Highly tumorigenic, drug‐resistant cancer stem‐like cells drive cancer progression. These aggressive cells can arise repeatedly from bulk tumor cells independently of mutational events, suggesting an epigenetic mechanism. To test this possibility, we studied bladder cancer cells as they cyclically shifted to and from a cancer stem‐like phenotype, and we discovered that these two states exhibit distinct DNA methylation and chromatin accessibility. Most differential chromatin accessibility was independent of methylation and affected the expression of driver genes such as E2F3, a cell cycle regulator associated with aggressive bladder cancer. Cancer stem‐like cells exhibited increased E2F3 promoter accessibility and increased E2F3 expression that drove cell migration, invasiveness and drug resistance. Epigenetic interference using a DNA methylation inhibitor blocked the transition to a cancer stem‐like state and reduced E2F3 expression. Our findings indicate that epigenetic plasticity plays a key role in the transition to and from an aggressive, drug‐resistant phenotype.
Introduction: Breast metastases from primary colorectal carcinoma are extremely rare, with only 45 cases being reported previously. Since the most common malignancy in the breast and axilla is primary breast cancer regardless of cancer history, non-hematologic metastases may be misdiagnosed initially. Nevertheless, differentiating breast metastases from primary breast cancer is crucial because of their differences in prognosis and management. Patient concerns: We present a case of a 44-year-old Asian woman who noticed a new right breast lump after undergoing surgery and chemotherapy for her primary sigmoid colon cancer. Diagnosis: Image and immunohistochemistry findings were consistent with breast metastasis from primary colorectal adenocarcinoma. Interventions: The patient underwent breast tumor excision and reinitiated chemotherapy. Outcomes: The patient's disease progressed despite the interventions. She passed away 7 months after the detection of breast metastasis. Conclusion: When a new breast lesion is detected in patients with colorectal cancer history, the physician should consider the possibility of breast metastasis due to the poor prognosis. If a biopsy is necessary, cancer history should be provided to the clinicians to prevent incorrect pathological interpretation. In establishing the diagnosis, certain immunohistochemical markers have been shown to be sensitive and specific in previously reported cases. The combination of tumor excision and chemotherapy was the most common strategy in managing this condition with inconsistent clinical outcomes.
Genetic mutations have long been recognized as drivers of cancer drug resistance, but recent work has defined additional non-genetic mechanisms of plasticity, wherein cancer cells assume a drug resistant phenotype marked by altered epigenetic and transcriptional states. Currently, little is known about the real-time, dynamic nature of this phenotypic shift. Using a bladder cancer model of nongenetic plasticity, we discovered that rapid transition to drug resistance entails upregulation of mitochondrial gene expression and a corresponding metabolic shift towards the tricarboxylic acid cycle and oxidative phosphorylation. Based on this distinction, we were able to track cancer cell metabolic profiles in real time using fluorescence lifetime microscopy (FLIM). We observed single cells transitioning spontaneously to an oxidative phosphorylation state over hours to days, a trend that intensified with exposure to cisplatin chemotherapy. Conversely, pharmacological inhibition of oxidative phosphorylation significantly reversed the FLIM metabolic signature and reduced cisplatin resistance. These rapid, spontaneous metabolic shifts offer a new means of tracking nongenetic cancer plasticity and forestalling the emergence of drug resistance.
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