bims-mibica 2025-08-24 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–08–24
fifteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University

The mevalonate pathway couples lipid metabolism to amino acid synthesis via ubiquinone-dependent redox control.
Mitochondrial genome copy number variation across tissues in mice and humans.
ZEB1 stratifies the response to Sorafenib and Mdivi-1 combination therapy in hepatocellular carcinoma.
BCL-xL dependency in chromophobe renal cell carcinoma.
Mitochondrial hyper-acetylation induced by an engineered acetyltransferase promotes cellular senescence.
Mutant p53 affects the mitochondrial proteome, promoting mitochondrial fragmentation and OXPHOS in pancreatic ductal adenocarcinoma cells.
High tide or low tide: the transport and metabolism of mitochondrial nucleotides.
Renal Coenzyme A (CoA) Production Fuels Stem Cell Proliferation and Tumor Growth.
The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming.
Role of Bcl-2 family anti-apoptosis inhibition in overcoming therapeutic resistance in prostate cancer: A systematic review.
In Pursuit of Best-in-Class MCL-1 Inhibitors: Discovery of Highly Potent 1,4-Indoyl Macrocycles with Favorable Physicochemical Properties.
Cytotoxic CD8+ T Cells Downregulate GPX4 to Promote Ferroptosis in Melanoma that Drives Antitumor Immunity.
Polyclonality and metabolic heterogeneity in a colorectal tumor model.
Mitochondrial fission genes MTFP1/MTFP2 as predictive biomarkers in prostate cancer: a mendelian randomization study.
Exercise improves survival of some people with colon cancer, clinical trial shows.

bioRxiv. 2025 Aug 12. pii: 2025.08.10.669191. [Epub ahead of print]

The mevalonate pathway couples lipid metabolism to amino acid synthesis via ubiquinone-dependent redox control.

Thi Thinh Nguyen, Mohit Bansal, Jane Ding, Sunil Sudarshan, Han-Fei Ding.

The mevalonate pathway produces sterols and isoprenoids that support cancer cell growth, yet its broader metabolic functions remain incompletely defined. Here, we show that this pathway sustains amino acid biosynthesis by promoting mitochondrial NAD⁺ regeneration through ubiquinone-dependent electron transport. Statin-mediated inhibition of the mevalonate pathway impairs oxidative phosphorylation, lowers the NAD⁺/NADH ratio, and suppresses de novo serine and aspartate synthesis, thereby activating the GCN2-eIF2α-ATF4 amino acid deprivation response. The resulting depletion of serine-derived glycine and one-carbon units, together with reduced aspartate availability, limits purine and pyrimidine nucleotide production. Expression of the bacterial NADH oxidase LbNOX or the alternative oxidase AOX restores NAD⁺ levels and rescues statin-induced growth inhibition. These findings suggest that impaired NAD⁺ regeneration is a key mechanism contributing to the anti-proliferative activity of statins, linking the mevalonate pathway to mitochondrial electron transport- dependent control of amino acid metabolism.
Significance: This study identifies the mevalonate pathway as a regulator of amino acid biosynthesis through mitochondrial electron transport-dependent NAD⁺ regeneration and reveals redox disruption as a key mechanism contributing to the anti-proliferative effects of statins.

DOI: https://doi.org/10.1101/2025.08.10.669191
Proc Natl Acad Sci U S A. 2024 Aug 13. 121(33): e2402291121

Mitochondrial genome copy number variation across tissues in mice and humans.

Sneha P Rath, Rahul Gupta, Ellen Todres, Hong Wang, Alexis A Jourdain, Kristin G Ardlie, Sarah E Calvo, Vamsi K Mootha.

