bims-mecami 2024-08-04 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2024‒08‒04
nine papers selected by
Oltea Sampetrean, Keio University

The significant role of amino acid metabolic reprogramming in cancer.
Emerging mechanisms and promising approaches in pancreatic cancer metabolism.
The Warburg Effect Revisited through Blood and Electron Flow.
Targeting YAP Activity and Glutamine Metabolism Cooperatively Suppresses Tumor Progression by Preventing Extracellular Matrix Accumulation.
Dissociating the metabolic and tumor-suppressive activity of p53.
Iron Chelation Therapy Elicits Innate Immune Control of Metastatic Ovarian Cancer.
Developing a machine learning-based prognosis and immunotherapeutic response signature in colorectal cancer: insights from ferroptosis, fatty acid dynamics, and the tumor microenvironment.
Spatial transcriptome and single-cell reveal the role of nucleotide metabolism in colorectal cancer progression and tumor microenvironment.
Gut microbiota carcinogen metabolism causes distal tissue tumours.

Cell Commun Signal. 2024 Jul 29. 22(1): 380

The significant role of amino acid metabolic reprogramming in cancer.

Xiaohong Liu, Bo Ren, Jie Ren, Minzhi Gu, Lei You, Yupei Zhao.

  Amino acid metabolism plays a pivotal role in tumor microenvironment, influencing various aspects of cancer progression. The metabolic reprogramming of amino acids in tumor cells is intricately linked to protein synthesis, nucleotide synthesis, modulation of signaling pathways, regulation of tumor cell metabolism, maintenance of oxidative stress homeostasis, and epigenetic modifications. Furthermore, the dysregulation of amino acid metabolism also impacts tumor microenvironment and tumor immunity. Amino acids can act as signaling molecules that modulate immune cell function and immune tolerance within the tumor microenvironment, reshaping the anti-tumor immune response and promoting immune evasion by cancer cells. Moreover, amino acid metabolism can influence the behavior of stromal cells, such as cancer-associated fibroblasts, regulate ECM remodeling and promote angiogenesis, thereby facilitating tumor growth and metastasis. Understanding the intricate interplay between amino acid metabolism and the tumor microenvironment is of crucial significance. Expanding our knowledge of the multifaceted roles of amino acid metabolism in tumor microenvironment holds significant promise for the development of more effective cancer therapies aimed at disrupting the metabolic dependencies of cancer cells and modulating the tumor microenvironment to enhance anti-tumor immune responses and inhibit tumor progression.

Keywords:  Amino acid metabolism; Angiogenesis; Epigenetic regulation; Immune tolerance; Redox; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12964-024-01760-1
Cell Death Dis. 2024 Aug 01. 15(8): 553

Emerging mechanisms and promising approaches in pancreatic cancer metabolism.

Hao Wu, Mengdi Fu, Mengwei Wu, Zhen Cao, Qiyao Zhang, Ziwen Liu.

Pancreatic cancer is an aggressive cancer with a poor prognosis. Metabolic abnormalities are one of the hallmarks of pancreatic cancer, and pancreatic cancer cells can adapt to biosynthesis, energy intake, and redox needs through metabolic reprogramming to tolerate nutrient deficiency and hypoxic microenvironments. Pancreatic cancer cells can use glucose, amino acids, and lipids as energy to maintain malignant growth. Moreover, they also metabolically interact with cells in the tumour microenvironment to change cell fate, promote tumour progression, and even affect immune responses. Importantly, metabolic changes at the body level deserve more attention. Basic research and clinical trials based on targeted metabolic therapy or in combination with other treatments are in full swing. A more comprehensive and in-depth understanding of the metabolic regulation of pancreatic cancer cells will not only enrich the understanding of the mechanisms of disease progression but also provide inspiration for new diagnostic and therapeutic approaches.

DOI: https://doi.org/10.1038/s41419-024-06930-0
Cancer Res. 2024 Jul 02. 84(13): 2046-2048

The Warburg Effect Revisited through Blood and Electron Flow.

Yahui Wang, Chi V Dang.

