bims-stacyt 2026-02-15 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2026–02–15
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Tumor-immune-neural circuit disrupts energy homeostasis in cancer cachexia.
Metabolic stress conditions dictate MAPKAPK2-dependent efficiency of MEK1/2 inhibition in colorectal carcinoma.
LDHB Deficiency in Fibroblasts Induces Lactate-Mediated Inflammatory Reprogramming that Promotes Breast Cancer Metastasis.
AMPK promotes TFEB transcriptional activity through dephosphorylation at both MTORC1-dependent and -independent sites.
Overview of glutamine metabolism in stromal components of the tumor microenvironment and potential anti-tumor therapies.
Emerging perspectives on metabolic reprogramming in the microenvironment of ovarian cancer metastasis.
Ketogenic diet modulates AMPK-mTOR pathway in breast cancer.
IL-6R blockade with tocilizumab disrupts pericyte-and tumor cell-driven IL-6/STAT3 signaling, enhancing docetaxel efficacy in ER+ breast cancer.

Cancer Cell. 2026 Feb 12. pii: S1535-6108(26)00053-X. [Epub ahead of print]

Tumor-immune-neural circuit disrupts energy homeostasis in cancer cachexia.

Xiuhui Shi, Alex X Arreola, Zhijun Zhou, Jingxuan Yang, Mingyang Liu, Yang Cai, Yu Ren, Hao Yuan, Qun Chen, Xinjie Chen, Xinyu Yang, Yimei Meng, Jingyi Wang, Wenyi Luo, Michael C Rudolph, Rohan Varshney, Kar-Ming Fung, Chao Xu, Wei R Chen, Michael S Bronze, Lei Zheng, Yi-Ping Li, Courtney W Houchen, Yuqing Zhang, Min Li.

  Cancer-induced cachexia and anorexia are debilitating complications across many cancers, yet effective treatments remain limited due to a poor understanding of the underlying mechanisms. Here, we identify an uncharacterized tumor-immune-neural circuit driving these syndromes, centered on growth and differentiation factor 15 (GDF15). Using genetically engineered mouse models, we find that loss of GDF15 protects against appetite loss, muscle wasting, and fat loss in pancreatic, lung, and skin cancers. Single-cell RNA sequencing reveals macrophages as a major source of GDF15, induced by tumor-derived colony-stimulating factor 1 (CSF1). GDF15 acts via the central nervous system to enhance β-adrenergic signaling in the tumor microenvironment, thereby amplifying cachexia. The disruption of this feedforward loop with GDF15-neutralizing antibody, anti-CSF1R antibody, or Rearranged during Transfection (RET) inhibitor markedly reduces both cachexia and anorexia. These findings reveal a non-cell-autonomous mechanism linking tumor signals, macrophage-derived GDF15, and neural pathways, highlighting the tumor-immune-neural triad as a promising therapeutic target.

Keywords:  adipose loss; body composition; energy expenditure; hormone; metabolic stress; muscle atrophy; norepinephrine; sympathetic nerve; tumor immune microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.ccell.2026.01.014
Proc Natl Acad Sci U S A. 2026 Feb 17. 123(7): e2505331123

Metabolic stress conditions dictate MAPKAPK2-dependent efficiency of MEK1/2 inhibition in colorectal carcinoma.

Niti Kumari, Xu Chen, Amber M Baldwin, Kristin I Clemons, Mohammad El-Harakeh, Lilian E Calisto, Balawant Kumar, Qiaoqiao Zhang, Jiang Min, Bin Xiao, Amar B Singh, Bin Wang, Brian J North.

