bims-tumime 2023-09-17 papers

Issue of 2023–09–17
five papers selected by
Alex Muir, University of Chicago

Cell Chem Biol. 2023 Sep 01. pii: S2451-9456(23)00281-7. [Epub ahead of print]

Tumor microenvironmental nutrients, cellular responses, and cancer.

Graham P Lobel, Yanqing Jiang, M Celeste Simon.

Over the last two decades, the rapidly expanding field of tumor metabolism has enhanced our knowledge of the impact of nutrient availability on metabolic reprogramming in cancer. Apart from established roles in cancer cells themselves, various nutrients, metabolic enzymes, and stress responses are key to the activities of tumor microenvironmental immune, fibroblastic, endothelial, and other cell types that support malignant transformation. In this article, we review our current understanding of how nutrient availability affects metabolic pathways and responses in both cancer and "stromal" cells, by dissecting major examples and their regulation of cellular activity. Understanding the relationship of nutrient availability to cellular behaviors in the tumor ecosystem will broaden the horizon of exploiting novel therapeutic vulnerabilities in cancer.

Keywords: Cancer metabolism; cancer therapeutics; cancer-associated fibroblasts; immune cell metabolism; nutrient exchange; stress responses; tumor microenvironment

DOI: https://doi.org/10.1016/j.chembiol.2023.08.011

Cold Spring Harb Perspect Med. 2023 Sep 11. pii: a041540. [Epub ahead of print]

The Role of Stroma in Cancer Metabolism.

Alec C Kimmelman, Mara H Sherman.

The altered metabolism of tumor cells is a well-known hallmark of cancer and is driven by multiple factors such as mutations in oncogenes and tumor suppressor genes, the origin of the tissue where the tumor arises, and the microenvironment of the tumor. These metabolic changes support the growth of cancer cells by providing energy and the necessary building blocks to sustain proliferation. Targeting these metabolic alterations therapeutically is a potential strategy to treat cancer, but it is challenging due to the metabolic plasticity of tumors. Cancer cells have developed ways to scavenge nutrients through autophagy and macropinocytosis and can also form metabolic networks with stromal cells in the tumor microenvironment. Understanding the role of the tumor microenvironment in tumor metabolism is crucial for effective therapeutic targeting. This review will discuss tumor metabolism and the contribution of the stroma in supporting tumor growth through metabolic interactions.

DOI: https://doi.org/10.1101/cshperspect.a041540

J Hematol Oncol. 2023 Sep 12. 16(1): 103

Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics.

Hao-Ran Jin, Jin Wang, Zi-Jing Wang, Ming-Jia Xi, Bi-Han Xia, Kai Deng, Jin-Lin Yang.

Lipid metabolic reprogramming is an emerging hallmark of cancer. In order to sustain uncontrolled proliferation and survive in unfavorable environments that lack oxygen and nutrients, tumor cells undergo metabolic transformations to exploit various ways of acquiring lipid and increasing lipid oxidation. In addition, stromal cells and immune cells in the tumor microenvironment also undergo lipid metabolic reprogramming, which further affects tumor functional phenotypes and immune responses. Given that lipid metabolism plays a critical role in supporting cancer progression and remodeling the tumor microenvironment, targeting the lipid metabolism pathway could provide a novel approach to cancer treatment. This review seeks to: (1) clarify the overall landscape and mechanisms of lipid metabolic reprogramming in cancer, (2) summarize the lipid metabolic landscapes within stromal cells and immune cells in the tumor microenvironment, and clarify their roles in tumor progression, and (3) summarize potential therapeutic targets for lipid metabolism, and highlight the potential for combining such approaches with other anti-tumor therapies to provide new therapeutic opportunities for cancer patients.

Keywords: Cancer progression; Immune response; Lipid metabolism; Targeted therapy; Tumor microenvironment

DOI: https://doi.org/10.1186/s13045-023-01498-2

Cell Chem Biol. 2023 Aug 31. pii: S2451-9456(23)00279-9. [Epub ahead of print]

Screening in serum-derived medium reveals differential response to compounds targeting metabolism.

A challenge for screening new anticancer drugs is that efficacy in cell culture models is not always predictive of efficacy in patients. One limitation of standard cell culture is a reliance on non-physiological nutrient levels, which can influence cell metabolism and drug sensitivity. A general assessment of how physiological nutrients affect cancer cell response to small molecule therapies is lacking. To address this, we developed a serum-derived culture medium that supports the proliferation of diverse cancer cell lines and is amenable to high-throughput screening. We screened several small molecule libraries and found that compounds targeting metabolic enzymes were differentially effective in standard compared to serum-derived medium. We exploited the differences in nutrient levels between each medium to understand why medium conditions affected the response of cells to some compounds, illustrating how this approach can be used to screen potential therapeutics and understand how their efficacy is modified by available nutrients.

Keywords: Cancer cell metabolism; Culture media; Drug sensitivity; High-throughput screening; Nutrient environment; Phenotypic drug screening; Physiologic media

DOI: https://doi.org/10.1016/j.chembiol.2023.08.007

Cytokine Growth Factor Rev. 2023 Aug 30. pii: S1359-6101(23)00056-4. [Epub ahead of print]

Exosome-mediated metabolic reprogramming: Implications in esophageal carcinoma progression and tumor microenvironment remodeling.

Yong Xi, Yaxing Shen, Lijie Chen, Lijie Tan, Weiyu Shen, Xing Niu.

Esophageal carcinoma is among the most fatal malignancies with increasing incidence globally. Tumor onset and progression can be driven by metabolic reprogramming, especially during esophageal carcinoma development. Exosomes, a subset of extracellular vesicles, display an average size of ∼100 nanometers, containing multifarious components (nucleic acids, proteins, lipids, etc.). An increasing number of studies have shown that exosomes are capable of transferring molecules with biological functions into recipient cells, which play crucial roles in esophageal carcinoma progression and tumor microenvironment that is a highly heterogeneous ecosystem through rewriting the metabolic processes in tumor cells and environmental stromal cells. The review introduces the reprogramming of glucose, lipid, amino acid, mitochondrial metabolism in esophageal carcinoma, and summarize current pharmaceutical agents targeting such aberrant metabolism rewiring. We also comprehensively overview the biogenesis and release of exosomes, and recent advances of exosomal cargoes and functions in esophageal carcinoma and their promising clinical application. Moreover, we discuss how exosomes trigger tumor growth, metastasis, drug resistance, and immunosuppression as well as tumor microenvironment remodeling through focusing on their capacity to transfer materials between cells or between cells and tissues and modulate metabolic reprogramming, thus providing a theoretical reference for the design potential pharmaceutical agents targeting these mechanisms. Altogether, our review attempts to fully understand the significance of exosome-based metabolic rewriting in esophageal carcinoma progression and remodeling of the tumor microenvironment, bringing novel insights into the prevention and treatment of esophageal carcinoma in the future.

Keywords: Esophageal carcinoma; Exosome; Lipid metabolism; Metabolic reprogramming; Tumor microenvironment; Tumor progression

DOI: https://doi.org/10.1016/j.cytogfr.2023.08.010