhijie Yu, Yuan Fang, Jinglin Xia.

Despite ferroptosis induction being a promising strategy for hepatocellular carcinoma (HCC), its clinical application is limited by intrinsic resistance mechanisms. Through CRISPR-Cas9 screening of epigenetic regulators, we identified JMJD6 as a critical mediator of ferroptosis resistance in HCC. JMJD6 knockdown or pharmacological inhibition (iJMJD6) enhanced ferroptosis induced by ferroptosis inducers (erastin and RSL3), as indicated by decreased cell viability, reduced intracellular glutathione levels, increased lipid peroxidation, and disrupted mitochondrial cristae morphology, thereby promoting the susceptibility of HCC to ferroptosis. Clinically, JMJD6 was highly expressed in HCC, and its elevated expression was correlated with a poor prognosis in HCC. Mechanistically, JMJD6 interacts with BRD4, forming a transcriptional complex that binds to the PPARγ promoter. Through its demethylase activity, JMJD6 reduces H4R3me2s levels at the promoter, thereby promoting PPARγ transcription, activating the PPARγ-GPX4 axis to enhance lipid peroxidation scavenging and ferroptosis resistance. Given the role of ferroptosis in resistance mechanisms of molecular-targeted therapies, we combined iJMJD6 with sorafenib or lenvatinib, demonstrating enhanced ferroptosis and potent suppression of HCC proliferation in vitro and in vivo. Our findings revealed the JMJD6/PPARγ/GPX4 axis as a key driver of ferroptosis resistance and established JMJD6 targeting as a novel strategy to improve ferroptosis-based HCC therapies.

DOI: https://doi.org/10.1038/s41388-025-03581-z
Cancer Lett. 2025 Sep 29. pii: S0304-3835(25)00638-X. [Epub ahead of print] 218066

STAT3 induced BRD9 activation promotes intrahepatic cholangiocarcinoma progression by enhancing CD36 controlled fatty acid metabolism.

Yichao Bu, Diyu Chen, Jie Li, Rui Yang, Jun Gao, Weifeng Qu, Xiutao Fu, Weiren Liu, Zhenbin Ding, Jian Zhou, Yinghong Shi, Jia Fan, Yuan Fang, Zheng Tang.

  Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile-duct malignancy with high mortality rates, poor sensitivity to chemotherapy, and poor prognosis. Treatment options are extremely limited. Bromodomain-containing protein 9 (BRD9) has been linked to the development of various cancers, and therapies targeting BRD9 have been found to be effective. However, the role of BRD9 in ICC has not been examined, and the mechanism underlying the effects of BRD9 in cancer remain unknown. In this study, we investigated the association between BRD9 expression and ICC tumor progression, finding that high levels of BRD9 were linked to ICC tumor growth and unfavorable prognosis. In terms of the mechanism, the STAT3-BRD9-CD36 axis was found to be involved in ICC tumor growth. High BRD9 expression was found to promote CD36 expression, enhancing fatty acid metabolism in tumor cells to enable more rapid proliferation, and high BRD9 levels were influenced by elevated STAT3 expression. Treatment with the CPT1A inhibitor Etomoxir further confirmed this mechanism by blocking lipid transfer into the mitochondria and suppressing fatty acid oxidation, resulting in lipid accumulation. In addition, it was found that inhibition of BRD9 reduced ICC tumor growth and could help overcome chemoresistance. Together, the results suggest the potential of BRD9 as a therapeutic target for intrahepatic cholangiocarcinoma and highlights its role in regulating fatty acid metabolism in cancer cells.

Keywords:  BRD9; Fatty Acid Metabolism; Intrahepatic cholangiocarcinoma; STAT3-BRD9-CD36 axis

DOI:  https://doi.org/10.1016/j.canlet.2025.218066
J Immunother Cancer. 2025 Oct 02. pii: e012201. [Epub ahead of print]13(10):

Targeting immunosuppressive macrophages by CSRP2-regulated CCL28 signaling sensitizes hepatocellular carcinoma to lenvatinib.

Changzhou Chen, Sheng Su, Pengcheng Wang, Xinming Ye, Songyang Yu, Yu Gong, Zehuan Li, Jia Li, Zhiqiang Hu, Xiaowu Huang.