The Warburg effect describes the propensity of many cancers to consume glucose avidly and convert it to lactate in the presence of oxygen. The benefit of the Warburg effect on cancer cells remains enigmatic, particularly because extracellular disposal of incompletely oxidized lactate is wasteful. However, lactate is not discarded from the body, but rather recycled as pyruvate for metabolism through the tricarboxylic acid cycle in oxidative tissues and cells. Hence, tissue and interorgan metabolism play important roles in tumor metabolism. The production of tumor lactate to be recycled elsewhere parallels the Cori cycle, in which lactate produced by muscle activity is shuttled to the liver, where it is converted to pyruvate and subsequently stored as glucose moieties in glycogen. This perspective will consider this organismal contextwhile discussing how glucose is used in tumors. We highlight several key articles published decades ago in Cancer Research that are foundational to our current understanding of cancer biology and metabolism.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0474
Cancer Res. 2024 Jul 29.

Targeting YAP Activity and Glutamine Metabolism Cooperatively Suppresses Tumor Progression by Preventing Extracellular Matrix Accumulation.

Mihyang Park, Jonghwa Jin, Da Young An, Dong-Ho Kim, Jaebon Lee, Jae Won Yun, Ilseon Hwang, Jae Seok Park, Mi Kyung Kim, You Mie Lee, Jun-Kyu Byun, Yeon-Kyung Choi, Keun-Gyu Park.

Cancer cells use multiple mechanisms to evade the effects of glutamine metabolism inhibitors. The pathways that govern responses to alterations in glutamine availability within the tumor may represent therapeutic targets for combinatorial strategies with these inhibitors. Here, we showed that targeting glutamine utilization stimulated Yes-associated protein (YAP) signaling in cancer cells by reducing cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)-dependent phosphorylation of large tumor suppressor (LATS). Elevated YAP activation induced extracellular matrix (ECM) deposition by increasing secretion of connective tissue growth factor (CTGF) that promoted production of fibronectin and collagen by surrounding fibroblasts. Consequently, inhibiting YAP synergized with inhibition of glutamine utilization to effectively suppress tumor growth in vivo, along with a concurrent decrease in ECM deposition. Blocking ECM remodeling also augmented the tumor suppressive effects of the glutamine utilization inhibitor. Collectively, these data reveal mechanisms by which targeting glutamine utilization increases ECM accumulation and identify potential strategies to reduce ECM levels and increase the efficacy of glutamine metabolism inhibitors.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-3933
Trends Endocrinol Metab. 2024 Aug 01. pii: S1043-2760(24)00199-1. [Epub ahead of print]

Dissociating the metabolic and tumor-suppressive activity of p53.

Yoshitaka Sakurai, Naoto Kubota, Takashi Kadowaki.

  The tumor suppressor p53 regulates metabolic homeostasis. Recently, Tsaousidou et al. reported that selective activation of p53 via downregulation of Tudor interacting repair regulator (TIRR) confers protection against cancer despite obesity and insulin resistance, providing new insights into the role of p53 at the intersection of oncogenesis and systemic metabolism.

Keywords:  cancer; inflammation; insulin resistance; obesity; oncogenesis; p53

DOI:  https://doi.org/10.1016/j.tem.2024.07.018
Cancer Discov. 2024 Jul 29.

Iron Chelation Therapy Elicits Innate Immune Control of Metastatic Ovarian Cancer.

Tito A Sandoval, Camilla Salvagno, Chang-Suk Chae, Deepika Awasthi, Paolo Giovanelli, Matias Marin Falco, Sung-Min Hwang, Eli Teran-Cabanillas, Lasse Suominen, Takahiro Yamazaki, Hui-Hsuan Kuo, Jenna E Moyer, M Laura Martin, Jyothi Manohar, Kihwan Kim, Maria A Sierra, Yusibeska Ramos, Chen Tan, Alexander Emmanuelli, Minkyung Song, Diana K Morales, Dmitriy Zamarin, Melissa K Frey, Evelyn Cantillo, Eloise Chapman-Davis, Kevin Holcomb, Christopher E Mason, Lorenzo Galluzzi, Zhen Ni Zhou, Anna Vaharautio, Suzanne M Cloonan, Juan R Cubillos-Ruiz.

