bims-meproc Biomed News
on Metabolism in Prostate Cancer
Issue of 2026–05–24
thirteen papers selected by
Grigor Varuzhanyan, UCLA
  1. HOXB13-Mediated Lipid Metabolism Regulates Prostate Cancer Metastasis.
  2. Engineered membrane-coated nanoparticles enhance ferroptosis and microtubule inhibition in prostate cancer.
  3. In Vitro Effects of Cabazitaxel and Menadione on Cell Growth, Metabolism, and Transcriptomic Profile of Human Prostate Cancer Cell Lines.
  4. Exploring the Role of Wt1/Spon2 Axis in Prostate Cancer Progression and Fibroblast Dynamics.
  5. Profiling crystal engineered ligands for targeting treatment resistant androgen receptors.
  6. MYC pathway reprogramming through a TIP60 coactivator switch in neuroendocrine lineage transition in prostate cancer.
  7. Sensitive detection and prostate cancer cellular evaluation of sarcosine via a fluorescence turn-on assay using an N-CQDs/Ag+ nanosensor.
  8. Dependencies in heterogeneous, lineage plastic patient-derived prostate cancer organoids revealed through integrated single-cell multiomics and CRISPR screening.
  9. Improve the Efficacy of B7-H3-Targeting Antibody-Drug Conjugate DS-7300a in TP53-deficient Tumors by Inducing Ferroptosis.
  10. FARP1 Mediates cMET-Driven Motility in Androgen-Independent Prostate Cancer Cells.
  11. Interplay of the 3D genome and epigenome in androgen-driven prostate cancer.
  12. Co-Targeting Nuclear Export and Translation Initiation Uncovers a Therapeutic Vulnerability in Lethal Prostate Cancer.
  13. Loss of PGC1α drives extracellular matrix remodelling in prostate cancer through CTHRC1.
  1. Serican J Med. 2024 Dec;pii: 23157. [Epub ahead of print]1(1):
    HOXB13-Mediated Lipid Metabolism Regulates Prostate Cancer Metastasis.
    Jianhua Xiong.
      The molecular mechanisms driving increased lipogenesis and lipid accumulation, key features of prostate cancer (PCa), remain largely unexplored. Recently, Lu and colleagues identified a novel role for the homeodomain transcription factor HOXB13 in regulating lipid metabolism and PCa progression, independent of its traditional involvement in androgen receptor (AR) signaling. Their study demonstrates how HOXB13 modulates PCa metastasis through epigenetic reprogramming, specifically by interacting with histone deacetylase 3 (HDAC3). These findings not only deepen our understanding of the molecular processes underlying PCa metastasis but also suggest lipid metabolism as a promising therapeutic target for castration-resistant and HOXB13-low PCa.
    Keywords:  HDAC3; HOXB13; androgen receptor; lipogenesis; prostate cancer
    DOI:  https://doi.org/10.17161/sjm.v1i1.23157
  2. J Mater Sci Mater Med. 2026 May 21.
    Engineered membrane-coated nanoparticles enhance ferroptosis and microtubule inhibition in prostate cancer.
    Kunmu Yang, Yingwei Wang, Chuan Guo, Xiaoxiong Zhang, Jian Wu.
      Prostate cancer (PCa), characterized by its high incidence and progression to treatment-resistant stages, remains a major clinical challenge. Herein, we developed a membrane-coated Cabazitaxel (Cab)@TA-Fe³⁺ nanoplatform for enhanced PCa therapy. The nanoparticles demonstrated notable anticancer effects, with cytotoxicity increasing over time and with dose, along with significant inhibition of cell migration and induction of G2/M phase arrest in LNCaP cells. In addition, treatment markedly increased intracellular reactive oxygen species (ROS) levels, depleted glutathione (GSH), downregulated Glutathione Peroxidase 4 (GPX4) expression, and upregulated NADPH Oxidase 1 (NOX1) and Prostaglandin-Endoperoxide Synthase 2 (PTGS2), indicating enhanced ferroptosis. Ferrostatin-1 partially restored cell viability and reduced ROS accumulation, further supporting the involvement of ferroptosis. Mechanistically, the nanoplatform enables pH/GSH-responsive release of Cab and iron ions in the tumor microenvironment, promoting microtubule disruption and redox imbalance. These combined effects enhance tumor cell death. Overall, this study demonstrates that Cab@TA-Fe³⁺ nanoparticles significantly improve anticancer efficacy by integrating microtubule inhibition and ferroptosis induction, providing a promising strategy for prostate cancer treatment.
