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Tackling tumor heterogeneity and phenotypic plasticity in cancer precision medicine: our experience and a literature review

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Abstract

The predominant cause of cancer mortality is metastasis. The major impediment to cancer cure is the intrinsic or acquired resistance to currently available therapies. Cancer is heterogeneous at the genetic, epigenetic, and metabolic levels. And, while a molecular-targeted drug may be pathway-precise, it can still fail to achieve wholesome cancer-precise toxicity. In the current review, we discuss the strategic differences between targeting the strengths of cancer cells in phenotypic plasticity and heterogeneity and targeting shared vulnerabilities of cancer cells such as the compromised integrity of membranous organelles. To better recapitulate subpopulations of cancer cells in different phenotypic and functional states, we developed a schematic combination of 2-dimensional culture (2D), 3-dimmensional culture in collagen I (3D), and mammosphere culture for stem cells (mammosphere), designated as Scheme 2D/3D/mammosphere. We investigated how the tumor suppressor maspin may limit carcinoma cell plasticity and affect their context-dependent response to drugs of different mechanisms including docetaxel, histone deacetylase (HDAC) inhibitor MS-275, and ionophore antibiotic salinomycin. We showed that tumor cell phenotypic plasticity is not an exclusive attribute to cancer stem cells. Nonetheless, three subpopulations of prostate cancer cells, enriched through Scheme 2D/3D/mammosphere, show qualitatively different drug responses. Interestingly, salinomycin was the only drug that effectively killed all three cancer cell subpopulations, irrespective of their capacity of stemness. Further, Scheme 2D/3D/mammosphere may be a useful model to accelerate the screening for curative cancer drugs while avoiding costly characterization of compounds that may have only selective toxicity to some, but not all, cancer cell subpopulations.

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Financial support

This work was supported by the NIH Grant P30CA022453 (to the Karmanos Cancer Institute (KCI) with Sheng, S. as a program leader), the Ruth Sager Memorial Fund (to Sheng, S.), the KCI Pilot Project Grant 25S5Z (to Sheng, S.), the KCI Prostate Cancer Research Pilot Project Grant (to Sheng, S.), and the KCI Tumor Biology and Microenvironment Program Pilot Project (to Sheng, S).

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Authors and Affiliations

  1. Department of Pathology, Wayne State University School of Medicine, 540 East Canfield Avenue, Detroit, MI, 48201, USA

    Shijie Sheng & M. Margarida Bernardo

  2. Department of Oncology, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Shijie Sheng, Sijana H. Dzinic, Kang Chen, Elisabeth I. Heath & Wael A. Sakr

  3. Tumor Biology and Microenvironment Program, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Shijie Sheng, M. Margarida Bernardo, Sijana H. Dzinic & Wael A. Sakr

  4. Molecular Therapeutics Program of the Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Sijana H. Dzinic, Kang Chen & Elisabeth I. Heath

  5. Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Kang Chen

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  1. Shijie Sheng
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Sheng, S., Margarida Bernardo, M., Dzinic, S.H. et al. Tackling tumor heterogeneity and phenotypic plasticity in cancer precision medicine: our experience and a literature review. Cancer Metastasis Rev 37, 655–663 (2018). https://doi.org/10.1007/s10555-018-9767-4

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