  The kinase MAPKAPK2 regulates cell survival, proliferation, and death, and is upregulated in colorectal carcinoma (CRC) where it is associated with tumor growth and progression. However, how it regulates tumor progression in conjunction with other signaling pathways, such as MEK/ERK, remains elusive. Solid tumors are often subjected to metabolic stress, notably glucose deprivation. Here, we demonstrate that MAPKAPK2 protein levels in CRC regulate cell fate decision during stress conditions, such as glucose deprivation and therapeutic treatment. While MAPKAPK2 expression is a limiting factor for CRC growth in vitro, depleting MAPKAPK2 or inhibiting its activity pharmacologically provides a survival advantage to CRC cells under glucose limiting conditions. Subjecting CRC cells to low glucose resulted in an ERK1/2-mediated decline in MAPKAPK2 to promote survival. Additionally, cells with reduced MAPKAPK2 activity were less sensitive to trametinib under glucose limiting conditions. Utilizing transcriptomic profiling, we found that glucose deprivation and MAPKAPK2 depletion activate pathways associated with survival during metabolic stress. This relationship was also observed in CRC patients (TCGA), where tumors with low MAPKAPK2 expression had higher ERK1/2 activation and upregulated stress-induced pathways, leading to poor survival. Finally, MAPKAPK2 modulated growth of CRC organoids, subcutaneous tumors, and patient-derived xenografts (PDX), and reduced MAPKAPK2 levels decreased efficacy of trametinib, in vitro and in vivo. Overall, this study identifies an interrelationship between MEK/ERK and p38/MAPKAPK2 signaling pathways during glucose deprivation to support cell survival and features MAPKAPK2 loss as a possible mechanism leading to reduced efficacy of trametinib-based anticancer therapy and poor patient outcomes in CRC.

Keywords:  ERK; MAPKAPK2; colorectal cancer; glucose; trametinib

DOI:  https://doi.org/10.1073/pnas.2505331123
Cancer Res. 2026 Feb 13.

LDHB Deficiency in Fibroblasts Induces Lactate-Mediated Inflammatory Reprogramming that Promotes Breast Cancer Metastasis.

Zhihong Luo, Kangdi Li, You Yu, Yi Liu, Hong Weng, Xian-Tao Zeng, Yi Zheng, Wenhua Li.

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and often undergo metabolic reprogramming. Metabolic shifts within CAFs can influence cancer cell behavior. In this study, we revealed that the loss of lactate dehydrogenase B (LDHB) in CAFs drives a metabolic shift that significantly enhances breast cancer metastasis. LDHB loss in CAFs drove a shift towards an inflammatory fibroblast phenotype. Mechanistically, LDHB deficiency led to lactate accumulation, which disrupted the interaction between dual specificity phosphatase 16 (DUSP16) and p38, causing sustained p38 activation. Persistent p38 signaling reprogrammed CAFs into an inflammatory phenotype characterized by abundant secretion of the chemokine CXCL8, which in turn enhanced metastasis of breast cancer cells. In summary, these findings identify LDHB as a key metabolic regulator in CAFs and provide insights into how metabolic reprogramming promotes the inflammatory, pro-metastatic phenotype of CAFs, highlighting activating LDHB as a potential strategy for limiting cancer metastasis.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2792
Autophagy. 2026 Feb 09.

AMPK promotes TFEB transcriptional activity through dephosphorylation at both MTORC1-dependent and -independent sites.

Florentina Negoita, Conchita Fraguas Bringas, Kristina Hellberg, Katarzyna M Luda, Hongling Liu, Zhiyuan Li, Joyceline Cuenco, Jin-Feng Zhao, Gajanan Sathe, Ian G Ganley, Gopal P Sapkota, Kei Sakamoto.