    DOI:  https://doi.org/10.1007/s10856-026-07074-7
  3. Prostate Cancer. 2026 ;2026 4174599
    In Vitro Effects of Cabazitaxel and Menadione on Cell Growth, Metabolism, and Transcriptomic Profile of Human Prostate Cancer Cell Lines.
    Ana Laura Gómez-Rosas, Mayel Chirinos, Nancy Noyola-Martínez, Mariana Segovia-Mendoza, Nayeli Torres-Ramírez, Sandra Romero-Córdoba, Lilia G Noriega, Mitzi García-Olivares, Fernando Larrea, David Barrera.
      Cabazitaxel is a second-generation semisynthetic taxane approved for the treatment of prostate cancer. Vitamin K, an essential nutrient involved in blood coagulation and bone metabolism, has also been shown to have antineoplastic effects. However, no information is currently available regarding the combinatorial effects of cabazitaxel and menadione (VK3, a derivative of vitamin K) on prostate cancer cells. Therefore, we investigated the in vitro effects of cabazitaxel, VK3, and their combination on growth, mitochondrial bioenergetics, and glycolytic parameters using the human prostate cancer cell lines PC-3 and DU 145. All treatments inhibited the cell growth, but the combination of cabazitaxel and VK3 produced a synergistic effect that was stronger than either compound alone, and these effects were accompanied by cell line-specific bioenergetic changes and glycolytic responses. Furthermore, high-throughput transcriptomic profiling of PC-3 cells revealed distinct sets of differentially expressed genes for each treatment, with the greatest effect established by the combinatorial treatment, followed by VK3, and then cabazitaxel. Gene ontology analyses showed that the combinatorial treatment was associated with biological processes such as positive regulation of reactive oxygen species metabolic process, steroid metabolic process, proteolysis, and signal transduction. Notably, the treatments altered the gene expression of several tumorigenic and immunologic mediators, including MSXI, ZRSR2, GALNTL6, IL24, and IL18R1, which may impact cancer cell behavior. In conclusion, these in vitro findings indicate that the combination of cabazitaxel with VK3 is more effective in inhibiting prostate cancer cell growth than either agent alone and provide exploratory mechanistic insight into their effects on cancer cell metabolism and gene expression.
    Keywords:  IL18R1; IL24; cabazitaxel; menadione; microarray; prostate cancer; reactive oxygen species
    DOI:  https://doi.org/10.1155/proc/4174599
  4. J Biochem Mol Toxicol. 2026 Jun;40(6): e70800
    Exploring the Role of Wt1/Spon2 Axis in Prostate Cancer Progression and Fibroblast Dynamics.
    Dun Xue, Long Tan, Fengshuai Yang, Xiaolan Tian, Xinghui Wu, Qian Zuo.
      The role of the transcription factor Wt1 in prostate cancer (PCa) remains unclear. This study utilized public scRNA-seq datasets and TCGA data to investigate how Wt1 regulates the transition from normal fibroblasts (NFs) to cancer-associated fibroblasts (CAFs) by activating the Spon2 axis. The results identified seven distinct cell types in PCa tissues through scRNA-seq annotation, revealing the heterogeneity of CAFs in PCa. Through screening, Spon2 was identified as a key gene involved in the transition from NFs to CAFs. Further upstream transcription factor prediction identified Wt1 as a regulator of Spon2, and in vitro mechanistic experiments confirmed that Wt1 transcriptionally activates Spon2, thereby promoting the conversion of NFs into CAFs. In vitro functional assays demonstrated that knocking down Wt1 in CAFs inhibited Spon2 expression, leading to reduced PCa cell metabolism, suppression of proliferation, migration, and invasion, while promoting apoptosis. Moreover, in vivo animal experiments confirmed that activation of the Wt1/Spon2 signaling axis promotes the conversion of NFs to CAFs, thereby enhancing tumorigenesis in PCa cells. In summary, Wt1 promotes the transition of NFs into CAFs by activating Spon2 expression, which enhances PCa cell metabolism, promotes proliferation, migration, and invasion, and inhibits apoptosis, ultimately facilitating PCa tumor growth in vivo.