   BACKGROUND: Despite comparable survival benefit has been obtained, the drug resistance remarkably reduced lenvatinib clinical efficacy. Here, we aimed to identify the potential mechanism by which cysteine and glycine-rich protein 2 (CSRP2) regulates the development of hepatocellular carcinoma (HCC) and participates in the resistance to lenvatinib.
METHODS: We harnessed RNA sequencing, multiplex immunofluorescence staining, and hydrodynamic tail vein (HTV) injection HCC model to systematically explore the function of CSRP2 in HCC progression. To precisely delineate how immunosuppressive macrophages, influenced by CSRP2-regulated C-C motif chemokine ligand 28 (CCL28) signaling, respond to lenvatinib-induced cytotoxicity, we established an in vitro co-culture system and conducted functional cytotoxicity assays.
RESULTS: Using RNA sequencing, multiplex immunofluorescence staining and HTV injection HCC mouse model, we identified CSRP2 as one of the most significantly upregulated genes in HCC tissues. CSRP2 overexpression drives anti-lenvatinib resistance by inducing high levels of tumor-associated macrophages (TAMs) infiltration and reshaping an immunosuppressive microenvironment. Then flow cytometry, mass spectrometry and chromatin immunoprecipitation were conducted to clarify the underlying mechanism of CSRP2. We showed CSRP2 promotes phosphorylation of activating transcription factor 2 (ATF2) at Thr69/71, leading to the transcriptional activation of CCL28 expression. HCC-derived CCL28 recruits TAMs to drive immunosuppression and anti-lenvatinib tolerance. BI6901, a potent and selective CCR10 antagonist, blocked TAMs recruitment and enhanced T-cell activation. Combining CCR10 inhibition improved the therapeutic benefit of anti-lenvatinib in HCC.
CONCLUSIONS: These results illustrate that CSRP2 regulates the tumor microenvironment to promote HCC growth and drive lenvatinib tolerance via the CSRP2/ATF2/CCL28 axis. Targeting this pathway could synergize with lenvatinib to treat HCC more effectively.

Keywords:  Hepatocellular Carcinoma; Macrophage; Tolerance; Tumor Microenvironment

DOI:  https://doi.org/10.1136/jitc-2025-012201
Adv Sci (Weinh). 2025 Oct 02. e03323

Deacetylation of ACLY Mediates RNA M6A-Modification of NOXA and Promotes Chemoresistance of Colorectal Cancer.

Jun Wen, Mengqin Shen, Haitao Zhao, Liu Liu, Qian Hua, Xiaoping Zhao, Jianjun Liu, Haizhong Feng, Gang Huang.

  Chemoresistance is a major challenge for colorectal cancer (CRC) therapy and is a leading cause of cancer mortality, yet the underlying molecular mechanism remains unclear. ATP citrate lyase (ACLY), a rate-limiting enzyme of de novo lipid synthesis, plays an important role in tumor progression and chemotherapy. Here, It is demonstrated that deacetylation of ACLY is critical for chemoresistance in CRC. Through proteomic screening acetylated proteins in chemoresistant patient-derived cells, It is identified that ACLY is deacetylated at K978 site, which induces the relocation of ACLY to the nucleus and promotes its binding to RNA-binding protein 15 (RBM15). This facilitates N6-methyladenosine (m6A) methylation of NOXA (also known as PMAIP1, phorbol-12-myristate-13-acetate-induced protein 1) and decreases the stability of NOXA mRNA, resulting in chemoresistance. With the selective inhibitor Santacruzamate A, targeting the deacetylase histone deacetylase 2 (HDAC2) to inhibit the acetylation may enhance the sensitivity of chemoresistance. These findings provide new insights into the mechanism of ACLY deacetylation promoting chemoresistance and suggest a potential therapeutic strategy to mitigate the chemoresistant effects.

Keywords:  ACLY; acetylation; chemoresistance; colorectal cancer; m6A

DOI:  https://doi.org/10.1002/advs.202503323
Pharmacogenomics J. 2025 Oct 03. 25(5): 26

Serine-arginine protein kinase 1 (SRPK1) is under-expressed in mucinous colorectal cancer, and may mediate resistance to oxaliplatin.

