bims-mecami 2024-04-14 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2024–04–14
ten papers selected by
Oltea Sampetrean, Keio University

Metabolic Regulation-Mediated Reversion of the Tumor Immunosuppressive Microenvironment for Potentiating Cooperative Metabolic Therapy and Immunotherapy.
A glycolytic metabolite bypasses "two-hit" tumor suppression by BRCA2.
The crosstalk between macrophages and cancer cells potentiates pancreatic cancer cachexia.
Fasting and fasting-mimicking conditions in the cancer immunotherapy era.
Metabolic Signaling in Cancer Metastasis.
Prostate fibroblasts and prostate cancer associated fibroblasts exhibit different metabolic, matrix degradation and PD-L1 expression responses to hypoxia.
Hostile bile limits anti-cancer immunity.
The Emerging Role of LPA as an Oncometabolite.
Gut microbiota regulates the ALK5/NOX1 axis by altering glutamine metabolism to inhibit ferroptosis of intrahepatic cholangiocarcinoma cells.
Resonance of fatty acid metabolism and immune infiltration in anti-PD-1 monotherapy for breast cancer.

Nano Lett. 2024 Apr 08.

Metabolic Regulation-Mediated Reversion of the Tumor Immunosuppressive Microenvironment for Potentiating Cooperative Metabolic Therapy and Immunotherapy.

Ping Ji, Xiao-Kang Jin, Xin-Chen Deng, Shi-Man Zhang, Jun-Long Liang, Qian-Ru Li, Wei-Hai Chen, Xian-Zheng Zhang.

  Tumor cells exhibit heightened glucose (Glu) consumption and increased lactic acid (LA) production, resulting in the formation of an immunosuppressive tumor microenvironment (TME) that facilitates malignant proliferation and metastasis. In this study, we meticulously engineer an antitumor nanoplatform, denoted as ZLGCR, by incorporating glucose oxidase, LA oxidase, and CpG oligodeoxynucleotide into zeolitic imidazolate framework-8 that is camouflaged with a red blood cell membrane. Significantly, ZLGCR-mediated consumption of Glu and LA not only amplifies the effectiveness of metabolic therapy but also reverses the immunosuppressive TME, thereby enhancing the therapeutic outcomes of CpG-mediated antitumor immunotherapy. It is particularly important that the synergistic effect of metabolic therapy and immunotherapy is further augmented when combined with immune checkpoint blockade therapy. Consequently, this engineered antitumor nanoplatform will achieve a cooperative tumor-suppressive outcome through the modulation of metabolism and immune responses within the TME.

Keywords:  immunotherapy; lactic acid depletion; metabolic therapy; red cell membrane; tumor microenvironment

DOI:  https://doi.org/10.1021/acs.nanolett.4c01307
Cell. 2024 Apr 08. pii: S0092-8674(24)00255-1. [Epub ahead of print]

A glycolytic metabolite bypasses "two-hit" tumor suppression by BRCA2.

Li Ren Kong, Komal Gupta, Andy Jialun Wu, David Perera, Roland Ivanyi-Nagy, Syed Moiz Ahmed, Tuan Zea Tan, Shawn Lu-Wen Tan, Alessandra Fuddin, Elayanambi Sundaramoorthy, Grace Shiqing Goh, Regina Tong Xin Wong, Ana S H Costa, Callum Oddy, Hannan Wong, C Pawan K Patro, Yun Suen Kho, Xiao Zi Huang, Joan Choo, Mona Shehata, Soo Chin Lee, Boon Cher Goh, Christian Frezza, Jason J Pitt, Ashok R Venkitaraman.

  Knudson's "two-hit" paradigm posits that carcinogenesis requires inactivation of both copies of an autosomal tumor suppressor gene. Here, we report that the glycolytic metabolite methylglyoxal (MGO) transiently bypasses Knudson's paradigm by inactivating the breast cancer suppressor protein BRCA2 to elicit a cancer-associated, mutational single-base substitution (SBS) signature in nonmalignant mammary cells or patient-derived organoids. Germline monoallelic BRCA2 mutations predispose to these changes. An analogous SBS signature, again without biallelic BRCA2 inactivation, accompanies MGO accumulation and DNA damage in Kras-driven, Brca2-mutant murine pancreatic cancers and human breast cancers. MGO triggers BRCA2 proteolysis, temporarily disabling BRCA2's tumor suppressive functions in DNA repair and replication, causing functional haploinsufficiency. Intermittent MGO exposure incites episodic SBS mutations without permanent BRCA2 inactivation. Thus, a metabolic mechanism wherein MGO-induced BRCA2 haploinsufficiency transiently bypasses Knudson's two-hit requirement could link glycolysis activation by oncogenes, metabolic disorders, or dietary challenges to mutational signatures implicated in cancer evolution.