    Keywords:  Wt1/Spon2 axis; cancer‐associated fibroblasts; metabolic regulation; prostate cancer; therapeutic targets; tumor microenvironment
    DOI:  https://doi.org/10.1002/jbt.70800
  5. bioRxiv. 2026 May 05. pii: 2026.05.01.721995. [Epub ahead of print]
    Profiling crystal engineered ligands for targeting treatment resistant androgen receptors.
    Avan Colah, Charles Ezekiel, Sára Ferková, Pierre-Luc Boudreault, Leonard MacGillivray, William Ricke.
      Prostate cancer (PCa) is one of the principal contributors to health burden in the aging male population. PCa develops through dysregulation of androgen receptor (AR) signaling pathways. Despite improvements in diagnostic techniques and interventions, no pharmacological measures with long term efficacy have been established once PCa advances to castration resistant prostate cancer (CRPC). To circumvent this issue, tetra-aryl cyclobutanes (CBs) have been proposed as structurally distinct compounds with a mechanism of action differing from traditional androgen receptor signaling inhibitor (ARSIs). Here, we apply principles of crystal engineering and solid state synthesis to expand the class of CBs through strategic derivatization. The synthesis of the CB occurs quantitatively, producing no side products and eliminating the need for product purification. We demonstrate how head-to-tail stacking interactions of halo-pyrimidine rings can be exploited to stack and align unsymmetrical alkenes to undergo [2+2] photodimerization to generate the CB in the solid state. We examine the structure-function relationships of CBs in vitro by profiling AR mediated transcriptional activity, receptor translocation, and cell viability. Moreover, we explore and identify putative binding interactions within CB/AR complexes and establish an adaptive ligand-binding potential using molecular docking platforms. In total, our data suggests that CBs have unexploited therapeutic potential in CRPC and that green chemistry and crystal engineering principles offer a unique route to generating these drug candidates.
    DOI:  https://doi.org/10.64898/2026.05.01.721995
  6. bioRxiv. 2026 May 08. pii: 2026.05.05.723058. [Epub ahead of print]
    MYC pathway reprogramming through a TIP60 coactivator switch in neuroendocrine lineage transition in prostate cancer.
    Zhen Sun, Jimmy L Zhao, Zahra F Khan, Wazim M Ismail, Teng Han, Subhiksha Nandakumar, Serina Young, Matthew Lange, Pan Cheng, Richard Koche, Nikolaus Schultz, Alexandre Gaspar-Maia, Charles L Sawyers.
      Prostate adenocarcinomas (PRAD) can acquire resistance to androgen receptor signaling inhibitors through lineage transition to a cell state known as neuroendocrine prostate cancer (NEPC). Using a panel of isogenic PRAD and NEPC mouse tumoroids, we show that NEPC cells acquire new transcription factor (TF) dependencies that function in a previously undefined network. Through selective perturbation of each TF, we identify ASCL1 as a key regulator of NE lineage fate whereas MYCL functions downstream to drive NEPC growth/survival by recruitment of the TIP60/KAT5 acetyltransferase. Interestingly, while dependencies on specific TF family paralogs can vary across NEPC models, all show markedly enhanced dependency on TIP60. Moreover, the H2A.Z-acetyltransferase activity of the TIP60 complex (TIP60-C) is required for NEPC as well as the acetyl-reader BRD8, which is newly incorporated as a TIP60-C subunit with the NEPC transition. Targeted degradation studies in isogenic tumoroids reveal increased dependence on MYCL in NEPC relative to its paralog MYC in PRAD. In addition to a paralog switch (MYC to MYCL), the MYC pathway-addicted NE state is accompanied by a chaperone switch (from TIP60-C to SRCAP) for H2A.Z histone exchange and a coactivator switch (to TIP60) for MYC target gene expression. The NE-specific coupling of MYCL with TIP60 reveals a previously unappreciated opportunity to target MYC-driven NE diseases through pharmacological inhibition of TIP60.