William P Duggan, Mohammedreza Azimi, Lyndsey Flanagan, Graeme P Sullivan, Ian S Reynolds, Joanna Fay, Heiko Dussmann, Tríona Ní Chonghaile, Katherine M Sheehan, Karin Jirström, Jochen H M Prehn, John P Burke.

5-15% of all colorectal cancers (CRCs) are mucinous. Mucinous CRCs are associated with an inhibited response to standard adjuvant and neoadjuvant therapies. Serine-Arginine Protein Kinase 1 (SRPK1) is an enzyme, which modulates the activity of multiple splicing factors. SRPK1 under-expression is associated with resistance to platinum-based chemotherapeutic agents in multiple tumor types. The objectives of this study were to evaluate SRPK1 expression in mucinous CRC and to explore the potential relationship between differential SRPK1 expression and oxaliplatin resistance in mucinous CRC. Rectal cancer and CRC Tissue Microarrays (TMA) were stained with SRPK1 to compare expression between mucinous and non-mucinous tumors. SRPK1 expression was analyzed in mucinous and non-mucinous CRC cell lines. Cells were treated with oxaliplatin to explore differences in treatment response. Mucinous cells were transfected with an SRPK1 CRISPR/Cas9 lentiviral activation plasmid to investigate the relationship between SRPK1 expression and oxaliplatin resistance. The TMA cohorts included 117 patients with mucinous and 441 patients with non-mucinous CRC. SRPK1 was found to be under-expressed in both the mucinous rectal cancer (P < 0.001) and CRC cohorts (P = 0.003). On univariate analysis, SRPK1 under-expression was found to be associated with worse 5-year OS (P = 0.001). Treatment of mucinous CRC cells with oxaliplatin did not result in a significant increase in cell death (P = 0.149). However overexpression of SRPK1 following transfection with a CRISPR/CAS9 activation plasmid resulted in a significant increase in sensitivity of these cells to oxaliplatin treatment (P = 0.029). SRPK1 is under-expressed in mucinous CRC, and under-expression is associated with worse OS. This may be due to the positive effects of SRPK1 on oxaliplatin sensitivity.

DOI: https://doi.org/10.1038/s41397-025-00384-z
J Exp Clin Cancer Res. 2025 Sep 30. 44(1): 271

FSTL3 is a biomarker of poor prognosis and associated with immunotherapy resistance in ovarian cancer.

Maeva Chauvin, Estelle Tromelin, Julien Roche-Prellezo, Hyshem H Lancia, Marie-Charlotte Meinsohn, Caroline Coletti, Ngoc Minh Phuong Nguyen, Virginie Lafont, Henri-Alexandre Michaud, Ranjan Mishra, Nathalie Bonnefoy, Laurent Gros, David Pépin.

High-grade serous ovarian carcinoma (HGSOC) is associated with high mortality rates due to late-stage diagnosis and limited treatment options. We investigated the role of FSTL3 in ovarian cancer progression both as a prognostic biomarker and as a potential therapeutic target.We measured levels of follistatin (FST) and follistatin-like 3 (FSTL3) in 96 ovarian cancer patient ascites samples and found that FSTL3 overexpression was more predominant than FST and associated with poorer survival outcomes. Mice implanted with an HGSOC syngeneic cell line bearing common alterations in ovarian cancer (KRASG12 V, P53R172H, CCNE1oe, AKT2oe) had increasing levels of FST and FSTL3 in serum during tumor growth. Further alteration of this model to generate a knockout of FST (KPCA.FSTKO) and an overexpression of human FSTL3 (KPCA.FSTKO_hFSTL3) revealed that FSTL3 expression was associated with a more fibrotic tumor microenvironment, correlating with an increased abundance of cancer-associated myofibroblasts (myCAFs), and cancer cells with a more mesenchymal phenotype. Tumors overexpressing FSTL3 also had significantly less immunocyte infiltration, reduced intratumoral T-cell abundance, and increased CD8+ T cell exhaustion. FSTL3 overexpression completely abrogated tumor response to PPC treatment (Prexasertib combined with PD-1 and CTLA-4 blockade) compared to controls, suggesting that FSTL3 may be involved in immunotherapy resistance. In conclusion, this study suggests a role for FSTL3 as a prognostic marker and as therapeutic target in HGSOC, where it may play a role in promoting a mesenchymal tumor phenotype, maintaining an immunosuppressive tumor microenvironment, and driving immunotherapy resistance.

