bims-mecami 2022-12-11 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2022–12–11
nine papers selected by
Linda Chan, Yale University

Not so neutral lipids: Metabolic regulation of the pre-metastatic niche.
Lipid-laden lung mesenchymal cells foster breast cancer metastasis via metabolic reprogramming of tumor cells and natural killer cells.
Hypoxic activation of PFKFB4 in breast tumor microenvironment shapes metabolic and cellular plasticity to accentuate metastatic competence.
Age-associated remodeling of T cell immunity and metabolism.
Metabolic hallmarks of natural killer cells in the tumor microenvironment and implications in cancer immunotherapy.
Metabolic reprogramming by miRNAs in the tumor microenvironment: Focused on immunometabolism.
Contribution of metabolic abnormalities to acute myeloid leukemia pathogenesis.
Crosstalk between pro-survival sphingolipid metabolism and complement signaling induces inflammasome-mediated tumor metastasis.
Cutting Edge: mTORC2 Regulates CD8+ Effector and Memory T Cell Differentiation through Serum and Glucocorticoid Kinase 1.

Cell Metab. 2022 Dec 06. pii: S1550-4131(22)00498-3. [Epub ahead of print]34(12): 1899-1900

Not so neutral lipids: Metabolic regulation of the pre-metastatic niche.

Joshua D Schoenfeld, Santosha A Vardhana.

How primary tumors alter distant tissue sites to facilitate seeding and metastasis remains unclear. In this issue, Gong et al. demonstrate that IL-1β-dependent lipid accumulation in lung mesenchymal cells supports both tumor growth and NK cell dysfunction, facilitating lung metastasis of primary breast tumors.

DOI: https://doi.org/10.1016/j.cmet.2022.11.007
Cell Metab. 2022 Dec 06. pii: S1550-4131(22)00494-6. [Epub ahead of print]34(12): 1960-1976.e9

Lipid-laden lung mesenchymal cells foster breast cancer metastasis via metabolic reprogramming of tumor cells and natural killer cells.

Zheng Gong, Qing Li, Jiayuan Shi, Edison T Liu, Leonard D Shultz, Guangwen Ren.

  While the distant organ environment is known to support metastasis of primary tumors, its metabolic roles in this process remain underdetermined. Here, in breast cancer models, we found lung-resident mesenchymal cells (MCs) accumulating neutral lipids at the pre-metastatic stage. This was partially mediated by interleukin-1β (IL-1β)-induced hypoxia-inducible lipid droplet-associated (HILPDA) that subsequently represses adipose triglyceride lipase (ATGL) activity in lung MCs. MC-specific ablation of the ATGL or HILPDA genes in mice reinforced and reduced lung metastasis of breast cancer respectively, suggesting a metastasis-promoting effect of lipid-laden MCs. Mechanistically, lipid-laden MCs transported their lipids to tumor cells and natural killer (NK) cells via exosome-like vesicles, leading to heightened tumor cell survival and proliferation and NK cell dysfunction. Blockage of IL-1β, which was effective singly, improved the efficacy of adoptive NK cell immunotherapy in mitigating lung metastasis. Collectively, lung MCs metabolically regulate tumor cells and anti-tumor immunity to facilitate breast cancer lung metastasis.

Keywords:  IL-1β; NK cells; breast cancer; disseminated tumor cells; inflammation; lipid storage; lung metastasis; mesenchymal cells; metabolic reprograming; triglycerides

DOI:  https://doi.org/10.1016/j.cmet.2022.11.003
Cell Rep. 2022 Dec 06. pii: S2211-1247(22)01639-4. [Epub ahead of print]41(10): 111756

Hypoxic activation of PFKFB4 in breast tumor microenvironment shapes metabolic and cellular plasticity to accentuate metastatic competence.

Tao Dai, Spencer R Rosario, Eriko Katsuta, Abhisha Sawant Dessai, Emily J Paterson, Aaron T Novickis, Eduardo Cortes Gomez, Bokai Zhu, Song Liu, Hai Wang, Scott I Abrams, Mukund Seshadri, Wiam Bshara, Subhamoy Dasgupta.

  Cancer cells encounter a hostile tumor microenvironment (TME), and their adaptations to metabolic stresses determine metastatic competence. Here, we show that the metabolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 (PFKFB4) is induced in hypoxic tumors acquiring metabolic plasticity and invasive phenotype. In mouse models of breast cancer, genetic ablation of PFKFB4 significantly delays distant organ metastasis, reducing local lymph node invasion by suppressing expression of invasive gene signature including integrin β3. Photoacoustic imaging followed by metabolomics analyses of hypoxic tumors show that PFKFB4 drives metabolic flexibility, enabling rapid detoxification of reactive oxygen species favoring survival under selective pressure. Mechanistically, hypoxic induction triggers nuclear translocation of PFKFB4 accentuating non-canonical transcriptional activation of HIF-1α, and breast cancer patients with increased nuclear PFKFB4 in their tumors are found to be significantly associated with poor prognosis. Our findings imply that PFKFB4 induction is crucial for tumor cell adaptation in the hypoxic TME that determines metastatic competence.