    DOI:  https://doi.org/10.64898/2026.05.05.723058
  7. Anal Methods. 2026 May 22.
    Sensitive detection and prostate cancer cellular evaluation of sarcosine via a fluorescence turn-on assay using an N-CQDs/Ag+ nanosensor.
    Xinyu Shen, Suli He, Lezhong Qi, Xiayong Jing, Xinqiang Gan, Xingjun He.
      Sarcosine, a key oncometabolite in prostate cancer (PCa), has emerged as a promising biomarker for disease diagnosis and progression monitoring. However, conventional detection methods often rely on urine samples and are susceptible to interference from individual metabolic variations. In this study, we developed a novel "turn-on" fluorescence sensor based on nitrogen-doped carbon quantum dots (N-CQDs) and silver ions (Ag+) for the sensitive and selective detection of sarcosine. The sensing mechanism relies on the initial quenching of N-CQD fluorescence by Ag+, followed by enzymatic generation of H2O2 from sarcosine oxidation catalyzed by sarcosine oxidase (SOx). The produced H2O2 reduces Ag+ to Ag nanoparticles, thereby restoring the fluorescence of N-CQDs. The sensor demonstrated a linear response to sarcosine in the range of 10-60 µM with a detection limit of 2.1 µM, and exhibited high selectivity against common interfering substances. Furthermore, the platform was successfully applied to detect sarcosine in lysates of prostate cell lines, revealing significantly elevated sarcosine levels in androgen-independent PC-3 cells compared to benign (BPH-1) and androgen-sensitive (LNCaP) cells. This work presents a cost-effective, and cell-compatible fluorescence strategy for sarcosine detection, holding potential for PCa early screening and metabolic profiling.
    DOI:  https://doi.org/10.1039/d6ay00357e
  8. bioRxiv. 2026 May 08. pii: 2026.05.07.723570. [Epub ahead of print]
    Dependencies in heterogeneous, lineage plastic patient-derived prostate cancer organoids revealed through integrated single-cell multiomics and CRISPR screening.
    Samir Zaidi, Maren Büttner, Weiran Feng, Caitlin Baxter, D Henry Kates, Tiago Paiva Prudente, Diana Zakharova, Sanjoy Mehta, Subhiksha Nandakumar, Chen Khuan Wong, Hojin Lee, Pierre-Jacques Hamard, Wenfei Kang, Jungmin Choi, Ronan Chaligné, Robert Cohen, Yu Chen, Ari Firestone, Zhenghao Chen, Charles L Sawyers.
      Lineage plasticity and tumor heterogeneity limit the effectiveness of targeted therapies, yet the functional dependencies used to nominate therapeutic targets are often derived from homogeneous systems that fail to capture this complexity. Here, we establish a framework to resolve state-specific genetic vulnerabilities by integrating single-cell multiomics (RNA and ATAC) with pooled CRISPR-Cas9 screening across a large panel of patient-derived organoids (PDOs) from castrate-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). We generate a single-cell multiome atlas spanning >190,000 cells across 22 PDOs, defining seven lineage states-including intermediate and plastic populations not resolved by bulk profiling-and demonstrate that these lineage programs robustly classify independent transcriptomic datasets from prostate cancer patient tumors. By systematically coupling this atlas to subtype-resolved CRISPR screens, we construct a functional dependency map linking cell state in heterogeneous 3D human tumor models. We show that intratumoral heterogeneity fundamentally reshapes the interpretation of gene essentiality, whereby gene-level depletion reflects the composite behavior of co-existing subpopulations, and identify a general principle in which resistant "limiting" populations disproportionately determine aggregate fitness effects. This framework reveals both canonical and previously unrecognized lineage-restricted dependencies within highly plastic tumor and NEPC states, including a therapeutically targetable dependency on the aryl hydrocarbon receptor (AHR) in a novel hybrid stem-like/ASCL1 population. Together, these data establish an extensive multi-dimensional prostate cancer resource, identify novel lineage-resolved biology, and provide a generalizable strategy for interpreting functional genomics in heterogeneous human tumors.