DOI: https://doi.org/10.1186/s13046-025-03425-4
Nat Commun. 2025 Sep 30. 16(1): 8716

A histone-centric multi-omics study shows that increased H3K4 methylation sustains triple-negative breast cancer phenotypes.

Roberta Noberini, Giulia Robusti, Alessandro Vai, Evelyn Oliva Savoia, Maria Giovanna Jodice, Giovanni Bertalot, Betül Çat, Isabella Pallavicini, Giuseppina Bonizzi, Maria Capra, Claudia Anna Sangalli, Federico Zambelli, Nicola Fusco, Salvatore Pece, Giulio Pavesi, Saverio Minucci, Tiziana Bonaldi.

Altered histone post-translational modifications are frequently associated with cancer. Here, we apply mass-spectrometry to study the epigenetic landscapes of breast cancer subtypes, with a particular focus on triple-negative breast cancers (TNBCs), a heterogeneous group lacking well-defined molecular targets and effective therapies. The analysis of over 200 tumors reveals epigenetic signatures that discriminate TNBCs from the other BC subtypes, and that distinguish TNBC patients with different prognoses. Employing a multi-OMICs approach integrating epigenomics, transcriptomics, and proteomics data, we investigate the mechanistic role of increased H3K4 methylation in TNBCs, demonstrating that H3K4me2 sustains the expression of genes associated with the TNBC phenotype. Through CRISPR-mediated editing, we establish a causal relationship between H3K4me2 and gene expression for several targets. Furthermore, treatment with H3K4 methyltransferase inhibitors reduce TNBC cell growth in vitro and in vivo. Collectively, our results unravel a novel epigenetic pathway implicated in TNBC pathogenesis and suggest new opportunities for targeted therapy.

DOI: https://doi.org/10.1038/s41467-025-63745-z
J Exp Clin Cancer Res. 2025 Sep 30. 44(1): 273

O-GlcNAcylation of UBAP2L regulates stress granule formation and sunitinib resistance in clear cell renal cell carcinoma.

Jiajun Xing, Baochao Li, Songbo Wang, Zengjun Wang, Chenkui Miao.

   BACKGROUND: Sunitinib resistance is one of the main reasons for the poor prognosis of clear renal cell carcinoma (ccRCC). Moreover, Stress granules (SGs) was found to enhance the stress adaptation capability of tumor cells, becoming an important mechanism for drug resistance in various cancers.
METHODS: We developed sunitinib-resistant patient-derived xenograft (PDX) and organoid (PDO) models to investigate sunitinib resistance in ccRCC. Proteomic analysis identified UBAP2L as a key mediator of this resistance. To explore its role in stress granule formation and sunitinib resistance, we conducted both in vitro and in vivo studies. We further elucidated the regulatory mechanisms of UBAP2L O-GlcNAcylation using immunoprecipitation, mass spectrometry, modification-based proteomics, RNA sequencing (RNA-seq), and RNA immunoprecipitation sequencing (RIP-seq).
RESULTS: In this study, enrichment of UBAP2L was elucidated to be significantly associated with sunitinib-resistant ccRCC patient-derived xenograft (PDX) model. Functional experiments showed that UBAP2L protected ccRCC from apoptosis and promoted ccRCC prolifecation and angiogenesis upon sunitinib treatment, thus enhancing drug resistance of ccRCC cells. Furthermore, mechanistic investigation demonstrated that O-GlcNAcylation of UBAP2L promoted its protein stability via inhibiting TRIM37-mediated ubiquitination and it regulated stress granule formation, thereby enhancing the mRNA stability of Melk and activating the PI3K signaling pathways.
CONCLUSIONS: These results validated the significant roles of O-GlcNAcylation of UBAP2L in ccRCC sunitinib resistance, which provided an innovative theoretical basis for the clinical diagnosis and therapy of ccRCC.