  The mammalian mitochondrial genome (mtDNA) is multicopy and its copy number (mtCN) varies widely across tissues, in development and in disease. Here, we systematically catalog this variation by assaying mtCN in 52 human tissues across 952 donors (10,499 samples from the Genotype-Tissue Expression project) and 20 murine tissues using qPCR, capturing 50- and 200-fold variation, respectively. We also estimate per cell mtCN across 173 human cell lines from the Cancer Cell Line Encyclopedia using whole-genome sequencing data and observe >50-fold variation. We then leverage the vast amount of genomics data available for these repositories to credential our resource and uncover mtDNA-related biology. Using already existing proteomics data, we show that variation in mtCN can be predicted by variation in TFAM, histone, and mitochondrial ribosome protein abundance. We also integrate mtCN estimates with the CRISPR gene dependency measurements to find that cell lines with high mtCN are resistant to loss of GPX4, a glutathione phospholipid hydroperoxidase. Our resource captures variation in mtCN across mammalian tissues and should be broadly useful to the research community.

Keywords:  GPX4; TFAM; histone; mitochondrial ribosome; mtDNA

DOI:  https://doi.org/10.1073/pnas.2402291121
Sci Rep. 2025 Aug 19. 15(1): 30451

ZEB1 stratifies the response to Sorafenib and Mdivi-1 combination therapy in hepatocellular carcinoma.

H Freudenstein, M Strecker, S Gylstorff, W Shi, M Boettcher, S Medunjanin, C Catapano, C Siba, C Wex, T Wartmann, A Y Sanin, M Franz, J Arend, D Mougiakakos, M Pech, R S Croner, U D Kahlert, F Stelter.

  Primary liver cancer is one of the most frequently diagnosed and deadliest cancers. Zinc finger E-box binding homeobox 1 (ZEB1) is negative prognostic factor in liver cancer by promoting therapy resistance and tumorigenesis. Interfering in pathways of cellular metabolism emerges as a potent strategy to overcome tumor cells resistance to therapy. Our study aims to investigate the apoptotic potential of pharmacological inhibition of mitochondrial metabolism in primary liver cancer and whether this strategy can reduce ZEB1-associated resistance to standard of care chemotherapy Sorafenib. ZEB1 mRNA levels in patient samples and cancer cell lines were computationally screened using public datasets. Transcript and protein abundance of ZEB1 and regulators of mitochondrial fission and fusion were quantified in patient-matched tumor and non-tumor tissues of hepatocellular carcinoma (HCC) and cholangiocellular adenocarcinoma (CCA) from our clinic and common liver cancer cell lines. Functional assays on cell models with varying ZEB1 expression exposed to mitochondrial division inhibitor Mdivi-1 included mitochondrial mass quantification, mitochondrial membrane potential examination, apoptosis, extracellular flux, and cell growth analyses. Mdivi-1 treatment in human-physiological achievable concentration effectively induced apoptosis in all tested cell models. ZEB1 expression was heightened in younger patients, and dynamin-related protein 1 (Drp1) protein abundance was elevated in a subgroup of tumor tissue compared to healthy tissue. Cancer cell lines with high ZEB1 expression showed increased mitochondrial fission marker Drp1 and larger total mitochondrial mass, preserved membrane potential with reduced mitochondrial ATP production and respiration, resulting in an overall reduced mitochondrial fitness. Pharmacological inhibition of mitochondrial fission using Mdivi-1 reduced HCC resistance to Sorafenib in ZEB1-driven liver cancer. A subset of HCC cell lines with elevated ZEB1 levels exhibit increased mitochondrial mass and reduced metabolic activity. Targeting mitochondrial division in HCC by treatment with Mdivi-1 in combination with Sorafenib demonstrates a synergistic therapeutic effect in hepatocellular carcinoma (HCC) cell lines characterized by high ZEB1 expression. Further in vivo validation is needed to confirm these findings and evaluate this potential combined treatment option.

Keywords:  EMT; Hepatocellular carcinoma; Mdivi-1; Mitochondrial metabolism; Sorafenib; ZEB1

DOI:  https://doi.org/10.1038/s41598-025-16379-6
Cancer Gene Ther. 2025 Aug 16.

BCL-xL dependency in chromophobe renal cell carcinoma.

Nadine Mahmoud, Xingping Qin, Wafaa Bzeih, Damir Khabibullin, Michel Alchoueiry, Steven Safi, Joelle Chami, Tiegang Han, Samer Salem, Carmen Priolo, Abhishek A Chakraborty, Kristopher A Sarosiek, Elizabeth P Henske.