    DOI:  https://doi.org/10.64898/2026.05.07.723570
  9. bioRxiv. 2026 May 08. pii: 2026.05.05.722958. [Epub ahead of print]
    Improve the Efficacy of B7-H3-Targeting Antibody-Drug Conjugate DS-7300a in TP53-deficient Tumors by Inducing Ferroptosis.
    Javier Leo, Feiyu Chen, Wei Shi, Xin Liang, Chenling Meng, Qianlin Gu, Yaman Albittar, Zhen Fan, Jie Zhang, Boyi Gan, Sangeeta Goswami, Kendra Carmon, Daniel E Frigo, Ana Aparicio, Di Zhao.
      Immune checkpoint B7-H3 is an emerging target for immunotherapy. DS-7300a is an advanced B7-H3-targeting antibody-drug conjugate (ADC) warheaded with the topoisomerase I inhibitor DXd. DS-7300a has demonstrated clinical activity, but molecular biomarkers to predict its therapeutic response remain elusive. TP53 is one of the most mutated tumor suppressor genes across cancers, and effective therapies are urgently needed for TP53 -deficient cancers. Using prostate cancer (PCa) as a model system, we reported that DS-7300a's anti-tumor efficacy is highly dependent on functional p53 in cancer cells, and TP53 defects confer resistance to DS-7300a. Mechanistically, we found that DS-7300a and its payload, DXd, induce DNA damage and activate the ATM/ATR/CHK signaling cascade, thereby stabilizing p53 and inducing a pro-apoptotic and senescence-associated transcriptome. In contrast, TP53 -deficient cells fail to detect DXd-induced DNA damage, maintain a high proliferation rate, and exhibit low levels of apoptosis and senescence, thereby conferring resistance to DS-7300a. Ferroptosis is an iron-dependent form of regulated cell death triggered by lipid peroxidation, which is mechanistically and morphologically distinct from apoptosis. Interestingly, DS-7300a treatment elevates lipid peroxidation in TP53-deficient cancer cells and upregulates glutathione peroxidase 4 (GPX4), an antioxidant enzyme that mitigates lipid peroxidation. Using isogeneic xenograft models and a newly developed humanized B7-H3 PCa model, we demonstrated that inducing ferroptosis by pharmacological inhibition of GPX4 enhances DS-7300a's efficacy in TP53 -deficient tumors. Our studies demonstrate that TP53 status dictates anti-tumor responses to DS-7300a, and ferroptosis induction represents a promising therapeutic approach to overcome resistance to DS-7300a in malignancies harboring TP53 defects.
    DOI:  https://doi.org/10.64898/2026.05.05.722958
  10. Endocrinology. 2026 May 23. pii: bqag062. [Epub ahead of print]
    FARP1 Mediates cMET-Driven Motility in Androgen-Independent Prostate Cancer Cells.
    Paola Robayo, Marcelo G Kazanietz, Martin J Baker, Mariana Cooke.
