bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2025–09–07
six papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. In Vivo Tumor Growth Control by General Control Nonderepressible 2-Targeting Agents Results from Kinase Activation.
  2. ChREBP-Mediated Choline Deprivation and Chemokine Secretion Shape Tumor-Associated Macrophages to Promote Immune Evasion.
  3. Differential cell survival outcomes in response to diverse amino acid stress.
  4. DKC1-mediated pseudouridylation of rRNA targets hnRNP A1 to sustain IRES-dependent translation and ATF4-driven metabolic adaptation.
  5. Tumors hijack macrophages for iron supply to promote bone metastasis and anemia.
  6. STING and Nonnecroptotic MLKL-Mediated Mechanisms Improve Dendritic Cell Maturation and Killing of Cancer Cells.
  1. Mol Cancer Ther. 2025 Sep 05. OF1-OF13
    In Vivo Tumor Growth Control by General Control Nonderepressible 2-Targeting Agents Results from Kinase Activation.
    Feven Tameire, Paulina Wojnarowicz, Crissy Dudgeon, Kathryn T Bieging-Rolett, Sho Fujisawa, Savi Ramurthy, Owen Reilly, Christopher G Thomson, Bradley S Sherborne, Simon J Taylor, Fang He, Pengwei Pan, Baozhong Li, Earl May, Alan C Rigby, Mark J Mulvihill, Nandita Bose, David Surguladze, Eric S Lightcap.
      General control nonderepressible 2 (GCN2; EIF2AK4) is a serine-threonine kinase in the integrated stress response signaling pathway that initiates adaptive responses during nutrient stress conditions. Although pharmacologic inhibition of GCN2 under nutrient stress conditions induces apoptosis and inhibits tumor growth, GCN2 inhibition without nutrient stress has been reported to have no effect on tumor growth. By exploring an array of GCN2 inhibitors, we demonstrate that multiple agents in fact activate GCN2 in biochemical and cell-based assays at low concentrations and inhibit GCN2 at higher concentrations. Unexpectedly, it is this activation, and not inhibition, of the GCN2 pathway that is associated with decreased viability in vitro and tumor growth inhibition in vivo across multiple models. Knockdown and knockout experiments show that activation of the integrated stress response by GCN2-targeting agents is dependent on GCN2. ISRIB, a modulator of eIF2B, ablates the viability effect, demonstrating the dependence on translation initiation. Activating doses result in the induction of cleaved caspase 3 and cleaved PARP. In contrast, a nonactivating GCN2-targeting agent does not affect viability. These results provide a clearer understanding of the challenges and opportunities for the clinical development of compounds targeting GCN2.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-24-0960
  2. Cancer Res. 2025 Sep 05.
    ChREBP-Mediated Choline Deprivation and Chemokine Secretion Shape Tumor-Associated Macrophages to Promote Immune Evasion.
    Jianhong Zhao, Baoxiang Chen, Yanrong Deng, Lifang Fan, Siyuan Yin, Haisheng Yu, Yongchang Wei, Jing Dai, Qun Qian, Quanjiao Chen, Xianghai Ren, Xiaoyu Xie, Wenyi Wei, Jinfang Zhang, Congqing Jiang.
      Tumor metabolic reprogramming has been recognized as a critical determinant in tumor development and cancer immunotherapy response. Aberrant choline metabolism is emerging as a defining hallmark of cancer. Here, we found that carbohydrate responsive element binding protein (ChREBP)-mediated choline deprivation induced tumor-associated macrophage (TAM) reprogramming and maintained an immunosuppressive tumor microenvironment (TME). Mechanistically, ChREBP interacted with SP1 to increase the expression of immunosuppressive chemokines CCL2 and CCL7 and choline transporter SLC44A1. As such, high CCL2 and CCL7 expression promoted recruitment of TAMs. Tumor cells with high SLC44A1 levels competed with M1-like TAMs for choline, inhibiting cGAS-STING signaling and promoting the repolarization of M1-like to M2-like macrophages. Clinically, ChREBP-SP1-choline metabolism axis expression was associated with poor clinical outcome in colorectal cancer. Thus, the study identified the interplay between tumors and TAMs via choline competition as a previously unknown immune evasion mechanism in the TME and propose ChREBP as a potential immunotherapeutic target in cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0235
  3. Life Sci Alliance. 2025 Nov;pii: e202503324. [Epub ahead of print]8(11):
    Differential cell survival outcomes in response to diverse amino acid stress.
    Marion Russier, Alessandra Fiore, Ana Bici, Annette Groß, Maria Tanzer, Assa Yeroslaviz, Matthias Mann, Peter J Murray.
      Amino acid (AA) detection is fundamental for cellular function, balancing translation demands, biochemical pathways, and signaling networks. Although the GCN2 and mTORC1 pathways are known to regulate AA sensing, the global cellular response to AA deprivation remains poorly understood, particularly in non-transformed cells, which may exhibit distinct adaptive strategies compared with cancer cells. Here, we employed murine pluripotent embryonic stem (ES) cells as a model system to dissect responses to AA stress. Using multi-omics analyses over an extended time course, we examined the effects of arginine (Arg) and leucine (Leu) deprivation. We uncovered a broad array of proteomic, phosphoproteomic, transcriptomic, and metabolomic adaptations, including an increase in lysosome production, all occurring without lethality. We found that Arg or Leu starvation induces reversible cell cycle exit, promoting a quiescent state that enhances resistance to cytotoxic stressors. In contrast, cysteine (Cys) and threonine (Thr) deprivation led to cell death via distinct pathways: ferroptosis for Cys starvation, whereas Thr deprivation triggered a previously uncharacterized form of cell death, which could be entirely suppressed by methionine (Met) co-starvation, and mTOR or translational inhibition. These findings suggest that ES cells implement specialized survival strategies in response to different AA limitations, highlighting their ability to reprogram cellular biochemistry under nutrient stress.
