Abstract
Progenitor-like cancer cells that can survive in reversible quiescence when faced with various challenges in the body are often behind disease progression. A lack of glutamine in culture medium, which eliminates >99.9% of proliferating SUM149 triple-negative breast cancer cells, selects such adaptable, pan-resistant cells. Our data support the hypothesis that a lack of glutamine forces the selection of an epigenetic state that does not require a high level of TET2, thus selecting an “undifferentiated” therapy-resistant phenotype as seen in TET2-mutant cancers. Our data suggesting that highly adaptable cells are generated through reprograming of the epigenome and transcriptome led us to evaluate low-dose 6-mercaptopurine as a potential therapy in our model. We found that a long treatment with low-dose 6-mercaptopurine inhibited the proliferation of these adaptable cells to a greater extent than it inhibited parental cells. Importantly, a small percentage of adaptable cells survived a low-dose 6-mercaptopurine treatment in a reversible quiescence, analogous to the persistence of abnormal progenitor-like cells in inflammatory bowel disease, which stays in a durable remission with a 6-mercaptopurine treatment. Based on a biomarkers analysis, a long treatment with 6-mercaptopurine or aspirin partially reversed epithelial to mesenchymal transition in adaptable cancer cells. A cell culture model of adaptable cancer cells that persist in the body will help in discovering superior therapies that can be offered before the disease advances to metastasis.
Highlights
Cancer progression is an evolution-like process, which is shaped by various selection pressures serving as bottlenecks [1,2,3,4,5,6]. Whether it is primary cancer, minimal residual disease (MRD) that persists after surgery and other therapies, distant metastasis, or even a cancer cell line, all comprise a large percentage of proliferative cells and a very small percentage of other cells whose role can be viewed as the preservation of cancer
We do not know which specific permutations of genetic and epigenetic alterations allowed successful “evolution” under this bottleneck in individual cells, our gene expression and gene amplification/deletion data obtained with the Metabolically adaptable (MA) cells, along with the results of our functional studies with MA cells summarized in the Introduction, are very informative in guiding our thinking about the mechanisms that enable cell survival and adaptation under a severe metabolic bottleneck [11,12,13,14]
We recently reported that glutamine deprivation in this cell line selected rare metabolically adaptable cancer cells termed FC-IBC02MA, which are resistant to doxorubicin, like SUM149MA cells [14]
Summary
Cancer progression is an evolution-like process, which is shaped by various selection pressures serving as bottlenecks [1,2,3,4,5,6]. While primary breast cancer is removed surgically, the presence of MRD could offer an opportunity for therapeutic intervention at a point when the disease is more treatable than metastasis [7,8,9]. This would require the ability to distinguish poorprognosis MRD at high risk for metastasis from the MRD that does not lead to metastasis as well as the ability to disable poor-prognosis MRD with safe therapies. The approach relies essentially on three elements: 1) choice of resistant cell lines that have a high capacity to generate cellular diversity; 2) selection of rare, highly evolvable cancer cells that survive and overcome a bottleneck in the form of a severe metabolic challenge; and 3) evaluation www.oncotarget.com of potential therapeutic agents in long-term assays so as to reveal their efficacy on evolvable cells rather than proliferative cells
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