bims-metorg 2026-01-11 papers

bims-metorg

Biomed News

on Metabolism and Organotropism

Issue of 2026–01–11
ten papers selected by
Bruna Martins Garcia, CABIMER

Metabolic reprogramming in bone metastasis of human cancers.
Organ-Specific Clinicopathological Features That Are Associated With Post-Relapse Survival of Metastatic Breast Cancer in Japanese Women: A Multicenter Cohort Study.
Tumor-associated neutrophils drive liver-specific metastatic progression in breast cancer through methionine metabolism mediated by methionine adenosyltransferase II alpha.
TMPO promotes cellular dissemination and metastasis in circulating tumor cells.
PRL-3 up-regulates exosomal ITGαvβ5 expression to promote liver pre-metastatic niche formation and colon cancer liver metastasis.
Tumor-on-chip's alliance with molecular pathology against metastatic disease.
Nutrient requirements of organ-specific metastasis in breast cancer.
Lung Cancer Cells Secrete Glutamine to Accumulate Tumor-Associated Macrophages.
Unraveling Stress-Adaptation Pathways in Cancer: Functional Dissection Through CRISPR-Based Genetic Screens.
Metabolic characteristics in hepatocellular carcinoma: amino acid metabolic reprogramming.

Front Cell Dev Biol. 2025 ;13 1711592

Metabolic reprogramming in bone metastasis of human cancers.

Tianda Li, Ziyi Wang, Haitao Yang, Yihan Kang.

  Bone metastasis represents a complex complication of advanced human malignancies. Metabolic reprogramming plays a critical role in bone metastasis. Tumor cells hijack and alter local metabolic pathways to fuel their energetic and biosynthetic demands for proliferation and survival within the bone metastatic microenvironment. This includes adaptations in glycolysis, oxidative phosphorylation, lipid metabolism and amino acid metabolism. Furthermore, this bone metastatic microenvironment exhibits distinct metabolic features, such as hypoxia and acidity. To survive in this hostile microenvironment, tumor cells that metastasize to bone have to undergo metabolic reprogramming. Collectively, understanding the intricate link between metabolic reprogramming and bone metastasis is crucial for developing novel therapeutic strategies. Targeting the specific metabolic addiction and interrupting the nutrient-based crosstalk between tumor cells and the bone stroma offers a promising way to inhibit the vicious cycle and bone metastatic progression.

Keywords:  bone metastasis; glycolysis; hypoxia; metabolic reprogramming; microenvironment

DOI:  https://doi.org/10.3389/fcell.2025.1711592
World J Oncol. 2026 Feb;17(1): 52-62

Organ-Specific Clinicopathological Features That Are Associated With Post-Relapse Survival of Metastatic Breast Cancer in Japanese Women: A Multicenter Cohort Study.

Yoichi Koyama, Yoshiya Horimoto, Akimitsu Yamada, Kazutaka Narui, Shinya Yamamoto, Hiroshi Kaise, Kimito Yamada, Takashi Ishikawa.

   Background: Metastatic breast cancer (MBC) presents heterogeneous clinical behavior depending on the metastatic site and molecular subtype. However, only a few studies have directly compared prognostic outcomes by the organ of initial distant recurrence. This multi-institutional retrospective study aimed to clarify the clinical and biological characteristics of MBC based on cases with single-organ metastasis at the time of initial MBC diagnosis, using real-world data from Japanese patients.
Methods: We retrospectively analyzed 309 Japanese women treated for early-stage breast cancer at six institutions between 2007 and 2021, who developed distant recurrence confined to a single organ (brain, lungs, liver, or bones) as the first site of metastasis. Patients with multi-organ metastases at initial recurrence were excluded.
Results: The median distant metastasis-free survival and post-relapse survival (PRS) were 29.4 and 39.7 months, respectively. PRS was longest in patients with bone recurrence, followed by those with lung and liver recurrence, and shortest in those with brain recurrence (P < 0.001). Bone and lung metastases were more frequently associated with hormone receptor-positive tumors, whereas liver and brain metastases were enriched for human epidermal growth factor receptor 2 (HER2)-negative and triple-negative tumors. The multivariable Cox model identified older age, triple-negative subtype, and symptomatic recurrence as independent poor prognostic factors, while liver and brain metastases were also independently associated with shorter PRS. Site-specific analyses revealed that triple-negative subtype and symptomatic presentation were consistent markers of poor prognosis across most metastatic sites.
Conclusions: Based on a single-organ metastasis cohort, this study identified distinctive clinicopathological features and survival outcomes according to the site of initial distant recurrence. Brain metastases were associated with the poorest outcomes, highlighting the need for improved risk stratification and treatment strategies.