Iron accumulation in tumors contributes to disease progression and chemoresistance. While targeting this process can influence various hallmarks of cancer, the immunomodulatory effects of iron chelation in the tumor microenvironment are unknown. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, unleashes innate immune responses that restrain ovarian cancer. Deferiprone reprogrammed ovarian cancer cells towards an immunostimulatory state characterized by production of type I interferon (IFN) and overexpression of molecules that activate natural killer (NK) cells. Mechanistically, these effects were driven by innate sensing of mitochondrial DNA in the cytosol and concomitant activation of nuclear DNA damage responses triggered upon iron chelation. Deferiprone synergized with chemotherapy and prolonged the survival of mice with ovarian cancer by bolstering type I IFN responses that drove NK cell-dependent control of metastatic disease. Hence, iron chelation may represent an alternative immunotherapeutic strategy for malignancies that are refractory to current T cell-centric modalities.

DOI: https://doi.org/10.1158/2159-8290.CD-23-1451
Front Immunol. 2024 ;15 1416443

Developing a machine learning-based prognosis and immunotherapeutic response signature in colorectal cancer: insights from ferroptosis, fatty acid dynamics, and the tumor microenvironment.

Junchang Zhu, Jinyuan Zhang, Yunwei Lou, Yijie Zheng, Xuzhi Zheng, Wei Cen, Lechi Ye, Qiongying Zhang.

  Instruction: Colorectal cancer (CRC) poses a challenge to public health and is characterized by a high incidence rate. This study explored the relationship between ferroptosis and fatty acid metabolism in the tumor microenvironment (TME) of patients with CRC to identify how these interactions impact the prognosis and effectiveness of immunotherapy, focusing on patient outcomes and the potential for predicting treatment response.Methods: Using datasets from multiple cohorts, including The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we conducted an in-depth multi-omics study to uncover the relationship between ferroptosis regulators and fatty acid metabolism in CRC. Through unsupervised clustering, we discovered unique patterns that link ferroptosis and fatty acid metabolism, and further investigated them in the context of immune cell infiltration and pathway analysis. We developed the FeFAMscore, a prognostic model created using a combination of machine learning algorithms, and assessed its predictive power for patient outcomes and responsiveness to treatment. The FeFAMscore signature expression level was confirmed using RT-PCR, and ACAA2 progression in cancer was further verified.
Results: This study revealed significant correlations between ferroptosis regulators and fatty acid metabolism-related genes with respect to tumor progression. Three distinct patient clusters with varied prognoses and immune cell infiltration were identified. The FeFAMscore demonstrated superior prognostic accuracy over existing models, with a C-index of 0.689 in the training cohort and values ranging from 0.648 to 0.720 in four independent validation cohorts. It also responses to immunotherapy and chemotherapy, indicating a sensitive response of special therapies (e.g., anti-PD-1, anti-CTLA4, osimertinib) in high FeFAMscore patients.
Conclusion: Ferroptosis regulators and fatty acid metabolism-related genes not only enhance immune activation, but also contribute to immune escape. Thus, the FeFAMscore, a novel prognostic tool, is promising for predicting both the prognosis and efficacy of immunotherapeutic strategies in patients with CRC.

Keywords:  TME; colorectal cancer; fatty acid metabolism; ferroptosis; immunotherapy; machine learning

DOI:  https://doi.org/10.3389/fimmu.2024.1416443
J Transl Med. 2024 Jul 29. 22(1): 702

Spatial transcriptome and single-cell reveal the role of nucleotide metabolism in colorectal cancer progression and tumor microenvironment.

Junzhi Liu, Huimin Li, Lantian Wang, Shurui Wang, Qiang Tang.