Keywords:  O-GlcNAcylation; Patient-derived xenograft; Renal cell carcinoma; Stress granule formation; Sunitinib resistance; UBAP2L

DOI:  https://doi.org/10.1186/s13046-025-03534-0
Bioact Mater. 2026 Jan;55 94-113

Dual targeting of lipid metabolic reprogramming and immunosuppressive sentinel lymph nodes potentiates anti-metastatic therapy for triple negative breast cancer.

Tingting He, Xuemei Liao, Shuangquan Gou, Genhua Liu, Qiaojian Duan, Zizhen Qin, Junli Yang, Yu Sun, Peng Zhao, Zhong Luo, Kaiyong Cai.

  Inducing immunogenic cell death (ICD) in cancer cells provides a promising approach in immunotherapy, however, oxidative stress relief and metabolic plasticity enhancement limit the immune-stimulating effect of traditional ICD inducer in sentinel lymph nodes (SLN), owing to the metabolism of fatty acids. In this article, a biocompatible green liposome CL-Lip was designed to not only selectively induce ICD in primary and metastatic 4T1 cells, but also relieved the immunosuppression in invasive SLN. CL-Lip is composed of engineered liposomes modified with linoleic acid and catalase, which synergistically trigger ICD, stimulate lipid peroxidation, PD-L1 carbonylation and effectively promote the maturation of dendritic cells and T cell differentiation. Moreover, catalase also downregulated the hypoxia level in SLN. Through cellular experiments and transcriptome analysis, it is proved that the ICD induction via CL-Lip is mediated by ROS generation, resulting from the YAP-dependent fatty acid oxidation (FAO) interference. Transcriptome analysis revealed that engineered CL-Lip diminishes YAP-dependent FAO pathway and effectively antagonizes the metabolic flexibility, thereby selectively triggering the metabolic dead-associated ICD process in both primary and metastatic 4T1 cells. In animal experiments, this little reported metabolic-driven ICD route not only significantly reduces metastatic foci, but also induces a "cold-to-hot" remodeling of SLN, resulting in the formation of a in situ tumor vaccine. These findings hold great significance for the development of next-generation ICD inducers and immunotherapy approaches.

Keywords:  Fatty acid oxidation; Immune microenvironment; Immunogenic cell death; Liposome; Sentinel lymph node

DOI:  https://doi.org/10.1016/j.bioactmat.2025.09.011
J Clin Invest. 2025 Oct 01. pii: e186467. [Epub ahead of print]135(19):

SOX9 drives a stem-like transcriptional state and platinum resistance in high-grade serous ovarian cancer.

Alexander J Duval, Fidan Seker-Polat, Magdalena Rogozinska, Meric Kinali, Ann E Walts, Ozlem Neyisci, Yaqi Zhang, Zhonglin Li, Edward J Tanner, Allison E Grubbs, Sandra Orsulic, Daniela Matei, Mazhar Adli.

  Chemotherapy resistance remains a formidable challenge to the treatment of high-grade serous ovarian cancer (HGSOC). The drug-tolerant cells may originate from a small population of inherently resistant cancer stem cells (CSCs) in primary tumors. In contrast, sufficient evidence suggests that drug tolerance can also be transiently acquired by nonstem cancer cells. Regardless of the route, key regulators of this plastic process are poorly understood. Here, we utilized multiomics, tumor microarrays, and epigenetic modulation to demonstrate that SOX9 is a key chemo-induced driver of chemoresistance in HGSOC. Epigenetic upregulation of SOX9 was sufficient to induce chemoresistance in multiple HGSOC lines. Moreover, this upregulation induced the formation of a stem-like subpopulation and significant chemoresistance in vivo. Mechanistically, SOX9 increased transcriptional divergence, reprogramming the transcriptional state of naive cells into a stem-like state. Supporting this, we identified a rare cluster of SOX9-expressing cells in primary tumors that were highly enriched for CSCs and chemoresistance-associated stress gene modules. Notably, single-cell analysis showed that chemo treatment results in rapid population-level induction of SOX9 that enriches for a stem-like transcriptional state. Altogether, these findings implicate SOX9 as a critical regulator of early steps of transcriptional reprogramming that lead to chemoresistance through a CSC-like state in HGSOC.

Keywords:  Cancer; Epigenetics; Oncology; Stem cells; Transcription

DOI:  https://doi.org/10.1172/JCI186467