Keywords:  Brain neoplasms; Breast neoplasms; Molecular typing; Neoplasm metastasis; Prognosis; Retrospective studies

DOI:  https://doi.org/10.14740/wjon2662
Transl Cancer Res. 2025 Dec 31. 14(12): 8949-8964

Tumor-associated neutrophils drive liver-specific metastatic progression in breast cancer through methionine metabolism mediated by methionine adenosyltransferase II alpha.

Lifeng Huang, Shuang Zhen, Qi Wang, Yue Sun, Tian Ji, Rui Chen, Jue Wang, Qiannan Zhu, Dongwei Xu, Xiaoming Zha.

   Background: The mechanisms underlying the pronounced organotropism of breast cancer (BC) for the liver remain incompletely elucidated. This study aims to investigate the role of the tumor microenvironment (TME), particularly tumor-associated neutrophils (TANs), and their metabolic regulation in breast cancer liver metastasis (BCLM).
Methods: We employed a multi-level integrative approach. Bioinformatic analysis of Gene Expression Omnibus (GEO) datasets characterized the immune landscape of BCLM. Clinical specimens, and in vitro assays were utilized to define the functional interplay between TANs and BC cells. Metabolomic profiling of patient samples was conducted to characterize metabolic alterations in BCLM.
Results: A neutrophil-enriched TME was identified as a distinct feature of BCLM. Functional studies demonstrated that TANs enhance cancer stemness and chemoresistance by upregulating methionine adenosyltransferase II alpha (MAT2A), a key enzyme that activates methionine metabolism. What is more, pharmacological inhibition of MAT2A successfully reversed the pro-tumorigenic phenotypes induced by TANs. Metabolomic analysis of patient specimens provided direct clinical evidence for the specific activation of the methionine cycle in BCLM tissues.
Conclusions: Our work uncovers a neutrophil-driven, MAT2A-dependent activation of methionine metabolism as a critical metabolic mechanism fueling liver metastasis in BC. These findings position the TAN-MAT2A-methionine axis as a promising therapeutic target for the treatment of BCLM.

Keywords:  Breast cancer (BC); cancer stemness; liver metastasis; methionine metabolism; tumor-associated neutrophils (TANs)

DOI:  https://doi.org/10.21037/tcr-2025-aw-2278
bioRxiv. 2025 Dec 27. pii: 2025.12.27.696673. [Epub ahead of print]

TMPO promotes cellular dissemination and metastasis in circulating tumor cells.

Arianna Giacobbe, Aleksandar Z Obradovic, Jinqiu Lu, Soonbum Park, Carlos Pedraz-Valdunciel, Giuseppe Nicolo' Fanelli, Aunika Zheng, Jaime Y Kim, Maya Stella Dixon, Jung Seung Nam, Florencia Picech, Caroline Laplaca, Renu K Virk, Matteo Di Bernardo, Alexander Chui, Juan M Arriaga, Stephanie Afari, Francisca Nunes de Almeida, Min Zou, Helen Garcia, Brian D Robinson, Hongshan Guo, Shyamala Maheswaran, Daniel A Haber, David T Miyamoto, David M Nanus, Scott T Tagawa, Tian Zheng, Massimo Loda, Iok In Christine Chio, Michael Shen, Paraskevi Giannakakou, Andrea Califano, Peter A Sims, Cory Abate-Shen.

