Differentiation therapy utilizes our understanding of the hierarchy of cellular systems to pharmacologically induce a shift toward terminal commitment. While this approach has been a paradigm in treating certain hematological malignancies, efforts to translate this success to solid tumors have met with limited success. Mammary-specific activation of PKA in mouse models leads to aberrant differentiation and diminished self-renewing potential of the basal compartment, which harbors mammary repopulating cells. PKA activation results in tumors that are more benign, exhibiting reduced metastatic propensity, loss of tumor-initiating potential, and increased sensitivity to chemotherapy. Analysis of tumor histopathology revealed features of overt differentiation with papillary characteristics. Longitudinal single-cell profiling at the hyperplasia and tumor stages uncovered an altered path of tumor evolution whereby PKA curtails the emergence of aggressive subpopulations. Acting through the repression of SOX4, PKA activation promotes tumor differentiation and represents a possible adjuvant to chemotherapy for certain breast cancers.

分化疗法利用我们对细胞系统层次结构的理解，在药理学上诱导向终末承诺转变。虽然这种方法已成为治疗某些血液系统恶性肿瘤的范例，但将这种成功转化为实体瘤的努力取得了有限的成功。小鼠模型中 PKA 的乳腺特异性激活导致基底区室的异常分化和自我更新潜力减弱，基底区室含有乳腺再生细胞。PKA 激活导致肿瘤更加良性，表现出降低的转移倾向、肿瘤起始潜能的丧失以及对化疗的敏感性增加。肿瘤组织病理学分析显示具有乳头状特征的明显分化特征。增生和肿瘤阶段的纵向单细胞分析揭示了肿瘤进化的改变路径，由此 PKA 减少了侵袭性亚群的出现。通过抑制 SOX4，PKA 激活促进肿瘤分化并代表某些乳腺癌化疗的可能辅助手段。