  TFEB (transcription factor EB) is a critical regulator of lysosomal biogenesis, macroautophagy/autophagy and energy homeostasis through controlling expression of genes belonging to the coordinated lysosomal expression and regulation network. AMP-activated protein kinase (AMPK) has been reported to phosphorylate TFEB at three conserved C-terminal serine residues (S466, S467, S469) and these phosphorylation events were reported to be essential for transcriptional activation of TFEB. In sharp contrast to this proposition, we demonstrate that AMPK activation leads to the dephosphorylation of the C-terminal sites. We show that a synthetic peptide encompassing the C-terminal serine residues of TFEB is a poor substrate of AMPK in vitro. Treatment of cells with an AMPK activator (MK-8722), glucose deprivation or MTOR inhibitor (torin1) robustly dephosphorylated TFEB not only at the MTORC1-targeted N-terminal serine sites, but also at the C-terminal sites. Loss of function of AMPK abrogated MK-8722- but not torin1-induced dephosphorylation and induction of the TFEB target genes.

Keywords:  BAY-3827; MK-8722; MTOR; TFE3; coordinated lysosomal expression and regulation; reversible phosphorylation

DOI:  https://doi.org/10.1080/15548627.2026.2629720
Genes Dis. 2026 May;13(3): 101834

Overview of glutamine metabolism in stromal components of the tumor microenvironment and potential anti-tumor therapies.

Zizhuo Li, Jiapeng Deng, Hai Wang, Tao Liu, Yuyang Zhou, Pei Ouyang, Xuan Liang, Xian Zhang, Songtao Qi, Yaomin Li.

  As a critical metabolite in the tumor microenvironment, glutamine plays a crucial role in tumor progression, and its dual effects on promoting and inhibiting tumors have garnered increasing attention in recent years. Glutamine metabolism in tumor cells has been extensively studied; however, there is currently a lack of a comprehensive description of how it interacts with tumor stromal components in the tumor microenvironment. This review focuses on the interaction of glutamine metabolism and a range of tumor stromal components, such as macrophages, dendritic cells, T cells, fibroblasts, collagen, and blood vessels in the tumor microenvironment, as well as a summary of current prospective anti-tumor therapeutics targeting glutamine metabolism. Furthermore, this study discusses the shortcomings of mechanism research, metabolic complexity, and metabolic therapy for glutamine metabolism and proposes future research directions that are expected to provide a theoretical foundation for clinical cancer treatment strategies.

Keywords:  Anti-tumor therapy; Glutamine; Glutamine metabolism; Stromal cells; Tumor microenvironment; Tumor stromal components

DOI:  https://doi.org/10.1016/j.gendis.2025.101834
Biochim Biophys Acta Rev Cancer. 2026 Feb 09. pii: S0304-419X(26)00026-0. [Epub ahead of print]1881(2): 189554

Emerging perspectives on metabolic reprogramming in the microenvironment of ovarian cancer metastasis.

Jing Ma, Sally K Y To, Xinyu Zhang, Weiyang Zhao, Peng Zhang, Alice S T Wong.

  Ovarian cancer (OC) is one of the most lethal malignancies in females, mainly due to the aggressive metastasis at the late stage and the unsatisfactory of current therapies. OC cells exhibit a special metastatic behavior compared to other common epithelial tumors, primarily spreading within the peritoneal cavity. Due to the complexity of tumor microenvironment, physical factors induce significant metabolic changes in OC cells, thereby enhancing their metastatic ability. Key cellular components, such as cancer-associated fibroblasts and adipocytes, act synergistically to support metastasis through metabolic interactions. Recent efforts in tumor immunometabolism showed that metabolic reprogramming of immune cells can also significantly impact metastatic progression. Moreover, the microbiome and cellular senescence are emerging as important factors that alter the metabolic landscape. This review provides a systematic review of metabolic reprogramming in the OC microenvironment and highlights the most recent clinical trials targeting metabolic pathways. By increasing our understanding of these metabolic interactions, we can develop innovative metabolism-targeting interventions for this devastating gynecological malignancy.

Keywords:  Immunometabolism; Metabolic crosstalk; Metabolic reprogramming; Ovarian cancer; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2026.189554
J Nutr Biochem. 2026 Feb 11. pii: S0955-2863(26)00054-9. [Epub ahead of print] 110312

Ketogenic diet modulates AMPK-mTOR pathway in breast cancer.