  BACKGROUND: The intricacies of nucleotide metabolism within tumor cells specific to colorectal cancer (CRC) remain insufficiently characterized. A nuanced examination of particular tumor clusters and their dynamic interplay with the tumor microenvironment (TME) may yield profound insights into these therapeutically auspicious communicative networks.METHODS: By integrating ten types of single-cell enrichment scoring methods, we carried out enrichment analysis on CRC cell types, which was validated through four additional single-cell cohorts. Groups of tumor cells were determined using the average values of the scores. Using cellphonedb, monocle, inferCNV, SCENIC, and Cytotrace, functional analyses were performed. Utilizing the RCTD approach, single-cell groupings were mapped onto spatial transcriptomics, analyzing cell dependency and pathway activity to distinguish between tumor cell subtypes. Differential expression analysis identified core genes in nucleotide metabolism, with single-cell and spatial transcriptomics analyses elucidating the function of these genes in tumor cells and the immune microenvironment. Prognostic models were developed from bulk transcriptome cohorts to forecast responses to immune therapy. Laboratory experiments were conducted to verify the biological function of the core gene.
RESULTS: Nucleotide metabolism is significantly elevated in tumor cells, dividing them into two groups: NUhighepi and NUlowepi. The phenotype NUhighepi was discerned to exhibit pronounced malignant attributes. Utilizing the analytical tool stlearn for cell-to-cell communication assessment, it was ascertained that NUhighepi engages in intimate interactions with fibroblasts. Corroborating this observation, spatial transcriptome cell interaction assessment through MISTy unveiled a particular reliance of NUhighepi on fibroblasts. Subsequently, we pinpointed NME1, a key gene in nucleotide metabolism, affirming its role in thwarting metastasis via in vitro examination. Utilizing multiple machine learning algorithms, a stable prognostic model (NRS) has been developed, capable of predicting survival and responses to immune therapy. In addition, targeted drugs have been identified for both high and low scoring groups. Laboratory experiments have revealed that NME1 can inhibit the proliferation and invasion of CRC tumor cells.
CONCLUSION: Our study elucidates the potential pro-tumor mechanism of NUhighepi and the role of NME1 in inhibiting metastasis, further deepening the understanding of the role of nucleotide metabolism in colorectal cancer, and providing valuable targets for disrupting its properties.

Keywords:  Colorectal cancer; Fibroblasts; NME1; Nucleotide metabolism; Single cell RNA-sequencing; Spatial transcriptomics

DOI:  https://doi.org/10.1186/s12967-024-05495-y
Nature. 2024 Jul 31.

Gut microbiota carcinogen metabolism causes distal tissue tumours.

Blanka Roje, Boyao Zhang, Eleonora Mastrorilli, Ana Kovačić, Lana Sušak, Ivica Ljubenkov, Elena Ćosić, Katarina Vilović, Antonio Meštrović, Emilija Lozo Vukovac, Viljemka Bučević-Popović, Željko Puljiz, Ivana Karaman, Janoš Terzić, Michael Zimmermann.

Exposure to environmental pollutants and human microbiome composition are important predisposition factors for tumour development1,2. Similar to drug molecules, pollutants are typically metabolized in the body, which can change their carcinogenic potential and affect tissue distribution through altered toxicokinetics3. Although recent studies demonstrated that human-associated microorganisms can chemically convert a wide range of xenobiotics and influence the profile and tissue exposure of resulting metabolites4,5, the effect of microbial biotransformation on chemical-induced tumour development remains unclear. Here we show that the depletion of the gut microbiota affects the toxicokinetics of nitrosamines, which markedly reduces the development and severity of nitrosamine-induced urinary bladder cancer in mice6,7. We causally linked this carcinogen biotransformation to specific gut bacterial isolates in vitro and in vivo using individualized bacterial culture collections and gnotobiotic mouse models, respectively. We tested gut communities from different human donors to demonstrate that microbial carcinogen metabolism varies between individuals and we showed that this metabolic activity applies to structurally related nitrosamine carcinogens. Altogether, these results indicate that gut microbiota carcinogen metabolism may be a contributing factor for chemical-induced carcinogenesis, which could open avenues to target the microbiome for improved predisposition risk assessment and prevention of cancer.

DOI: https://doi.org/10.1038/s41586-024-07754-w