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The circadian clock circuitry deconvolutes colorectal cancer and lung adenocarcinoma heterogeneity in a dynamic time-related framework

Cancer Gene Therapy volume 30, pages 1323–1329 (2023)Cite this article

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Abstract

Increasing evidence imputes cancer progression and resistance to therapy to intra-tumor molecular heterogeneity set off by cancer cell plasticity. Re-activation of developmental programs strictly linked to epithelial-to-mesenchymal transition and gaining of stem cells properties are crucial in this setting. Many biological processes involved in cancer onset and progression show rhythmic fluctuations driven by the circadian clock circuitry. Novel cancer patient stratification tools taking into account the temporal dimension of these biological processes are definitely needed. Lung cancer and colorectal cancer (CRC) are the leading causes of cancer death worldwide. Here, by developing an innovative computational approach we named Phase-Finder, we show that the molecular heterogeneity characterizing the two deadliest cancers, CRC and lung adenocarcinoma (LUAD), rather than a merely stochastic event is the readout of specific cancer molecular states which correlate with time-qualified patterns of gene expression. We performed time-course transcriptome analysis of CRC and LUAD cell lines and upon computing circadian genes expression-based correlation matrices we derived pseudo-time points to infer time-qualified patterns in the transcriptomic analysis of real-world data (RWD) from large cohorts of CRC and LUAD patients. Our temporal classification of CRC and LUAD cohorts was able to effectively render time-specific patterns in cancer phenotype switching determining dynamical distribution of molecular subtypes impacting patient prognosis.

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Fig. 1: Phase Set Enrichment Analysis (PSEA) and Phase-Finder analysis of CRC transcriptomes.
Fig. 2: Phase Set Enrichment Analysis (PSEA) and Phase-Finder analysis of LUAD transcriptomes.

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Acknowledgements

This work was supported in part by the Italian Minister of Health [Ricerca Corrente program 2022-2024 to FB and GM; Ricerca Finalizzata GR-2016-02363975, RF-2021-12372433 and CLEARLY to FB], by the Associazione Italiana Ricerca sul Cancro (AIRC) [IG-22827 to FB]. The study funders had no role in the design of the study, the collection, analysis, and interpretation of the data, the writing of the manuscript, and the decision to submit the manuscript for publication. All authors gave their consent to publication.

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Author notes

  1. These authors contributed equally: Valentina Melocchi, Roberto Cuttano.

  2. These authors jointly supervised this work: Gianluigi Mazzoccoli, Fabrizio Bianchi.

Authors and Affiliations

  1. Unit of Cancer Biomarkers, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini snc, 71013, San Giovanni Rotondo, FG, Italy

    Valentina Melocchi, Roberto Cuttano & Fabrizio Bianchi

  2. Department of Medical Sciences, Division of Internal Medicine and Chronobiology Laboratory, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini snc, 71013, San Giovanni Rotondo, FG, Italy

    Emanuele Murgo & Gianluigi Mazzoccoli

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  1. Valentina Melocchi
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  2. Roberto Cuttano
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Contributions

Conception and design: GM, FB. Statistical and bioinformatics analyses: VM, RC, EM, FB. Interpretation of data: VM, RC, GM, FB. Writing, review of the manuscript: GM, FB. All authors approved the final version of the manuscript.

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Correspondence to Gianluigi Mazzoccoli or Fabrizio Bianchi.

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Melocchi, V., Cuttano, R., Murgo, E. et al. The circadian clock circuitry deconvolutes colorectal cancer and lung adenocarcinoma heterogeneity in a dynamic time-related framework. Cancer Gene Ther 30, 1323–1329 (2023). https://doi.org/10.1038/s41417-023-00646-7

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