Keywords:  DNA repair and replication; breast cancer gene BRCA2; cancer genome; cancer metabolism; environmental carcinogenesis; gene-environment interaction; glycolysis; methylglyoxal; mutational signature; tumor suppression

DOI:  https://doi.org/10.1016/j.cell.2024.03.006
Cancer Cell. 2024 Mar 29. pii: S1535-6108(24)00094-1. [Epub ahead of print]

The crosstalk between macrophages and cancer cells potentiates pancreatic cancer cachexia.

Mingyang Liu, Yu Ren, Zhijun Zhou, Jingxuan Yang, Xiuhui Shi, Yang Cai, Alex X Arreola, Wenyi Luo, Kar-Ming Fung, Chao Xu, Ryan D Nipp, Michael S Bronze, Lei Zheng, Yi-Ping Li, Courtney W Houchen, Yuqing Zhang, Min Li.

  With limited treatment options, cachexia remains a major challenge for patients with cancer. Characterizing the interplay between tumor cells and the immune microenvironment may help identify potential therapeutic targets for cancer cachexia. Herein, we investigate the critical role of macrophages in potentiating pancreatic cancer induced muscle wasting via promoting TWEAK (TNF-like weak inducer of apoptosis) secretion from the tumor. Specifically, depletion of macrophages reverses muscle degradation induced by tumor cells. Macrophages induce non-autonomous secretion of TWEAK through CCL5/TRAF6/NF-κB pathway. TWEAK promotes muscle atrophy by activating MuRF1 initiated muscle remodeling. Notably, tumor cells recruit and reprogram macrophages via the CCL2/CCR2 axis and disrupting the interplay between macrophages and tumor cells attenuates muscle wasting. Collectively, this study identifies a feedforward loop between pancreatic cancer cells and macrophages, underlying the non-autonomous activation of TWEAK secretion from tumor cells thereby providing promising therapeutic targets for pancreatic cancer cachexia.

Keywords:  CCL2; CCL5; RELB; TWEAK; cancer cachexia; macrophages; metabolic reprogramming; muscle wasting; p65; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2024.03.009
J Physiol Biochem. 2024 Apr 08.

Fasting and fasting-mimicking conditions in the cancer immunotherapy era.

Ruben Pio, Yaiza Senent, Beatriz Tavira, Daniel Ajona.

  Fasting and fasting-mimicking conditions modulate tumor metabolism and remodel the tumor microenvironment (TME), which could be exploited for the treatment of tumors. A body of evidence demonstrates that fasting and fasting-mimicking conditions can kill cancer cells, or sensitize them to the antitumor activity of standard-of-care drugs while protecting normal cells against their toxic side effects. Pre- and clinical data also suggest that immune responses are involved in these therapeutic effects. Therefore, there is increasing interest in evaluating the impact of fasting-like conditions in the efficacy of antitumor therapies based on the restoration or activation of antitumor immune responses. Here, we review the recent progress in the intersection of fasting-like conditions and current cancer treatments, with an emphasis on cancer immunotherapy.

Keywords:  Cancer immunotherapy; Cancer treatment toxic side effects; Fasting; Fasting-mimicking conditions; Tumor immunity

DOI:  https://doi.org/10.1007/s13105-024-01020-3
Cancer Discov. 2024 Mar 29. OF1-OF19

Metabolic Signaling in Cancer Metastasis.

Sarah Krieg, Sara Isabel Fernandes, Constantinos Kolliopoulos, Ming Liu, Sarah-Maria Fendt.