Chromophobe renal cell carcinoma (ChRCC) is the third most common subtype of kidney cancer, with limited therapeutic options. Using BH3 profiling to screen ChRCC-derived cell lines, we discovered that BH3 peptides targeting BCL-xL promote apoptosis in ChRCC. Downregulation of BCL2L1 is sufficient to induce apoptosis in ChRCC-derived cells, consistent with our screening results. BCL2L1, encoding BCL-xL, is fourfold upregulated in ChRCC compared to normal kidney and has the second highest expression in The Cancer Genome Atlas. BCL2L1 downregulation enhances MCL-1 expression, suggesting a possible compensatory role for MCL-1. Based on these results, we evaluated two BH3 mimetics, A-1331852 (targeting BCL-xL) and S63845 (targeting MCL-1). Their combination resulted in 80% cell death. DT2216, a proteolysis-targeting chimera (PROTAC) that targets BCL-xL for degradation, induced cleaved PARP and caspase 3, indicators of apoptosis. ChRCC cells are known to be highly sensitive to ferroptosis. We combined A-1331852 and S63845 with IKE or RSL3 (ferroptosis-inducing drugs). BCL-xL and MCL-1 inhibition enhanced the susceptibility to ferroptosis, suggesting a link between apoptosis and ferroptosis in ChRCC. These data indicate that BCL-xL maintains ChRCC cell survival by suppressing apoptosis. The BCL-xL-specific PROTAC DT2216, currently in clinical trials, may provide an opportunity for ChRCC therapy.

DOI: https://doi.org/10.1038/s41417-025-00953-1
iScience. 2025 Sep 19. 28(9): 113233

Mitochondrial hyper-acetylation induced by an engineered acetyltransferase promotes cellular senescence.

Tadahiro Shimazu, Ayane Kataoka, Takehiro Suzuki, Naoshi Dohmae, Yoichi Shinkai.

  Protein acetylation plays crucial roles in diverse biological functions, including mitochondrial metabolism. Although SIRT3 catalyzes the removal of acetyl groups in mitochondria, the addition of the acetyl groups is thought to be primarily controlled in an enzyme-independent manner due to the absence of potent acetyltransferases. In this study, we developed an engineered mitochondria-localized acetyltransferase, named engineered mitochondrial acetyltransferase (eMAT). eMAT localized in the mitochondrial matrix and introduced robust global protein lysine acetylation, including 413 proteins with 1,119 target lysine residues. Notably, 74% of the acetylated proteins overlapped with previously known acetylated proteins, indicating that the eMAT-mediated acetylation system is physiologically relevant. Functionally, eMAT negatively regulated mitochondrial energy metabolism, inhibited cell growth, and promoted cellular senescence, suggesting that mitochondrial hyper-acetylation drives metabolic inhibition and cellular senescence. SIRT3 counteracted eMAT-induced acetylation and metabolic inhibition, restored cell growth, and protected cells from senescence, highlighting the contribution of SIRT3 in maintaining energy metabolism and preventing cellular senescence.

Keywords:  Metabolic flux analysis; Metabolomics; Protein

DOI:  https://doi.org/10.1016/j.isci.2025.113233
FEBS J. 2025 Aug 17.

Mutant p53 affects the mitochondrial proteome, promoting mitochondrial fragmentation and OXPHOS in pancreatic ductal adenocarcinoma cells.

Maria Poles, Raffaella Pacchiana, Chiara Mortali, Barbara Cisterna, Nidula Mullappilly, Adriana Celesia, Federica Danzi, Martina Gaspari, Daniela Cecconi, Massimo Donadelli, Alessandra Fiore.

  Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer marked by poor prognosis and frequent gain-of-function mutations in the TP53 tumor suppressor gene. Given the crucial role of mutant p53 in the context of metabolic reprogramming and aggressive tumor behavior, we explored its role on mitochondria, which may present a valuable therapeutic target. In this study, we characterized the unique mitochondrial proteome observed in PDAC cells harboring the gain-of-function TP53R273H mutation and discovered a strong mutant p53-dependent upregulation of myosin heavy chain 14 (MYH14), a nonmuscle myosin, implicated in mitochondrial dynamics. We deeply investigated the role of mutant p53 in the regulation of mitochondrial architecture and functionality in PDAC cells. Our morphological and morphometric analyses with transmission electron microscopy and three-dimensional confocal imaging revealed that mutant p53 induced marked mitochondrial fragmentation, whereas wild-type p53 stimulated mitochondrial elongation. Interestingly, the fragmented mitochondrial morphology is associated with higher mitochondrial respiration levels and more efficient mitochondrial cristae. These findings support the role of oncogenic mutant p53 isoforms in inducing mitochondrial fragmentation through a mechanism involving MYH14, resulting in an increased oxidative phosphorylation level that may support PDAC cell growth and aggressiveness.

Keywords:  MYH14; mitochondrial dynamics; mutant p53; pancreatic ductal adenocarcinoma cancer metabolism

DOI:  https://doi.org/10.1111/febs.70223
Biochem J. 2025 Aug 18. pii: BCJ20253237. [Epub ahead of print]482(16):

High tide or low tide: the transport and metabolism of mitochondrial nucleotides.

Thomas MacVicar.

  Mitochondria are multifaceted organelles that support numerous cellular metabolic pathways, including the biosynthesis of nucleotides required for cell growth and proliferation. Owing to an ancient endosymbiotic origin, mitochondria contain multiple copies of their own genome and therefore demand sufficient (deoxy)nucleotides in the mitochondrial matrix for DNA replication and transcription into RNA. Disturbed mitochondrial deoxynucleotide homeostasis can lead to a decline in mitochondrial DNA abundance and integrity, causing mitochondrial diseases with diverse and severe symptoms. Mitochondrial nucleotides are not only required for nucleic acid synthesis but also for bioenergetics and mitochondrial enzymatic activity. This review first explores how mitochondria supply energy and anabolic precursors for nucleotide synthesis and how the mitochondrial network influences the spatial control of cellular nucleotide metabolism. Then follows an in-depth discussion of the mechanisms that supply mitochondria with sufficient and balanced nucleotides and why these mechanisms are relevant to human mitochondrial disease. Lastly, the review highlights the emergence of regulated mitochondrial nucleotide supply in physiological processes including innate immunity and discusses the implications of dysregulated mitochondrial and cytosolic nucleotide homeostasis in pathophysiology.

Keywords:  metabolism; mitochondria; mitochondrial disease; nucleotide salvage; nucleotide transport; nucleotides

DOI:  https://doi.org/10.1042/10.1042/BCJ20253237
bioRxiv. 2025 Aug 11. pii: 2025.08.08.669325. [Epub ahead of print]

Renal Coenzyme A (CoA) Production Fuels Stem Cell Proliferation and Tumor Growth.

Ting Miao, Ying Liu, Mujeeb Qadiri, John M Asara, Yanhui Hu, Xiaomei Sun, Christian Dibble, Norbert Perrimon.

Coenzyme A (CoA), derived from Vitamin B5 (VB5), is essential for lipid metabolism, energy production, and cell proliferation. While the intracellular functions of CoA are well characterized, its tissue-specific regulation and systemic physiological roles remain poorly understood. Here, using Drosophila melanogaster , we uncover a gut-renal circuit in which dietary VB5 stimulates CoA biosynthesis specifically in the Malpighian tubules (MTs, the fly kidney), non-autonomously impacting gut homeostasis. We show that Myc boosts renal CoA production by directly upregulating Fbl ( PANK1-3 homolog) and downregulating dPANK4 in the MTs. Elevated CoA biosynthesis enhances the mevalonate-isoprenoid pathway activity in the gut, promoting intestinal stem cell proliferation. We further demonstrate that renal CoA production is required for gut tumor growth in a fly model. Consistently, MYC and genes within the CoA-isoprenoid axis display strong association with clinical outcomes in human cancers. Together, our findings establish that Myc-driven CoA metabolism generates an inter-organ signal that couples VB5 availability to stem cell control and tumor growth, and identify the CoA-isoprenoid axis as a targetable metabolic vulnerability in cancer.

