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

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.

Keywords: Cancer stem cells; Cancer strength; Cancer vulnerability; Cell death; Cell survival; Docetaxel; Drug resistance; Drug screening strategy; Epithelial-to-mesenchymal transition (EMT); Heterogeneity; Integrity of membranous subcellular structures; MS-275; Maspin; Proliferation; Salinomycin; Scheme 2D/3D/mammosphere; Transient quiescence.

Fig. 1

Multifaceted heterogeneity in cancer phenotypes as the cause of functional gains, survival vulnerabilities, and drug resistance. a Key cellular operatives and mechanisms underlying the functional gains and survival vulnerabilities of cancer cells. b The heterogeneity of cancer cells in the continuum of tumor progression and metastasis that underlie the insufficiency of drugs that targeted subpopulations, but not the whole population of cancer cells. ★ Marks cancer stem cells

Fig. 2

Scheme 2D/3D/mammosphere recapitulates distinct functional states of cancer cells for robust and comprehensive drug screening. a The effects of maspin on context-dependent prostate tumor cell phenotypic plasticity. b The drug response of phenotypically distinct subpopulations of prostate cancer cells in the presence or absence of maspin