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Contact-based thymidylate transfer promotes collective tumor growth

ABSTRACT: Sustained cell proliferation is a fundamental hallmark of cancer, yet its mechanism remains elusive. While tumor cells often cooperate to enhance survival, the specific molecular forces driving this behavior are unknown. We uncover a novel mechanism of tumor growth, that cancer cells proliferate through a contact-dependent transfer of thymidylate (dTMP) via gap junctions with neighboring cells, bypassing canonical biosynthetic and salvage pathways driven by thymidylate synthase (TS) and thymidine kinase (TK1). Importantly, using a genetic mouse model of lung cancer harboring dual TS/TK1 tumor-specific knockout, we show that cancer cells lacking canonical synthesis maintain proliferation. These findings advance the current dogma of a ubiquitous nucleotide-driven activation in cancer, suggesting that a programmed dTMP re-equilibration sustains tumor growth. This novel mechanism could be exploited in cancer therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271721 | GEO | 2024/08/05

REPOSITORIES: GEO

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Project description:Morrison1989 - Folate Cycle The model describes the folate cycle kinetics in breast cancer cells. This model is described in the article: Folate cycle kinetics in human breast cancer cells. Morrison PF, Allegra CJ. J. Biol. Chem. 1989 Jun; 264(18): 10552-10566 Abstract: A mathematical description of polyglutamated folate kinetics for human breast carcinoma cells (MCF-7) has been formulated based upon experimental folate, methotrexate (MTX), purine, and pyrimidine pool sizes as well as reaction rate parameters obtained from intact MCF-7 cells and their enzyme isolates. The schema accounts for the interconversion of highly polyglutamated tetrahydrofolate, 5-methyl-FH4, 5-10-CH2FH4, dihydrofolate (FH2), 10-formyl-FH4 (FFH4), and 10-formyl-FH2 (FFH2), as well as formation and transport of the MTX polyglutamates. Inhibition mechanisms have been chosen to reproduce all observed non-, un-, and pure competition inhibition patterns. Steady state folate concentrations and thymidylate and purine synthesis rates in drug-free intact cells were used to determine normal folate Vmax values. The resulting average-cell folate model, examined for its ability to predict folate pool behavior following exposure to 1 microM MTX over 21 h, agreed well with the experiment, including a relative preservation of the FFH4 and CH2FH4 pools. The results depend strongly on thymidylate synthase (TS) reaction mechanism, especially the assumption that MTX di- and triglutamates inhibit TS synthesis as greatly in the intact cell as they do with purified enzyme. The effects of cell cycle dependence of TS and dihydrofolate reductase activities were also examined by introducing G- to S-phase activity ratios of these enzymes into the model. For activity ratios down to at least 5%, cell population averaged folate pools were only slightly affected, while CH2FH4 pools in S-phase cells were reduced to as little as 10% of control values. Significantly, these folate pool dynamics were indicated to arise from both direct inhibition by MTX polyglutamates as well as inhibition by elevated levels of polyglutamated FH2 and FFH2. Note: two flow BCs were converted into two downstream concentration BCs, thus removing the GAR and dUMP state variables. This dropped the number of ODEs from 21 to 19. This model is hosted on BioModels Database and identified by: BIOMD0000000018. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Contact-based thymidylate transfer promotes collective tumor growth

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