DOI: https://doi.org/10.1101/2025.08.08.669325
bioRxiv. 2025 Aug 12. pii: 2023.12.02.569652. [Epub ahead of print]

The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming.

Aidan R Cole, Raquel Buj, Apoorva Uboveja, Evan Levasseur, Hui Wang, Katarzyna M Kedziora, Adam Chatoff, Andrea Andress Huacachino, Mariola M Marcinkiewicz, Amandine Amalric, Baixue Yang, Naveen Kumar Tangudu, Jeff Danielson, Amal Elwah, Sierra White, Danyang Li, Callen T Wallace, Felicia Lazure, Esther Elishaev, Lauren Borho, Dorota E Jazwinska, Matthew S Laird, Huda Atiya, Benjamin G Bitler, Denarda Dangaj, Lan G Coffman, George Tseng, Steffi Oesterreich, Ana P Gomes, Aditi U Gurkar, Francisco J Schopfer, Francesmary Modugno, Simon C Watkins, Ioannis K Zervantonakis, Wayne Stallaert, Nadine Hempel, Nathaniel W Snyder, Katherine M Aird.

Cellular senescence, characterized by a stable cell cycle arrest, is a well-documented consequence of several widely used chemotherapeutics that has context-dependent roles in cancer. Although senescent cells are non-proliferative, they remain biologically active and secrete a complex and diverse array of factors collectively known as the se-nescence-associated secretome (SAS), which exerts pro-tumorigenic effects. Here, we aimed to mechanistically investigate how the SAS contributes to metastatic dissemination of high grade serous ovarian cancer (HGSOC) using standard-of-care cisplatin as a se-nescence inducer. Our findings demonstrate that the cisplatin-induced SAS enhances the dissemination of HGSOC in vivo without affecting cell proliferation or viability. We found that the SAS facilitates cell detachment, an effect that is mediated by a metabolic com-ponent. Using a metabolically focused CRISPR knockout screen, we identified complex I as the key driver of SAS-mediated cell detachment in bystander cells and validated that inhibition of complex I activity decreases HGSOC dissemination in vivo . Mechanistically, this effect was driven by SAS-mediated inhibition of an NAD + -SIRT-SREBP axis, leading to decreased plasma membrane cholesterol that increased cell detachment. Excitingly, we found that fructose is the key SAS component upstream of the NAD + -SIRT-SREBP-cholesterol axis mediating increased detachment of bystander cells, and a high fructose diet increases HGSOC dissemination in vivo . These findings reveal that the cisplatin-induced SAS reprograms the metabolic microenvironment in HGSOC, driving cancer cell detachment and promoting metastatic dissemination in a paracrine fashion. They also point to a previously unrecognized pro-tumorigenic effect of the SAS that may contribute to the high recurrence rate of HGSOC patients.

DOI: https://doi.org/10.1101/2023.12.02.569652
Crit Rev Oncol Hematol. 2025 Aug 14. pii: S1040-8428(25)00283-5. [Epub ahead of print]215 104895

Role of Bcl-2 family anti-apoptosis inhibition in overcoming therapeutic resistance in prostate cancer: A systematic review.

Indra Jaya, Ferry Safriadi, Indra Wijaya, Pritha Pitaloka, Ervi Afifah, Faiza Shifa Medina, Muhammad Hasan Bashari.