Keywords:  CP: Cancer; CP: Metabolism; breast cancer; hypoxia; metabolism; metastasis; redox; stress; transcription; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2022.111756
Cell Metab. 2022 Nov 29. pii: S1550-4131(22)00496-X. [Epub ahead of print]

Age-associated remodeling of T cell immunity and metabolism.

SeongJun Han, Peter Georgiev, Alison E Ringel, Arlene H Sharpe, Marcia C Haigis.

  Aging results in remodeling of T cell immunity and is associated with poor clinical outcomes in age-related diseases such as cancer. Among the hallmarks of aging, changes in host and cellular metabolism critically affect the development, maintenance, and function of T cells. Although metabolic perturbations impact anti-tumor T cell responses, the link between age-associated metabolic dysfunction and anti-tumor immunity remains unclear. In this review, we summarize recent advances in our understanding of aged T cell metabolism, with a focus on the bioenergetic and immunologic features of T cell subsets unique to the aging process. We also survey insights into mechanisms of metabolic T cell dysfunction in aging and discuss the impacts of aging on the efficacy of cancer immunotherapy. As the average life expectancy continues to increase, understanding the interplay between age-related metabolic reprogramming and maladaptive T cell immunity will be instrumental for the development of therapeutic strategies for older patients.

Keywords:  T cells; aging; cancer; immunity; immunotherapy; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.cmet.2022.11.005
Oncogene. 2022 Dec 06.

Metabolic hallmarks of natural killer cells in the tumor microenvironment and implications in cancer immunotherapy.

Yuqing Yang, Lin Chen, Bohao Zheng, Shengtao Zhou.

Natural killer (NK) cells belong to the early responder group against cancerous cells and viral infection. Emerging evidence reveals that distinct metabolic reprogramming occurs concurrently with activation and memory formation of NK cells. However, metabolism of NK cells is disturbed in the tumor immune microenvironment, which may promote tumor progression while limiting immunotherapy responses. In this review, we highlight how cell metabolism influences NK cell activity, the key molecular regulators of NK cell metabolism, and emerging strategies to alter metabolism to improve cytotoxicity of NK cells to kill tumor cells for cancer patients.

DOI: https://doi.org/10.1038/s41388-022-02562-w
Front Oncol. 2022 ;12 1042196

Metabolic reprogramming by miRNAs in the tumor microenvironment: Focused on immunometabolism.

Shadia Hamoud Alshahrani, Yousif Saleh Ibrahim, Abduladheem Turki Jalil, Abdelgadir Alamin Altoum, Harun Achmad, Rahman S Zabibah, Gamal A Gabr, Andrés Alexis Ramírez-Coronel, Ameer A Alameri, Qutaiba A Qasim, Sajad Karampoor, Rasoul Mirzaei.

  MicroRNAs (miRNAs) are emerging as a significant modulator of immunity, and their abnormal expression/activity has been linked to numerous human disorders, such as cancer. It is now known that miRNAs potentially modulate the production of several metabolic processes in tumor-associated immune cells and indirectly via different metabolic enzymes that affect tumor-associated signaling cascades. For instance, Let-7 has been identified as a crucial modulator for the long-lasting survival of CD8+ T cells (naive phenotypes) in cancer by altering their metabolism. Furthermore, in T cells, it has been found that enhancer of zeste homolog 2 (EZH2) expression is controlled via glycolytic metabolism through miRNAs in patients with ovarian cancer. On the other hand, immunometabolism has shown us that cellular metabolic reactions and processes not only generate ATP and biosynthetic intermediates but also modulate the immune system and inflammatory processes. Based on recent studies, new and encouraging approaches to cancer involving the modification of miRNAs in immune cell metabolism are currently being investigated, providing insight into promising targets for therapeutic strategies based on the pivotal role of immunometabolism in cancer. Throughout this overview, we explore and describe the significance of miRNAs in cancer and immune cell metabolism.

Keywords:  MicroRNAs; cancer; immune cell; immunometabolism; metabolism

DOI:  https://doi.org/10.3389/fonc.2022.1042196
Trends Cell Biol. 2022 Dec 05. pii: S0962-8924(22)00255-0. [Epub ahead of print]

Contribution of metabolic abnormalities to acute myeloid leukemia pathogenesis.

