bims-tumime 2023-10-08 papers

Issue of 2023‒10‒08
six papers selected by
Alex Muir, University of Chicago

Front Oncol. 2023 ;13 1289397

Editorial: Cancer metabolism: molecular insights, metabolic crosstalk in the tumor microenvironment, and implications for therapy.

Balkrishna Chaube, Parmanand Malvi.

Keywords: bioenergetics; cancer; cancer/immune metabolism; metabolic disorder and cancer; metabolic imaging; metabolomics; tumor microenvironment

DOI: https://doi.org/10.3389/fonc.2023.1289397

Int J Biol Sci. 2023 ;19(15): 4915-4930

The emerging roles of metabolism in the crosstalk between breast cancer cells and tumor-associated macrophages.

Yuxin Liang, Jun He, Xiguang Chen, Liyang Yin, Qiong Yuan, Qiting Zeng, Xuyu Zu, Yingying Shen.

Breast cancer is the most common cancer affecting women worldwide. Investigating metabolism in breast cancer may accelerate the exploitation of new therapeutic options for immunotherapies. Metabolic reprogramming can confer breast cancer cells (BCCs) with a survival advantage in the tumor microenvironment (TME) and metabolic alterations in breast cancer, and the corresponding metabolic byproducts can affect the function of tumor-associated macrophages (TAMs). Additionally, TAMs undergo metabolic reprogramming in response to signals present in the TME, which can affect their function and breast cancer progression. Here, we review the metabolic crosstalk between BCCs and TAMs in terms of glucose, lipids, amino acids, iron, and adenosine metabolism. Summaries of inhibitors that target metabolism-related processes in BCCs or TAMs within breast cancer have also served as valuable inspiration for novel therapeutic approaches in the fight against this disease. This review provides new perspectives on targeted anticancer therapies for breast cancer that combine immunity with metabolism.

Keywords: breast cancer; crosstalk; metabolism; targeted therapy; tumor-associated macrophages

DOI: https://doi.org/10.7150/ijbs.86039

Front Endocrinol (Lausanne). 2023 ;14 1217875

The impact of poor metabolic health on aggressive breast cancer: adipose tissue and tumor metabolism.

Barbara Mensah Sankofi, Estefania Valencia-Rincón, Malika Sekhri, Adriana L Ponton-Almodovar, Jamie J Bernard, Elizabeth A Wellberg.

Obesity and type 2 diabetes are chronic metabolic diseases that impact tens to hundreds of millions of adults, especially in developed countries. Each condition is associated with an elevated risk of breast cancer and with a poor prognosis after treatment. The mechanisms connecting poor metabolic health to breast cancer are numerous and include hyperinsulinemia, inflammation, excess nutrient availability, and adipose tissue dysfunction. Here, we focus on adipose tissue, highlighting important roles for both adipocytes and fibroblasts in breast cancer progression. One potentially important mediator of adipose tissue effects on breast cancer is the fibroblast growth factor receptor (FGFR) signaling network. Among the many roles of FGFR signaling, we postulate that key mechanisms driving aggressive breast cancer include epithelial-to-mesenchymal transition and cellular metabolic reprogramming. We also pose existing questions that may help better understand breast cancer biology in people with obesity, type 2 diabetes, and poor metabolic health.

Keywords: adipose; breast cancer; diabetes; fibroblast growth factor; obesity

DOI: https://doi.org/10.3389/fendo.2023.1217875

Curr Opin Biotechnol. 2023 Sep 30. pii: S0958-1669(23)00105-2. [Epub ahead of print]84 102995

The aging tumor metabolic microenvironment.

Steven E Pilley, Edgar Esparza, Peter J Mullen.

Despite the higher incidence of cancer with increasing age, few preclinical or clinical studies incorporate age. This, coupled with an aging world population, requires that we improve our understanding of how aging affects cancer development, progression, and treatment. One key area will be how the tumor microenvironment (TME) changes with age. Metabolite levels are an essential component of the TME, and they are affected by the metabolic requirements of the cells present and systemic metabolite availability. These factors are affected by aging, causing different TME metabolic states between young and older adults. In this review, we will summarize what is known about how aging impacts the TME metabolic state, and suggest how we can improve our understanding of it.

DOI: https://doi.org/10.1016/j.copbio.2023.102995

Res Sq. 2023 Sep 11. pii: rs.3.rs-3317816. [Epub ahead of print]

Adaptive rewiring of purine metabolism promotes treatment resistance in H3K27M-mutant diffuse midline glioma.

Background: Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are a fatal form of brain cancer. These tumors often carry a driver mutation on histone H3 converting lysine 27 to methionine (H3K27M). DMG-H3K27M are characterized by altered metabolism and resistance to standard of care radiation (RT), but how the H3K27M mediates the metabolic response to radiation and consequent treatment resistance is uncertain. Methods: We performed metabolomics on irradiated and untreated H3K27M isogenic DMG cell lines and observed an H3K27M-specific enrichment for purine synthesis pathways. We profiled the expression of purine synthesis enzymes in publicly available patient data and in our models, quantified purine synthetic flux using stable isotope tracing, and characterized the in vitro and in vivo response to de novo and salvage purine synthesis inhibition in combination with RT. Results: DMG-H3K27M cells activate purine metabolism in an H3K27M-specific fashion. In the absence of genotoxic treatment, H3K27M-expressing cells have higher relative activity of de novo synthesis and lower activity of purine salvage due to decreased expression of the purine salvage enzymes. Inhibition of de novo synthesis radiosensitized DMG-H3K27M cells in vitro and in vivo. Irradiated H3K27M cells adaptively upregulate purine salvage enzyme expression and pathway activity. Silencing the rate limiting enzyme in purine salvage, hypoxanthine guanine phosphoribosyl transferase (HGPRT) when combined with radiation markedly suppressed DMG-H3K27M tumor growth in vivo. Conclusions: H3K27M expressing cells rely on de novo purine synthesis but adaptively upregulate purine salvage in response to RT. Inhibiting purine salvage may help overcome treatment resistance in DMG-H3K27M tumors.

DOI: https://doi.org/10.21203/rs.3.rs-3317816/v1

EMBO J. 2023 Oct 02. e114032

Hypoxia activates SREBP2 through Golgi disassembly in bone marrow-derived monocytes for enhanced tumor growth.

Bone marrow-derived cells (BMDCs) infiltrate hypoxic tumors at a pre-angiogenic state and differentiate into mature macrophages, thereby inducing pro-tumorigenic immunity. A critical factor regulating this differentiation is activation of SREBP2-a well-known transcription factor participating in tumorigenesis progression-through unknown cellular mechanisms. Here, we show that hypoxia-induced Golgi disassembly and Golgi-ER fusion in monocytic myeloid cells result in nuclear translocation and activation of SREBP2 in a SCAP-independent manner. Notably, hypoxia-induced SREBP2 activation was only observed in an immature lineage of bone marrow-derived cells. Single-cell RNA-seq analysis revealed that SREBP2-mediated cholesterol biosynthesis was upregulated in HSCs and monocytes but not in macrophages in the hypoxic bone marrow niche. Moreover, inhibition of cholesterol biosynthesis impaired tumor growth through suppression of pro-tumorigenic immunity and angiogenesis. Thus, our findings indicate that Golgi-ER fusion regulates SREBP2-mediated metabolic alteration in lineage-specific BMDCs under hypoxia for tumor progression.

Keywords: Golgi-ER fusion; SREBP2; cholesterol biosynthesis; hypoxia; myeloid differentiation

DOI: https://doi.org/10.15252/embj.2023114032