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Identification of ATF3 as a novel protective signature of quiescent colorectal tumor cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.ORCID iD: 0000-0002-1650-9974
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine. Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, Sichuan, China.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
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2023 (English)In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 14, no 10, article id 676Article in journal (Refereed) Published
Abstract [en]

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of death in the world. In most cases, drug resistance and tumor recurrence are ultimately inevitable. One obstacle is the presence of chemotherapy-insensitive quiescent cancer cells (QCCs). Identification of unique features of QCCs may facilitate the development of new targeted therapeutic strategies to eliminate tumor cells and thereby delay tumor recurrence. Here, using single-cell RNA sequencing, we classified proliferating and quiescent cancer cell populations in the human colorectal cancer spheroid model and identified ATF3 as a novel signature of QCCs that could support cells living in a metabolically restricted microenvironment. RNA velocity further showed a shift from the QCC group to the PCC group indicating the regenerative capacity of the QCCs. Our further results of epigenetic analysis, STING analysis, and evaluation of TCGA COAD datasets build a conclusion that ATF3 can interact with DDIT4 and TRIB3 at the transcriptional level. In addition, decreasing the expression level of ATF3 could enhance the efficacy of 5-FU on CRC MCTS models. In conclusion, ATF3 was identified as a novel marker of QCCs, and combining conventional drugs targeting PCCs with an option to target QCCs by reducing ATF3 expression levels may be a promising strategy for more efficient removal of tumor cells.

Place, publisher, year, edition, pages
Springer Nature, 2023. Vol. 14, no 10, article id 676
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Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-517089DOI: 10.1038/s41419-023-06204-1ISI: 001100416900003PubMedID: 37833290OAI: oai:DiVA.org:uu-517089DiVA, id: diva2:1816526
Funder
Swedish Childhood Cancer Foundation, TJ2021-0111Harald Jeanssons stiftelseGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of Technology, 2022-2229Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of Technology, 2023-2350Swedish Research Council, 2022-00658Swedish Cancer Society, 21 1449PSwedish Cancer Society, 22 0491Available from: 2023-12-03 Created: 2023-12-03 Last updated: 2023-12-04Bibliographically approved

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Lu, XiZhong, LeiLindell, EmmaVeanes, MargusZhao, MiaoSwartling, Fredrik J.Chen, XingqiSjöblom, TobiasZhang, Xiaonan

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Lu, XiZhong, LeiLindell, EmmaVeanes, MargusZhao, MiaoSwartling, Fredrik J.Chen, XingqiSjöblom, TobiasZhang, Xiaonan
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Neurooncology and neurodegenerationCancer precision medicineDepartment of Immunology, Genetics and PathologyMolecular Tools and Functional Genomics
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