Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 11, 2024

Abstract The ability of CD8 + T cells to infiltrate solid tumors and reach cancer is associated with improved patient survival responses immunotherapy. Thus, identifying the factors controlling cell migration in critical, so that strategies intervene on these targets can be developed. Although interstitial motility a highly energy-demanding process, metabolic requirements migrating 3D environment remain unclear. Here, we demonstrate tricarboxylic acid (TCA) cycle main pathway sustaining human collagen gels tumor slices while glycolysis plays more minor role. Using pharmacological genetic approaches, report depends mitochondrial oxidation glucose glutamine, but not fatty acids, both ATP ROS produced by mitochondria are required for migrate. Pharmacological interventions increase activity improve intratumoral CAR recruitment into islets leading better control growth xenograft models. Our study highlights rationale targeting metabolism enhance antitumor efficacy treating tumors.

Language: Английский

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Therapeutic Targeting of Hypoxia-Inducible Factors in Cancer

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(4), P. 2060 - 2060

Published: Feb. 8, 2024

In the realm of cancer therapeutics, targeting hypoxia-inducible factor (HIF) pathway has emerged as a promising strategy. This study delves into intricate web HIF-associated mechanisms, exploring avenues for future anticancer therapies. Framing investigation within broader context progression and hypoxia response, this article aims to decipher pivotal role played by HIF in regulating genes influencing angiogenesis, cell proliferation, glucose metabolism. Employing diverse approaches such inhibitors, anti-angiogenic therapies, hypoxia-activated prodrugs, research methodologically intervenes at different nodes pathway. Findings showcase efficacy agents like EZN-2968, Minnelide, Acriflavine modulating HIF-1α protein synthesis destabilizing HIF-1, providing preliminary proof mRNA modulation antitumor activity. However, challenges, including toxicity, necessitate continued exploration development, exemplified ongoing clinical trials. concludes emphasizing potential targeted therapies disrupting cancer-related signaling pathways.

Language: Английский

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Increased dosage of DYRK1A leads to congenital heart defects in a mouse model of Down syndrome

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(731)

Published: Jan. 24, 2024

Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21). DS a gene dosage disorder that results in multiple phenotypes including congenital heart defects. This clinically important cardiac pathology the result third copy one or more approximately 230 genes on Hsa21, but identity causative dosage–sensitive and hence mechanisms underlying this remain unclear. Here, we show hearts from fetuses with embryonic Dp1Tyb mouse model reduced expression mitochondrial respiration cell proliferation genes. Using systematic genetic mapping, determined three copies dual-specificity tyrosine phosphorylation–regulated kinase 1A ( Dyrk1a ) gene, encoding serine/threonine protein kinase, are associated disease pathology. In embryos mice, reducing number to two reversed defects cellular cardiomyocytes rescued septation Increased DYRK1A resulted impairment function mice DS, suggesting may be useful therapeutic target for treating common condition.

Language: Английский

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Hypoxia promotes non-small cell lung cancer cell stemness, migration, and invasion via promoting glycolysis by lactylation of SOX9

Cancer Biology & Therapy, Journal Year: 2024, Volume and Issue: 25(1)

Published: Jan. 16, 2024

Background Lung cancer is the deadliest form of malignancy and most common subtype non-small cell lung (NSCLC). Hypoxia a typical feature solid tumor microenvironment. In current study, we clarified effects hypoxia on stemness metastasis molecular mechanism.

Language: Английский

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Energy metabolism in health and diseases

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 18, 2025

Language: Английский

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