bims-mecami 2024-08-18 papers

Issue of 2024–08–18
five papers selected by
Oltea Sampetrean, Keio University

Cancer Lett. 2024 Aug 08. pii: S0304-3835(24)00551-2. [Epub ahead of print] 217156

Glycolysis, The Sweet Appetite of the Tumour Microenvironment.

Zeinab Kooshan, Lilibeth Cárdenas-Piedra, Judith Clements, Jyotsna Batra.

Cancer cells display an altered metabolic phenotype, characterised by increased glycolysis and lactate production, even in the presence of sufficient oxygen - a phenomenon known as the Warburg effect. This metabolic reprogramming is a crucial adaptation that enables cancer cells to meet their elevated energy and biosynthetic demands. Importantly, the tumor microenvironment plays a pivotal role in shaping and sustaining this metabolic shift in cancer cells. This review explores the intricate relationship between the tumor microenvironment and the Warburg effect, highlighting how communication within this niche regulates cancer cell metabolism and impacts tumor progression and therapeutic resistance. We discuss the potential of targeting the Warburg effect as a promising therapeutic strategy, with the aim of disrupting the metabolic advantage of cancer cells and enhancing our understanding of this complex interplay within the tumor microenvironment.

Keywords: Glucose metabolism; Warburg effect; cancer therapy; clinical implications; hypoxia; tumour microenvironment

DOI: https://doi.org/10.1016/j.canlet.2024.217156

Trends Endocrinol Metab. 2024 Aug 08. pii: S1043-2760(24)00197-8. [Epub ahead of print]

Adapt and shape: metabolic features within the metastatic niche.

Erica Pranzini, Luigi Ippolito, Elisa Pardella, Elisa Giannoni, Paola Chiarugi.

The success of disseminating cancer cells (DTCs) at specific metastatic sites is influenced by several metabolic factors. Even before DTCs arrival, metabolic conditioning from the primary tumor participates in creating a favorable premetastatic niche at distant organs. In addition, DTCs adjust their metabolism to better survive along the metastatic journey and successfully colonize their ultimate destination. However, the idea that the environment of the target organs may metabolically impact the metastatic fate is often underestimated. Here, we review the coexistence of two distinct strategies by which cancer cells shape and/or adapt to the metabolic profile of colonized tissues, ultimately creating a proper soil for their seeding and proliferation.

Keywords: metabolic adaptation; metastatic niche; nutrient availability; organotropism; tissue metabolism

DOI: https://doi.org/10.1016/j.tem.2024.07.016

bioRxiv. 2024 Jul 30. pii: 2024.07.29.605645. [Epub ahead of print]

Senescent fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity.

Jin Young Lee, Nabora Reyes, Sang-Ho Woo, Sakshi Goel, Fia Stratton, Chaoyuan Kuang, Aaron S Mansfield, Lindsay M LaFave, Tien Peng.

Senescence has been demonstrated to either inhibit or promote tumorigenesis. Resolving this paradox requires spatial mapping and functional characterization of senescent cells in the native tumor niche. Here, we identified senescent p16 Ink4a + cancer-associated fibroblasts with a secretory phenotype that promotes fatty acid uptake and utilization by aggressive lung adenocarcinoma driven by Kras and p53 mutations. Furthermore, rewiring of lung cancer metabolism by p16 Ink4a + cancer-associated fibroblasts also altered tumor cell identity to a highly plastic/dedifferentiated state associated with progression in murine and human LUAD. Our ex vivo senolytic screening platform identified XL888, a HSP90 inhibitor, that cleared p16 Ink4a + cancer-associated fibroblasts in vivo. XL888 administration after establishment of advanced lung adenocarcinoma significantly reduced tumor burden concurrent with the loss of plastic tumor cells. Our study identified a druggable component of the tumor stroma that fulfills the metabolic requirement of tumor cells to acquire a more aggressive phenotype.

DOI: https://doi.org/10.1101/2024.07.29.605645

FEBS J. 2024 Aug 11.

Manipulating mannose metabolism as a potential anticancer strategy.

Yoichiro Harada.

Cancer cells acquire metabolic advantages over their normal counterparts regarding the use of nutrients for sustained cell proliferation and cell survival in the tumor microenvironment. Notable among the metabolic traits in cancer cells is the Warburg effect, which is a reprogrammed form of glycolysis that favors the rapid generation of ATP from glucose and the production of biological macromolecules by diverting glucose into various metabolic intermediates. Meanwhile, mannose, which is the C-2 epimer of glucose, has the ability to dampen the Warburg effect, resulting in slow-cycling cancer cells that are highly susceptible to chemotherapy. This anticancer effect of mannose appears when its catabolism is compromised in cancer cells. Moreover, de novo synthesis of mannose within cancer cells has also been identified as a potential target for enhancing chemosensitivity through targeting glycosylation pathways. The underlying mechanisms by which alterations in mannose metabolism induce cancer cell vulnerability are just beginning to emerge. This review summarizes the current state of our knowledge of mannose metabolism and provides insights into its manipulation as a potential anticancer strategy.

Keywords: Warburg effect; cancer; chemotherapy; glucose; glycolysis; glycosylation; mannose; metabolism; tumor

DOI: https://doi.org/10.1111/febs.17230

J Biol Chem. 2024 Aug 09. pii: S0021-9258(24)02171-9. [Epub ahead of print] 107670

Emerging roles for Mitochondrial Rho GTPases in tumor biology.

Dillon P Boulton, M Cecilia Caino.

Mitochondrial Rho GTPases (MIRO1 and MIRO2) are primarily studied for their role as resident mitochondrial anchor proteins that facilitate mitochondria trafficking in neurons. However, it is now appreciated that these proteins have critical roles in cancer. In this review, we focus on examining the role of MIROs in cancer, including expression changes in tumors and the molecular mechanisms by which MIROs impact tumor cell growth, invasion, and metastasis. Additionally, we give an overview of how MIRO's functions in normal cells within the tumor microenvironment can support or inhibit tumor growth and metastasis. Although this is still an emerging field, the current consensus is that the MIROs primarily promote tumor progression of disparate tumor types. As mitochondrial proteins are now being targeted in the clinic, we discuss their potential as novel proteins to target in cancer.

Keywords: MIRO1; MIRO2; cancer; metastasis; mitochondria

DOI: https://doi.org/10.1016/j.jbc.2024.107670