Metastasis-the process by which cancer cells spread beyond the primary tumor to distant organs-accounts for the vast majority of cancer-related deaths. To elucidate mechanisms underlying dissemination and metastasis in prostate cancer, we have investigated circulating tumor cells (CTCs) obtained from genetically engineered mouse models (GEMMs). The phenotypic and molecular properties of the CTCs, and organoids derived from these CTCs, closely model the tumor and metastatic phenotypes of their parental GEMMs. Moreover, organoids derived from individual CTCs exhibit molecular and morphological heterogeneity that is associated with distinct metabolic states as well as differences in human prostate cancer outcome. Using computational systems analyses, we have identified TMPO , encoding the nuclear membrane protein lamina-associated polypeptide 2 (Lap2), as a key driver of this heterogeneity. TMPO activity is upregulated in advanced human prostate tumors, metastases, and CTCs, and is associated with adverse clinical outcome. Our findings indicate that TMPO promotes dissemination and metastasis in vivo by enhancing survival in conditions of metabolic stress, and reveal a novel mechanistic link between CTC heterogeneity, stress adaptation, and metastatic potential.

DOI: https://doi.org/10.64898/2025.12.27.696673
Exp Hematol Oncol. 2026 Jan 08.

PRL-3 up-regulates exosomal ITGαvβ5 expression to promote liver pre-metastatic niche formation and colon cancer liver metastasis.

Qiusheng Lan, Heyang Xu, Yujie Zeng, Lu Liu, Xinwen Hu, Qiong Yang, Yang Zhang, Wentao Liu, Junchen Wu, Jiahao Weng, Jiehua He, Xiaoding Xu, Wei Lai, Zhonghua Chu.

  Liver pre-metastatic niches (PMN) formation is a pivotal process in colorectal cancer liver metastasis (CLM). Phosphatase of regenerating liver-3 (PRL-3) has been demonstrated as a key factor in promoting CRC progression (e.g., therapeutic resistance and metastasis), but its role in liver PMN formation remains unknown. Using mouse models and CRC patient samples, we herein reveal that high PRL-3 expression in CRC cells could enhance the recruitment of myeloid-derived suppressor cells (MDSCs) into the liver and impair the hepatic infiltration of CD8+ T cells, thereby promoting the liver PMN formation and CLM. Mechanistically, high PRL-3 expression could activate the Src/STAT3 signaling pathway in CRC cells and thus up-regulate integrin αvβ5 (ITGαvβ5) expression in their secreted exosomes, which could specifically target F4/80+ macrophages in the liver to activate the P38/STAT1 signaling pathway. With this activation of P38/STAT1 pathway, the secretion of C-X-C motif chemokine ligand 12 (CXCL12) from F4/80+ macrophages is significantly improved, which could enhance the recruitment of MDSCs into the liver and impair the hepatic infiltration of CD8+ T cells, ultimately leading to the liver PMN formation and CLM. Taken together, our findings not only uncover the important role of PRL-3 in CLM via promoting the liver PMN formation, but also provide the evidence for the treatment of CLM by targeting PRL-3.

Keywords:  Colorectal cancer; Exosomal ITGαvβ5; Liver metastasis; PMN; PRL-3

DOI:  https://doi.org/10.1186/s40164-025-00733-5
J Biomed Sci. 2026 Jan 06. 33(1): 9

Tumor-on-chip's alliance with molecular pathology against metastatic disease.

Emma Di Carlo.