Yaxin Luo, Junjun Li, Yuxin Yang, Lei Yan, Ziyang Huang, Lixia Chen, Lili Zhao, Jing Wang, Yongming Yang, Xianping Liu, Xihua Yang.

  Breast cancer (BC) is one of the most prevalent malignant tumors among women globally. This disease is modulated by the interaction of multiple complex factors and exhibits a high mortality rate, posing a severe threat to women's lives and health. The ketogenic diet (KD), a dietary regimen characterized by high fat and low carbohydrate content, has emerged as a potential adjuvant therapeutic strategy for BC; however, its mechanistic roles in regulating tumor metabolism remain not fully elucidated. In the present study, the underlying mechanism of KD in the context of BC were investigated in depth. In 4T1 mammary tumor-bearing mice, KD suppressed tumor growth by 50.73% (P<0.01) and activated the AMPK-mTOR axis, as evidenced by a 2.1-fold increase in AMPK phosphorylation and a reduction in mTOR activity. At the cellular level, Glucose restriction regulated mTOR expression at the cellular level by upregulating intracellular reactive oxygen species (ROS) in 4T1 cells and activating AMPK. Combining results at the animal and cellular levels, KD may induce alternations in intracellular ROS levels by restricting glucose uptake, thereby modulating the expression of the AMPK-mTOR pathway and ultimately inhibiting tumor growth. Collectively, our results demonstrate that KD exerts anti-tumor effects via ROS-mediated regulation of the AMPK/mTOR signaling pathway, supporting its potential as a metabolic intervention strategy for BC.

Keywords:  AMPK-mTOR pathway; Breast cancer; Glucose restriction; Ketogenic diet

DOI:  https://doi.org/10.1016/j.jnutbio.2026.110312
bioRxiv. 2026 Jan 30. pii: 2026.01.29.702661. [Epub ahead of print]

IL-6R blockade with tocilizumab disrupts pericyte-and tumor cell-driven IL-6/STAT3 signaling, enhancing docetaxel efficacy in ER+ breast cancer.

Roza Kamila Przanowska, Jacky Gomez-Villa, Victoria J Liu, Natalia Antonides-Jensen, Lavanya Visvabharathy, John C Alverdy, Sonia L Hernandez, Samantha S Yee.

Metastatic breast cancer is a global health concern with a persistently low five-year survival rate. Taxane microtubule stabilizers, including docetaxel (DTX), are the standard of care in various treatment protocols. DTX is used both as a single agent and in combination therapies, with a majority of ER+ breast cancer patients ultimately developing chemoresistance. The mechanisms contributing to chemoresistance involving the tumor microenvironment (TME) have not been fully elucidated. Specifically, the role of vascular cells within the TME, particularly pericytes, is understudied, and their role in promoting chemoresistance remains unknown. Inflammatory cytokines such as interleukin 6 (IL-6) are known to drive drug resistance via activation of the pro-survival JAK/STAT pathway. We found that DTX induced IL-6 secretion of pericytes by at least two-fold compared to vehicle-treated controls in vitro. All tested breast cancer cell lines expressed subunits of the IL-6 receptor (IL-6R) complex, indicating their capacity to respond to JAK/STAT signaling. Conditioned media from DTX-treated pericytes activated STAT3 in ER+ breast cancer cells to levels comparable to recombinant IL-6. Pharmacologic blockade of IL-6 signaling with the IL-6R inhibitor, tocilizumab, reduced DTX-induced STAT3 activation in vitro. Furthermore, combined treatment with tocilizumab and DTX synergistically suppressed the growth of zero-passage patient-derived ER+ breast cancer organoids expressing intact IL-6 signaling. Together, our findings suggest that combining DTX with tocilizumab may revert DTX-induced chemoresistance in ER+ breast cancer patients by inhibiting IL-6-mediated activation of the STAT3 pathway.

DOI: https://doi.org/10.64898/2026.01.29.702661