Metastases, which are the leading cause of death in patients with cancer, have metabolic vulnerabilities. Alterations in metabolism fuel the energy and biosynthetic needs of metastases but are also needed to activate cell state switches in cells leading to invasion, migration, colonization, and outgrowth in distant organs. Specifically, metabolites can activate protein kinases as well as receptors and they are crucial substrates for posttranslational modifications on histone and nonhistone proteins. Moreover, metabolic enzymes can have moonlighting functions by acting catalytically, mainly as protein kinases, or noncatalytically through protein-protein interactions. Here, we summarize the current knowledge on metabolic signaling in cancer metastasis.
SIGNIFICANCE: Effective drugs for the prevention and treatment of metastases will have an immediate impact on patient survival. To overcome the current lack of such drugs, a better understanding of the molecular processes that are an Achilles heel in metastasizing cancer cells is needed. One emerging opportunity is the metabolic changes cancer cells need to undergo to successfully metastasize and grow in distant organs. Mechanistically, these metabolic changes not only fulfill energy and biomass demands, which are often in common between cancer and normal but fast proliferating cells, but also metabolic signaling which enables the cell state changes that are particularly important for the metastasizing cancer cells.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0174
Front Mol Biosci. 2024 ;11 1354076

Prostate fibroblasts and prostate cancer associated fibroblasts exhibit different metabolic, matrix degradation and PD-L1 expression responses to hypoxia.

Jesus Pacheco-Torres, Raj Kumar Sharma, Yelena Mironchik, Flonne Wildes, W Nathaniel Brennen, Dmitri Artemov, Balaji Krishnamachary, Zaver M Bhujwalla.

  Fibroblasts are versatile cells that play a major role in wound healing by synthesizing and remodeling the extracellular matrix (ECM). In cancers, fibroblasts play an expanded role in tumor progression and dissemination, immunosuppression, and metabolic support of cancer cells. In prostate cancer (PCa), fibroblasts have been shown to induce growth and increase metastatic potential. To further understand differences in the functions of human PCa associated fibroblasts (PCAFs) compared to normal prostate fibroblasts (PFs), we investigated the metabolic profile and ECM degradation characteristics of PFs and PCAFs using a magnetic resonance imaging and spectroscopy compatible intact cell perfusion assay. To further understand how PFs and PCAFs respond to hypoxic tumor microenvironments that are often observed in PCa, we characterized the effects of hypoxia on PF and PCAF metabolism, invasion and PD-L1 expression. We found that under normoxia, PCAFs displayed decreased ECM degradation compared to PFs. Under hypoxia, ECM degradation by PFs increased, whereas PCAFs exhibited decreased ECM degradation. Under both normoxia and hypoxia, PCAFs and PFs showed significantly different metabolic profiles. PD-L1 expression was intrinsically higher in PCAFs compared to PFs. Under hypoxia, PD-L1 expression increased in PCAFs but not in PFs. Our data suggest that PCAFs may not directly induce ECM degradation to assist in tumor dissemination, but may instead create an immune suppressive tumor microenvironment that further increases under hypoxic conditions. Our data identify the intrinsic metabolic, ECM degradation and PD-L1 expression differences between PCAFs and PFs under normoxia and hypoxia that may provide novel targets in PCa treatment.

Keywords:  PD-L1; cancer associated fibroblast; fibroblast; hypoxia; metabolism; prostate cancer

DOI:  https://doi.org/10.3389/fmolb.2024.1354076
Immunity. 2024 Apr 09. pii: S1074-7613(24)00127-4. [Epub ahead of print]57(4): 834-836

Hostile bile limits anti-cancer immunity.

Pavitha Parathan, Lisa A Mielke.

Various microbial metabolites promote cell transformation. In this issue of Immunity, Cong et al. show that deoxycholic acid (DCA), a microbial metabolite of bile, promotes tumor growth by suppressing antitumor CD8+ T cell responses via dysregulation of calcium efflux.

DOI: https://doi.org/10.1016/j.immuni.2024.03.006
Cells. 2024 Apr 04. pii: 629. [Epub ahead of print]13(7):

The Emerging Role of LPA as an Oncometabolite.

Theodoros Karalis, George Poulogiannis.

  Lysophosphatidic acid (LPA) is a phospholipid that displays potent signalling activities that are regulated in both an autocrine and paracrine manner. It can be found both extra- and intracellularly, where it interacts with different receptors to activate signalling pathways that regulate a plethora of cellular processes, including mitosis, proliferation and migration. LPA metabolism is complex, and its biosynthesis and catabolism are under tight control to ensure proper LPA levels in the body. In cancer patient specimens, LPA levels are frequently higher compared to those of healthy individuals and often correlate with poor responses and more aggressive disease. Accordingly, LPA, through promoting cancer cell migration and invasion, enhances the metastasis and dissemination of tumour cells. In this review, we summarise the role of LPA in the regulation of critical aspects of tumour biology and further discuss the available pre-clinical and clinical evidence regarding the feasibility and efficacy of targeting LPA metabolism for effective anticancer therapy.