   BACKGROUND: Cancer is the second leading cause of death worldwide. While significant progress has been made in early detection and treatment, metastasis remains the major cause of cancer-related morbidity and mortality. In the last decade the rate of long-term survivorship of metastatic cancer has continued to improve and overcoming resistance to therapy has now become a challenge. Developing strategies to prevent and treat metastatic disease is a priority for public health and requires a thorough understanding of the mechanisms driving progression of a specific patient's tumor and the rapid identification of targetable cancer drivers and drug resistance genes.
DISCUSSION: Custom bioprinted tumors, which recreate the interactions between tumors and surrounding tissues, can be integrated into organ-on-chip platforms, and leveraging molecular pathology and OMICS data, can provide highly realistic patient-specific models. These biomimetic tools enable the investigation of metastasis organotropism, the identification of therapeutic targets and the design of drug administration protocols to prevent metastasis and to overcome resistance. Benefits, limitations, and challenges to address for an efficient and routine application of this cutting-edge approach, together with the role of Artificial-Intelligence (AI) in managing the complex datasets generated by OMICS technologies will be highlighted in this review, as well as their real-life implications and evolutionary prospects.
CONCLUSION: Applying patient-derived bioprinted tumors and organs for clinical purpose and developing standardized 4D and 5D bioprinting protocols would allow assessment of cancer response to treatments in a dynamic and faithfully reconstructed microenvironment. Integration of advanced molecular diagnostics and multi-OMICS data, with customized small-scale tumor models, assisted by AI-powered tools, requires a multidisciplinary framework. This integrated approach can upgrade clinical management of metastatic diseases, by accelerating the identification of actionable biomarkers and resistance mechanisms for timely therapy adjustments, thus enabling tailored treatment regimens based on individual tumor behavior.

Keywords:  Bioprinting; Metastasis; Molecular pathology; Organ-on-chip; Personalized medicine; Tumor modeling

DOI:  https://doi.org/10.1186/s12929-025-01209-8
Nature. 2026 Jan 07.

Nutrient requirements of organ-specific metastasis in breast cancer.

Keene L Abbott, Sonu Subudhi, Raphael Ferreira, Yetiş Gültekin, Sophie C Steinbuch, Muhammad Bin Munim, Diya L Ramesh, Sophie E Honeder, Ashwin S Kumar, Michelle Wu, Jacob A Hansen, Anna Shevzov-Zebrun, Edrees H Rashan, Kian M Eghbalian, Sharanya Sivanand, Anna M Barbeau, Lisa M Riedmayr, Mark Duquette, Ahmed Ali, Nicole Henning, Sonia E Trojan, Millenia Waite, Tenzin Kunchok, Mayu A Nakano, Florian Gourgue, Gino B Ferraro, Brian T Do, Virginia Spanoudaki, Francisco J Sánchez-Rivera, Xin Jin, George M Church, Rakesh K Jain, Matthew G Vander Heiden.

Cancer metastasis is a major contributor to patient morbidity and mortality1, yet the factors that determine the organs where cancers can metastasize are incompletely understood. Here we quantify the absolute levels of 124 metabolites in multiple tissues in mice and investigate how this relates to the ability of breast cancer cells to grow in different organs. We engineered breast cancer cells with broad metastatic potential to be auxotrophic for specific nutrients and assessed their ability to colonize different tissue sites. We then asked how tumour growth in different tissues relates to nutrient availability and tumour biosynthetic activity. We find that single nutrients alone do not define the sites where breast cancer cells can grow as metastases. In addition, we identify purine synthesis as a requirement for tumour growth and metastasis across many tissues and find that this phenotype is independent of tissue nucleotide availability or tumour de novo nucleotide synthesis activity. These data suggest that a complex interplay between multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth, and highlights the interdependence between extrinsic environmental factors and intrinsic cellular properties in influencing where breast cancer cells can grow as metastases.

DOI: https://doi.org/10.1038/s41586-025-09898-9
Mol Carcinog. 2026 Jan 07.

Lung Cancer Cells Secrete Glutamine to Accumulate Tumor-Associated Macrophages.

Joshua P Reddy, Rebecca A Clague, Beatriz P Peixoto, Sara Bernstein, Emma E Lauth, Clara Y Takanohashi, Sophie C Kim, Hiromi I Wettersten.