   BACKGROUND: Therapeutic resistance continues to pose one of major problem in effectively managing prostate cancer (PCa) is the advancement of therapeutic resistance. A key mechanism underlying this resistance is the suppression of apoptosis, often triggered by increased expression of anti-apoptotic Bcl-2 family proteins.
OBJECTIVE: To evaluate the outcomes of combining standard prostate cancer therapies with inhibitors targeting Bcl-2 family anti-apoptotic proteins.
SEARCH STRATEGY: A systematic literature research was screened using the PubMed database, Scopus, and EBSCOhost (Medline Ultimate) databases up to October 30, 2024. Studies investigating the combination of standard PCa therapies with Bcl-2 family anti-apoptosis inhibitors were included. Study assessment, analysing data, and quality assessment were independently conducted by four reviewers.
RESULTS: Twelve studies fulfilled the inclusion criteria. Six employed in vitro methods, while the remaining six used both in vitro and in vivo approaches. The standard therapies evaluated included androgen deprivation (castration), anti-androgens, and chemotherapy. Most studies utilized non-selective Bcl-2 family inhibitors, including ABT-263 and ABT-737, as well as the selective Bcl-2 inhibitor such as ABT-199. However, no studies employed selective inhibitors for Bcl-xL or Mcl-1. All selected studies indicated that anti-apoptotic inhibitors not only amplified the cytotoxic efficacy of conventional treatments but also demonstrated senolytic properties, effectively mitigating therapy-induced cellular senescence.
CONCLUSIONS: This systematic review demonstrates that inhibition of Bcl-2 family anti-apoptotic proteins can potentiate the efficacy of standard treatments for prostate cancer. These findings provide a compelling rationale for further research into targeted combination therapies to overcome therapeutic resistance in PCa.

Keywords:  Anti-apoptosis inhibitors; Bcl-2 family; Prostate cancer; Therapeutic resistance

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104895
J Med Chem. 2025 Aug 18.

In Pursuit of Best-in-Class MCL-1 Inhibitors: Discovery of Highly Potent 1,4-Indoyl Macrocycles with Favorable Physicochemical Properties.

Ingrid Adriana Velter, William Lento, Aldo Peschiulli, Tristan D Reuillon, Sofia Ferrer, Sergio Orgaz-Gordillo, Peter Buijnsters, Benoît C A G De Boeck, Samuel Demin, Yves Van Roosbroeck, Matthieu Jouffroy, Ann Vos, Bradley Miller, Paul Shaffer, Seong Joo Koo, Maria Dominguez Blanco, Lisa McQueen, Cristina Altrocchi, Ruud Bueters, Petra Vinken, Mariette Bekkers, Helena Steyvers, Christina Guttke, David Walker, Marcus Bauser, David M Wilson, Ulrike Philippar, Frederik J R Rombouts.

Myeloid Cell Leukemia 1, or MCL-1, is an anti-apoptotic protein belonging to the BCL-2 family of proteins, which regulate the mitochondrial pathway of cellular apoptosis via binding of pro- and anti-apoptotic family members. Genetic amplification and overexpression of MCL-1 is one mechanism cancer cells utilize to avoid death and thus MCL-1 has emerged as an attractive target for cancer treatment. Herein, we describe our strategy and medicinal chemistry efforts to identify best-in-class MCL-1 inhibitors with high cytotoxic potency and improved biorelevant solubility while aiming to maximize therapeutic index versus on-target toxicity via IV dosing. These efforts led to the discovery of JNJ-78394355: a highly efficient anti-tumor agent, as demonstrated by the in vivo studies in human-xenograft mouse models of acute myeloid leukemia (AML) and multiple myeloma (MM).

DOI: https://doi.org/10.1021/acs.jmedchem.4c03166
Cancer Res. 2025 Aug 19.

Cytotoxic CD8+ T Cells Downregulate GPX4 to Promote Ferroptosis in Melanoma that Drives Antitumor Immunity.

Karine Flem-Karlsen, Ronan Talty, Meaghan K McGeary, Koonam Park, Durga Thakral, Veronica T Brooks, Andrew J Daniels, William Damsky, Simon F Roy, Goran Micevic, Marcus Bosenberg.

Identifying factors that mediate successful anticancer immune responses is necessary to improve outcomes for patients with advanced cancers. Here, we performed single-cell RNA sequencing on mouse melanomas experiencing successful and unsuccessful immune responses and discovered a prominent ferroptosis signature in tumors undergoing immune-mediated regression. Pairing ferroptosis inducers and inhibitors with immunotherapies ex vivo and in vivo highlighted a central role for ferroptosis in stimulating the anti-melanoma immune response. In co-culture models, CD8+ T cells drove melanoma cell ferroptosis by altering the expression of glutathione peroxidase 4 (GPX4), a crucial antioxidant enzyme known for its role in preventing lipid peroxidation. Direct contact between tumor cells and CD8+ T cells was needed to sustain GPX4 downregulation over time, resulting in ferroptotic cell death. Finally, single-cell RNA sequencing data from human melanoma tumors responding to immunotherapy revealed a ferroptosis signature that mirrors the mouse model. Together, these results offer crucial insights into the role of ferroptosis in antitumor immunity and highlight the potential of modulating ferroptosis to enhance immunotherapy responses.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1952
iScience. 2025 Aug 15. 28(8): 113090

Polyclonality and metabolic heterogeneity in a colorectal tumor model.