      Activation of Rac1, a member of the Rho family of small GTPases and a well-established downstream effector of receptor tyrosine kinases (RTKs), has been linked to prostate cancer progression and predicts poor progression in prostate cancer patients. Rac1 and its upstream activators, the Rac guanine nucleotide exchange factors (Rac-GEFs), act as key drivers for RTK-mediated formation of actin-rich protrusions, structures involved in cancer cell motility and invasion. Our previous study identified VAV2 as the main Rac-GEF effector of epidermal growth factor receptor (EGFR) in androgen-independent cellular models. An unbiased RNAi screen targeting Rac-GEFs as effectors of cMET, an RTK frequently overexpressed in castration-resistant prostate cancer (CRPC) and associated with invasion and metastasis, identified FARP1 as a pivotal contributor to Rac1-mediated migration and invasion. Notably, stimulation of cMET with its ligand HGF promotes the formation of actin-rich protrusions through a PI3K-FARP1-Rac1-dependent pathway and independently of VAV2. Furthermore, FARP1 relocalizes to actin-rich protrusions in PC3 cells in response to HGF stimulation. Our results shed light on the distinctive contribution of Rac-GEFs to prostate cancer cell motility via RTKs and identify FARP1 as a crucial cMET-invasive effector. The differential coupling of RTKs to Rac-GEFs underscores the complexities of signaling events leading to Rac1 activation. It provides insight into the RTK effectors that contribute to prostate cancer cell invasiveness.
    Keywords:  FARP1; Rac1; cMET; invasion; migration; prostate cancer
    DOI:  https://doi.org/10.1210/endocr/bqag062
  11. Epigenomics. 2026 May 22. 1-13
    Interplay of the 3D genome and epigenome in androgen-driven prostate cancer.
    Elyssa M Campbell, Dayna Challis, Susan J Clark, Joanna Achinger-Kawecka.
      Understanding of the therapeutic landscape for androgen-driven prostate cancer has undergone significant evolution, yet treatment resistance remains an ongoing challenge. The androgen receptor (AR) plays a central role in androgen-dependent prostate tumor growth, and therapeutic agents targeting AR represent the main treatment modality for prostate cancer. AR transcriptional activity is tightly regulated by coregulatory transcription factors and their DNA binding and activity. However, the precise interactions between AR and three-dimensional (3D) chromatin structure and its dynamic remodeling represent a critical yet underexploited therapeutic frontier. Here, we present a perspective on how the spatial architecture of the epigenome, including 3D chromatin structure and dynamics, orchestrates dysregulation of transcription factor networks that help to drive disease progression in androgen-driven prostate cancer. We argue that successful therapeutic intervention requires moving beyond linear epigenetic marks toward a three-dimensional understanding of the epigenetic landscape. Such a shift is essential to capture the complex enhancer-promoter communications and chromatin state transitions that define the disease. Drawing on recent advances in prostate cancer biology and technological developments, we propose a unique integrated framework centered on patient-specific 3D epigenomic vulnerabilities for next-generation epigenetic therapies designed to disrupt oncogenic transcriptional programs by specifically targeting chromatin topology.
    Keywords:  3D genome; Chromatin; androgen receptor; epigenetics; prostate cancer
    DOI:  https://doi.org/10.1080/17501911.2026.2676129
  12. bioRxiv. 2026 May 07. pii: 2026.05.04.722693. [Epub ahead of print]
    Co-Targeting Nuclear Export and Translation Initiation Uncovers a Therapeutic Vulnerability in Lethal Prostate Cancer.
    Jessica D Kindrick, Kinjal Bhadresha, Xiaohu Zhang, Erica L Beatson, Spencer S Gaut, Benjamin C Brim, Patrick J Signorelli, Roger Depaz, Jessica L Horner, Posey S Whidden, John M Ching, Kelli M Wilson, Savannah Wood, Crystal McKnight, Erin Beck, Carleen Klumpp-Thomas, Ross Lake, Elijah Edmondson, Michele Ceribelli, Cindy H Chau, Craig J Thomas, William D Figg.