  Tumor-associated macrophages (TAMs) are critical contributors to cancer progression and are often recruited by cancer cells to support a pro-tumorigenic microenvironment. Integrin αvβ3 is a known driver and marker of cancer stem-like properties, including tumor initiation, in various epithelial cancers. We have previously shown a positive correlation between αvβ3 expression and TAM infiltration across multiple tumor types; however, the mechanistic link remains undefined. Here, we demonstrated that integrin αvβ3 expression in non-small cell lung cancer (NSCLC) cells is both necessary and sufficient to drive TAM accumulation. In orthotopic murine and human NSCLC models, ectopic integrin αvβ3 expression increased TAM infiltration independently of T cells, whereas genetic deletion of integrin β3 significantly reduced TAM numbers and tumor burden. Mechanistically, integrin αvβ3 promotes glutamine secretion from NSCLC cells, which enhances the survival and/or differentiation of bone marrow-derived macrophages. Functionally, TAMs are essential for the elevated tumor-initiating capacity of αvβ3+ cancer cells, as macrophage depletion abolished this effect. Together, our findings uncover a novel mechanism by which NSCLC cells remodel the tumor microenvironment via αvβ3-mediated glutamine secretion, promoting TAM enrichment and tumor initiation. Targeting this axis may offer therapeutic benefits in αvβ3-expressing cancers.

Keywords:  cancer metabolism; integrin αvβ3; non‐small cell lung cancer

DOI:  https://doi.org/10.1002/mc.70077
Cancer Lett. 2026 Jan 06. pii: S0304-3835(26)00009-1. [Epub ahead of print] 218246

Unraveling Stress-Adaptation Pathways in Cancer: Functional Dissection Through CRISPR-Based Genetic Screens.

Fatemeh Mokhles, Mohammad Amin Moosavi, Alvaro Gutierrez-Uzquiza, Guillermo Velasco, Min Li, Marco Cordani.

  Cancer cells face a hostile microenvironment characterized by hypoxia, nutrient deprivation, endoplasmic reticulum (ER) stress, and oxidative imbalance. To cope with these challenges, they activate an interconnected network of adaptive pathways including autophagy, the unfolded protein response, metabolic reprogramming, and the integrated stress response., which promote cell survival, therapy resistance, immune evasion, and metastasis. CRISPR-based functional genomics has emerged as a powerful strategy to systematically dissect these stress-adaptive networks, enabling the identification of key regulators and vulnerabilities across diverse contexts. In this review, we first summarize tumor progression in major stress conditions and then highlight how CRISPR screening strategies ranging from genome-wide loss-of-function studies to single-cell and combinatorial platforms, are unraveling critical stress regulators. We further discuss emerging tools, model systems, and translational perspectives, underscoring how the integration of CRISPR technologies with multi-omics, artificial intelligence, and advanced preclinical models is reshaping our understanding of cancer stress biology and guiding the development of novel therapeutic strategies. Finally, we addressed how these novel dissection technologies influence translational opportunities, specifically in the context of combining stress-pathway modulators with immunotherapy and targeted therapy drugs.

Keywords:  CRISPR functional genomics; metabolic rewiring; oxidative stress; therapy resistance mechanisms; tumor stress adaptation

DOI:  https://doi.org/10.1016/j.canlet.2026.218246
Mol Cancer. 2026 Jan 08.

Metabolic characteristics in hepatocellular carcinoma: amino acid metabolic reprogramming.

Ran Zhou, Yuejun Li, Guanghui Li, Yan Li, Lie Luo, Bin Wang, Liping Wang.

  Hepatocellular carcinoma (HCC) is a common type of primary liver cancer and is considered the third leading cause of cancer-related deaths worldwide. The high aggressiveness and resistance to therapies exhibited by HCC present significant challenges to global public health. As the primary metabolic organ in the human body, the liver undergoes substantial metabolic reprogramming during carcinogenesis, affecting various metabolic pathways including those involved in carbohydrates, lipids, and amino acids. Notably, disruptions in amino acid metabolism play a critical role in the initiation and progression of HCC, helping to sustain its malignant characteristics. This review aims to provide an in-depth analysis of the alterations observed in aromatic amino acids metabolism, branched chain amino acids (BCAAs) metabolism, glutamine metabolism, and other amino acid metabolism processes, including serine, arginine, and methionine, along with the expression patterns of associated metabolic enzymes. Furthermore, it discusses potential therapeutic approaches and their clinical relevance, offering insights and strategies for improving HCC diagnosis and treatment in the future.

Keywords:  Amino acid metabolism; Hepatocellular carcinoma; Metabolic reprogramming

DOI:  https://doi.org/10.1186/s12943-025-02492-7