Pierre Delamotte, Mickael Poidevin, Yan Jaszczyszyn, Arnaud Le Rouzic, Jacques Montagne.

  The monoclonal origin of cancer is widely accepted, although numerous studies suggest that some are of polyclonal origin. Loss of checkpoints in transformed cells gives rise to carcinomas comprising a wide diversity of cell types that fulfill distinct, even complementary, metabolic functions, contrasting with a hypothetical monoclonal origin. Here, using a Drosophila intestinal tumor model, we show that, despite an identical genetic background, these tumors (1) comprise a conserved set of different metabolic-specialized clusters; (2) are always polyclonal and derive from several clones characterized by distinct metabolic specificity; (3) depend on motility of the founder clones for their growth; and (4) share metabolic needs similar to those of human cancers. In summary, our study indicates that, in this model, tumor formation always requires assembly between founder clones potentially providing distinct cellular functions, as visualized by their metabolic heterogeneity. Thus, this polyclonal assembly would constitute a critical step of tumor progression.

Keywords:  Cancer; Experimental models in systems biology; Metabolic flux analysis

DOI:  https://doi.org/10.1016/j.isci.2025.113090
Discov Oncol. 2025 Aug 18. 16(1): 1579

Mitochondrial fission genes MTFP1/MTFP2 as predictive biomarkers in prostate cancer: a mendelian randomization study.

Xuejun Huangfu, Zhiqiang Fan, Jia Zheng, Jiabei Xie.

   BACKGROUND: Mitochondrial dynamics, particularly the balance between fission and fusion, play a crucial role in cancer progression, including prostate cancer, by influencing cellular metabolism and survival. MTFP1 and MTFP2 are key regulators of mitochondrial fission, and their roles in prostate cancer warrant further investigation.
METHODS: We conducted a comprehensive bioinformatics analysis using RNA-seq data from The Cancer Genome Atlas (TCGA) and SNP data from the UK Biobank (ukb-b-13348) GWAS dataset. Differential gene expression analysis was performed using the limma package, and pathway enrichment analysis was conducted using clusterProfiler. Hub genes were ranked using the CytoHubba algorithms. MCC was prioritized due to its robustness in identifying fully connected subgraphs. Mendelian Randomization (MR) analysis was performed using the TwoSampleMR package to assess the causal relationships between identified hub genes and prostate cancer.
RESULTS: The analysis revealed significant differential expression of MTFP1 and MTFP2 between tumor and adjacent normal tissues, with MTFP2 showing a highly significant upregulation (p-value = 7.06e-06) and an AUC of 0.698, suggesting its potential as a biomarker. In the MR analysis, several hub genes, including ANLN, CDC45, CDCA2, and KIF15, were identified as having a significant causal relationship with prostate cancer, with effect estimates ranging from - 0.03 to 0.15 and statistically significant p-values. These findings suggest that mitochondrial dynamics and related pathways play a critical role in prostate cancer pathogenesis.
CONCLUSION: The study highlights the potential diagnostic and prognostic value of mitochondrial fission-related genes, particularly MTFP2, in prostate cancer and underscores the importance of further investigating these pathways as therapeutic targets.

Keywords:  Cytoscape; GWAS; Hub genes; MTFP1; MTFP2; Mendelian randomization; Mitochondrial fission; Prostate cancer

DOI:  https://doi.org/10.1007/s12672-025-03215-6
Nature. 2025 Aug 19.

Exercise improves survival of some people with colon cancer, clinical trial shows.

Doris S M Chan, Marc J Gunter.



Keywords:  Cancer; Medical research; Metabolism

DOI:  https://doi.org/10.1038/d41586-025-02591-x