      Metastatic castration-resistant prostate cancer (mCRPC) remains lethal as adaptive resistance to standard-of-care therapy develops, often driven by AR splice variants alongside transcriptional and translational reprogramming. To identify strategies capable of overcoming these mechanisms, we performed an unbiased high-throughput screen of 2,480 mechanistically annotated compounds across advanced prostate cancer models. Exportin-1 (XPO1)-mediated nuclear export emerged as a critical dependency, and matrix-based combination screening uncovered robust synergy between inhibitors of XPO1 and the translation initiation factor EIF4A1. Dual inhibition induced coordinated disruption of oncogenic protein networks, including AR/AR-V7, triggering apoptosis and suppressing cell-cycle and metabolic programs. These effects extended to genetically diverse patient-derived organoids and in vivo xenografts at low doses, approximately 8-fold (Eltanexor) and 12-fold (Zotatifin) below established human single-agent regimens. Together, these findings reveal concurrent control of nuclear export and protein translation as a therapeutic vulnerability in mCRPC, providing a strong rationale for clinical evaluation of XPO1-EIF4A1 co-inhibition to overcome AR-driven resistance.
    STATEMENT OF SIGNIFICANCE: Unbiased combinatorial screening reveals co-inhibition of nuclear export and translation initiation as a vulnerability in metastatic castration-resistant prostate cancer. Dual targeting of XPO1 and EIF4A1 drives synergistic collapse of oncogenic protein networks, including AR/AR-V7 signaling, to overcome key resistance mechanisms and induce potent antitumor responses across heterogeneous models. Notably, these effects are achieved at substantially reduced doses using clinically tractable agents, defining a mechanistically grounded therapeutic strategy poised for rapid clinical translation.
    DOI:  https://doi.org/10.64898/2026.05.04.722693
  13. bioRxiv. 2026 May 08. pii: 2026.05.05.722659. [Epub ahead of print]
    Loss of PGC1α drives extracellular matrix remodelling in prostate cancer through CTHRC1.
    A Gonzalo-Paulano, A Macchia, A Schaub-Clerigué, B Lectez, J Gardoki, I Lejona, U Armendariz-Martínez, N Martín-Martín, I Astobiza, P Alonso, M Azkargorta, F Elortza, A M Aransay, I Rondon-Lorefice, I Mendizabal, L Egia-Mendikute, A Palazon, I Hermanova, A Azueta, A Loizaga, A Ugalde-Olano, A Carracedo, J J Bravo-Cordero, L Valcarcel-Jimenez, V Torrano.
      Despite the high curation rate of localized prostate cancer, the fraction of patients that progress to metastasis still accounts for thousands of deaths worldwide, underscoring the need to identify early molecular events that prime tumours for aggressive disease. Here, we demonstrate that loss of the metabolic transcriptional coactivator PGC1α drives early extracellular matrix (ECM) remodelling in PCa, functionally linking epithelial transcriptional programs to tumour-microenvironment interactions. Using genetically engineered mouse models, we show that combined deletion of Pten and Pgc1α induces early activation of ECM-related transcriptional programs, increased collagen deposition, and a transition towards an aligned collagen fibre architecture-hallmarks of aggressive disease-prior to metastatic dissemination. Consistently, human prostate tumours with low PGC1α expression display increased collagen deposition, supporting the clinical relevance of these findings. Restoration of PGC1α expression in prostate cancer cells suppresses cell adhesion to multiple ECM substrates, disrupts collagen organization, and impairs tumour growth in a transcription-dependent manner. Through integrative matrisome proteomics and transcriptomics, we identify the secreted glycoprotein CTHRC1 as a key downstream effector that enhances the prognostic value of PGC1α in PCa patients. Functional loss- and gain-of-function studies establish CTHRC1 expression as both necessary and sufficient to restore ECM adhesion, cytoskeletal organization, collagen architecture, and tumorigenic capacity in PGC1α-expressing cells. Importantly, recombinant CTHRC1 rescues adhesion defects, indicating that its extracellular pool mediates this phenotype, whereas deglycosylation abolishes its pro-adhesive function, revealing a mechanistic requirement for glycosylation. Collectively, our findings uncover an early, cell-intrinsic ECM remodelling program driven by PGC1α loss and identify the PGC1α-CTHRC1 axis as a mechanistic and clinically relevant regulator of PCa aggressiveness.
    DOI:  https://doi.org/10.64898/2026.05.05.722659
This page is being maintained by Thomas Krichel. It was last updated on 2026‒06‒01 at 2:06.