Studies in various model systems have established that the malignant cells within a tumor can exist in distinct states marked by differential growth rates, differentiation states, metastatic potential, and drug sensitivities. For example, subpopulations of tumor cells with dedifferentiated or mesenchymal features, or activated developmental pathways like Notch, Wnt, and Hedgehog, have been described. Further, evidence suggests that tumor cells may be able to interconvert from one subpopulation to another, and ongoing studies are seeking to define therapeutic strategies to target defined subpopulations. However, translating these concepts to the clinic has been challenging because of the difficulty inherent in studying relevant subpopulations in human tumors, a lack of clear biomarkers to distinguish these subpopulations, and a lack of therapies to effectively target them.
A team led by Maheswaran and Haber recently described the use of circulating tumor cell (CTC) capture, coupled with advanced culture methods, to uncover the existence of two functionally defined subpopulations of CTCs from patients with advanced estrogen receptor–positive (ER+), HER2-negative (HER2–) breast cancers. The first subpopulation is defined by the emergence of HER2 expression, activation of multiple receptor tyrosine kinase (RTK) signaling pathways, and rapid proliferation. In contrast, the second subpopulation lacks HER2 expression, shows activated Notch and DNA damage pathways, and proliferates more slowly. Interestingly, cells can interconvert between these functional states rapidly, on the timescale of a few cell divisions. These HER2+ and HER2– cells have comparable tumor-initiating potential, indicating that either population is capable of initiating secondary tumors upon their arrival at a metastatic site, and each express the stem cell marker ALDH1, providing support to the notion that different subpopulations of CTCs can coexist within a given tumor. Further, these CTC subpopulations have distinct drug sensitivities: HER2+ cells are sensitive to cytotoxic chemotherapies like paclitaxel (but not HER2 kinase inhibitors), whereas HER2– cells are resistant to chemotherapy but sensitive to Notch inhibition using gamma secretase inhibitors. Thus, the combination of paclitaxel and Notch inhibition produced sustained tumor growth inhibition that was not observed with either treatment alone.
This work validates and extends previous studies by demonstrating the coexistence of functionally distinct CTC populations within human patients. Importantly, the authors have shown that the plasticity enabling rapid interconversions between these distinct CTC populations is likely to contribute to acquired therapeutic resistance. Moreover, these data provide evidence that combining therapies to simultaneously target distinct CTC populations may improve therapeutic responses in the clinic. This study further raises the possibility that future efforts to inhibit cancer cell plasticity may be a viable strategy for preventing metastatic disease.
N. V. Jordan et al., HER2 expression identifies dynamic functional states within circulating breast cancer cells. Nature 537, 102–106 (2016). [Abstract]
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