Keywords:  cancer metabolism; lysophosphatidic acid; oncometabolite; phospholipid

DOI:  https://doi.org/10.3390/cells13070629
Biochim Biophys Acta Mol Basis Dis. 2024 Apr 05. pii: S0925-4439(24)00141-8. [Epub ahead of print]1870(5): 167152

Gut microbiota regulates the ALK5/NOX1 axis by altering glutamine metabolism to inhibit ferroptosis of intrahepatic cholangiocarcinoma cells.

Qi Zhang, Jixiang Zhou, Denggao Zhai, Qin Jiang, Manyi Yang, Maojun Zhou.

  Intrahepatic cholangiocarcinoma (ICC) is a kind of hepatobiliary tumor that is increasing in incidence and mortality. The gut microbiota plays a role in the onset and progression of cancer, however, the specific mechanism by which the gut microbiota acts on ICC remains unclear. In this study, feces and plasma from healthy controls and ICC patients were collected for 16S rRNA sequencing or metabolomics analysis. Gut microbiota analysis showed that gut microbiota abundance and biodiversity were altered in ICC patients compared with controls. Plasma metabolism analysis showed that the metabolite glutamine content of the ICC patient was significantly higher than that of the controls. KEGG pathway analysis showed that glutamine plays a vital role in ICC. In addition, the use of antibiotics in ICC animals further confirmed that changes in gut microbiota affect changes in glutamine. Further experiments showed that supplementation with glutamine inhibited ferroptosis and downregulated ALK5 and NOX1 expression in HuCCT1 cells. ALK5 overexpression or NOX1 overexpression increased NOX1, p53, PTGS2, ACSL4, LPCAT3, ROS, MDA and Fe2+ and decreased FTH1, SLC7A11 and GSH. Knockdown of NOX1 suppressed FIN56-induced ferroptosis. In vivo, supplementation with glutamine promoted tumor growth. Overexpression of ALK5 repressed tumor growth and induced ferroptosis in nude mice, which could be reversed by the addition of glutamine. Our results suggested that the gut microbiota altered glutamine metabolism to inhibit ferroptosis in ICC by regulating the ALK5/NOX1 axis.

Keywords:  ALK5/NOX1; Ferroptosis; Glutamine; Gut microbiota; Intrahepatic cholangiocarcinoma

DOI:  https://doi.org/10.1016/j.bbadis.2024.167152
Transl Oncol. 2024 Apr 10. pii: S1936-5233(24)00087-1. [Epub ahead of print]44 101960

Resonance of fatty acid metabolism and immune infiltration in anti-PD-1 monotherapy for breast cancer.

Andi Zhao, Jin Yang, Ran Ran, Shidi Zhao, Yuxin Cui, Fang Hu, Yan Zhou.

  The interaction between tumor fatty acid metabolism and immune microenvironment is a novel topic in oncology research, and the relationship of lipid-derived factors with immune editing in tumor is unclear. The breast cancer samples from the TCGA database were used as the training set, and samples from GSE42568 were employed as the validation set for constructing a model to identify a signature associated with fatty acid metabolism through Lasso Cox regression. And the changes in immune related signatures and risk score before and after anti-PD-1 monotherapy were caught by the differential analysis in GSE225078. A 14-gene prognostic risk scoring model identifying by fatty acid metabolism relevant signature was conducted, and the high risk group had shorter overall survival and progression free survival than low risk group. Many metabolism-related pathways were enriched in the high risk group, and many immune-related pathways were enriched in low risk group. The crucial differentially expressed genes between the high/low risk groups, CYP4F8 and CD52, were found to be strongly associated with SUCLA2 and ACOT4 of 14-gene model, and strongly related to immune infiltration. Immune related signatures, fatty acid metabolism-risk score and the expression level of ALDH1A1 (in 14-gene-model) changed after anti-PD-1 monotherapy. And the mice model results also showed anti-PD-1 mAb could significantly reduce the expression level of ALDH1A1 (p < 0.01). These results brought up the crosstalk between immune components and fatty acid metabolism in breast cancer microenvironment, which provided a new possibility of targeting fatty acid metabolism for combination therapy in breast cancer immunotherapy.

Keywords:  Biomarkers of breast cancer; Fatty acid metabolism; Immunogenetics; Tumor immune microenvironment; Tumor immunology

DOI:  https://doi.org/10.1016/j.tranon.2024.101960