Grace Egan, Aaron D Schimmer.

  Acute myeloid leukemia (AML) is a malignant disease of myeloid precursors. Somatic mutations have long been accepted as drivers of this malignancy. Over the past decade, unique mitochondrial and metabolic dependencies of AML and AML stem cells have been identified, including a reliance on oxidative phosphorylation. More recently, metabolic enzymes have demonstrated noncanonical roles in regulating gene expression in AML, controlling cell differentiation and stemness. These mitochondrial and metabolic adaptations occur independent of underlying genomic abnormalities and contribute to chemoresistance and relapse. In this opinion article, we discuss the current understanding of AML pathogenesis and whether mitochondrial and metabolic abnormalities drive leukemogenesis or are a non-contributory phenotype.

Keywords:  acute myeloid leukemia; metabolism; mitochondria; oxidative phosphorylation; pathogenesis

DOI:  https://doi.org/10.1016/j.tcb.2022.11.004
Cell Rep. 2022 Dec 06. pii: S2211-1247(22)01620-5. [Epub ahead of print]41(10): 111742

Crosstalk between pro-survival sphingolipid metabolism and complement signaling induces inflammasome-mediated tumor metastasis.

Alhaji H Janneh, Mohamed Faisal Kassir, F Cansu Atilgan, Han Gyul Lee, Megan Sheridan, Natalia Oleinik, Zdzislaw Szulc, Christina Voelkel-Johnson, Hung Nguyen, Hong Li, Yuri K Peterson, Elisabetta Marangoni, Ozge Saatci, Ozgur Sahin, Michael Lilly, Carl Atkinson, Stephen Tomlinson, Shikhar Mehrotra, Besim Ogretmen.

  Crosstalk between metabolic and signaling events that induce tumor metastasis remains elusive. Here, we determine how oncogenic sphingosine 1-phosphate (S1P) metabolism induces intracellular C3 complement activation to enhance migration/metastasis. We demonstrate that increased S1P metabolism activates C3 complement processing through S1P receptor 1 (S1PR1). S1P/S1PR1-activated intracellular C3b-α'2 is associated with PPIL1 through glutamic acid 156 (E156) and aspartic acid 111 (D111) residues, resulting in NLRP3/inflammasome induction. Inactivation mutations of S1PR1 to prevent S1P signaling or mutations of C3b-α'2 to prevent its association with PPIL1 attenuate inflammasome activation and reduce lung colonization/metastasis in mice. Also, activation of the S1PR1/C3/PPIL1/NLRP3 axis is highly associated with human metastatic melanoma tissues and patient-derived xenografts. Moreover, targeting S1PR1/C3/PPIL1/NLRP3 signaling using molecular, genetic, and pharmacologic tools prevents lung colonization/metastasis of various murine cancer cell lines using WT and C3a-receptor1 knockout (C3aR1-/-) mice. These data provide strategies for treating high-grade/metastatic tumors by targeting the S1PR1/C3/inflammasome axis.

Keywords:  CP: Cancer; CP: Metabolism; S1P; S1P receptor 1; S1PR1; complement signaling; inflammasome; metastasis; sphingolipids; sphingosine 1-phosphate

DOI:  https://doi.org/10.1016/j.celrep.2022.111742
J Immunol. 2022 Dec 15. 209(12): 2287-2291

Cutting Edge: mTORC2 Regulates CD8+ Effector and Memory T Cell Differentiation through Serum and Glucocorticoid Kinase 1.

Chirag H Patel, Emily B Heikamp, Wei Xu, Im-Hong Sun, Min-Hee Oh, Im-Meng Sun, Jiayu Wen, Ada J Tam, Richard L Blosser, Jonathan D Powell.

The mechanistic target of rapamycin is an essential regulator of T cell metabolism and differentiation. In this study, we demonstrate that serum- and glucocorticoid-regulated kinase 1 (SGK1), a downstream node of mechanistic target of rapamycin complex 2 signaling, represses memory CD8+ T cell differentiation. During acute infections, murine SGK1-deficient CD8+ T cells adopt an early memory precursor phenotype leading to more long-lived memory T cells. Thus, SGK1-deficient CD8+ T cells demonstrate an enhanced recall capacity in response to reinfection and can readily reject tumors. Mechanistically, activation of SGK1-deficient CD8+ T cells results in decreased Foxo1 phosphorylation and increased nuclear translocation of Foxo1 to promote early memory development. Overall, SGK1 might prove to be a powerful target for enhancing the efficacy of vaccines and tumor immunotherapy.

DOI: https://doi.org/10.4049/jimmunol.2100669