    DOI:  https://doi.org/10.26508/lsa.202503324
  4. Sci Adv. 2025 Aug 29. 11(35): eadv9401
    DKC1-mediated pseudouridylation of rRNA targets hnRNP A1 to sustain IRES-dependent translation and ATF4-driven metabolic adaptation.
    Anamika Gupta, Mohit Bansal, Jane Ding, Suman Karki, Madhuparna Pandit, Sunil Sudarshan, Han-Fei Ding.
      The pseudouridine synthase DKC1 regulates internal ribosome entry site (IRES)-dependent translation and is up-regulated in cancers by the MYC family of oncogenes. The functional significance of DKC1 up-regulation and the mechanistic connection between pseudouridylation and IRES-mediated translation remain poorly understood. Here, we report that DKC1 drives an ATF4-mediated transcriptional program that supports amino acid metabolism and stress adaptation. We identify hnRNP A1, an IRES trans-acting factor, as a critical downstream mediator of DKC1 in sustaining ATF4 expression and IRES-dependent translation. Mechanistically, DKC1-mediated pseudouridylation at two specific 28S ribosomal RNA sites is crucial for maintaining hnRNP A1 protein expression. In turn, hnRNP A1 binds and stabilizes ATF4 messenger RNA, preferentially promoting IRES-dependent translation of ATF4 variant 1. Furthermore, cellular stress induces hnRNP A1, which is necessary for stress-induced ATF4 protein expression. Collectively, our findings uncover an MYC-driven DKC1-hnRNP A1 axis that links IRES-dependent translation and ATF4-mediated metabolic adaptation, thereby supporting cancer cell survival under metabolic stress during tumor progression.
    DOI:  https://doi.org/10.1126/sciadv.adv9401
  5. Cell. 2025 Aug 26. pii: S0092-8674(25)00927-4. [Epub ahead of print]
    Tumors hijack macrophages for iron supply to promote bone metastasis and anemia.
    Yujiao Han, Hirak Sarkar, Zhan Xu, Sereno Lopez-Darwin, Yong Wei, Xiang Hang, Fengshuo Liu, Kimberley Tran, Wei Wang, Jennifer M Miller, Christina J DeCoste, Dylan S Blohm, Robert L Satcher, Xiang H-F Zhang, Yibin Kang.
      Bone marrow is both a primary site for hematopoiesis and a fertile niche for metastasis. The mechanism of the common occurrence of anemia among patients with bone metastasis remains poorly understood. Here, we show that a specialized population of VCAM1+CD163+CCR3+ macrophages, normally essential for erythropoiesis by transporting iron to erythroblasts, are highly enriched in the bone metastatic niche in mouse models. Tumor cells hijack these macrophages for iron supply, reducing iron availability for erythroblasts, impairing erythropoiesis, and contributing to anemia. Increased iron supply enables tumor cells to produce hemoglobin in response to hypoxia, mimicking erythroblasts. We identify macrophages with similar iron-transporting features in human bone metastases and show that elevated HBB expression correlates with increased risk of bone metastasis. These findings establish iron-transporting macrophages as an essential component of the metastatic bone niche, revealing a critical interplay between immune cells, metal metabolism, and tumor cell plasticity in driving metastasis and anemia.
    Keywords:  anemia; bone metastasis; breast cancer; cellular plasticity; erythropoiesis; hypoxia; iron metabolism; macrophage; metastatic niche; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cell.2025.08.013
  6. Eur J Immunol. 2025 Sep;55(9): e70044
    STING and Nonnecroptotic MLKL-Mediated Mechanisms Improve Dendritic Cell Maturation and Killing of Cancer Cells.
    Trine S Jensen, Marlene F Laursen, Lea Schort, Agnieszka J Banasik, Ralf Agger, Martin R Jakobsen, Emil Kofod-Olsen.
      Activation of the cGAS-STING pathway plays an important role in antitumor immunity through maturation of tumor-infiltrating DCs. DCs engulf extracellular DNA released by dying cancer cells, supporting activation of the cGAS-STING pathway and concomitant DC maturation. Extracellular DNA in the tumor microenvironment is primarily derived from cells undergoing uncontrolled necrosis or programmed inflammatory death, such as necroptosis, which can be induced when apoptosis pathways are inhibited. Here, we report that caspase inhibition primes activation of a RIPK1/3, MLKL, and STING signaling axis in DCs, resulting in maturation without the need for any further maturation stimuli such as LPS or TNF-α. Notably, these signaling events do not induce DC death, indicating a nonnecroptotic role of the RIPK1-RIPK3-MLKL pathway and novel crosstalk with the STING pathway. Caspase inhibition in DC/cancer cell co-cultures results in DC maturation, inducing TNF-α secretion, which delivers the co-signal to induce cancer cell necroptosis. In summary, we find a collaborative mechanism of the STING and necroptosis pathway in DC maturation, and that activation of the necroptosis pathway has opposite effects on cancer cells and DCs, proposing a possibility for new targets in cancer immunotherapy.
    Keywords:  MLKL; STING; caspases; dendritic cells; necroptosis
    DOI:  https://doi.org/10.1002/eji.70044
This page is being maintained by Thomas Krichel. It was last updated on 2025‒10‒11 at 18:37.