科学家发现乳腺肿瘤化疗耐药新机制
乳腺癌患者一旦发生化疗耐药，尤其对于主要依靠化疗的三阴性乳腺癌患者，将是致命的打击。因此，了解乳腺癌化疗耐药机制对于克服该临床难题具有重要意义。虽然既往研究已经发现Notch受体活化与癌症化疗耐药密切相关，但是引起乳腺癌化疗耐药的特定Notch配体及其分子机制仍然扑朔迷离。
2021年1月18日，英国《自然》旗下《自然通讯》在线发表美国宾夕法尼亚大学、基因泰克、福克斯切斯癌症中心、犹他大学、普林斯顿大学康毅滨等学者的研究报告，对引起乳腺癌化疗耐药的特定Notch配体及其分子机制进行了探讨。
该研究利用条件基因敲除和报道基因小鼠模型证实，表达Notch配体δ样蛋白Dll1的肿瘤细胞对于肿瘤生长和转移十分重要，并且与乳腺癌静息肿瘤干细胞非常相似。利用报道基因模型和患者的核糖核酸测序和转座酶染色质高通量测序数据表明，肿瘤坏死因子超家族成员NF-κB激活位于Dll1信号传导通路下游，并与化疗耐药表现型密切相关。利用Dll1单克隆抗体或NF-κB抑制剂IMD-0354，可使Dll1阳性乳腺癌对多柔比星化疗完全缓解。
因此，该研究结果表明，Dll1阳性乳腺癌静息肿瘤干细胞通过NF-κB号传导通路可引起乳腺癌化疗耐药，这将为化疗耐药乳腺癌患者开辟了新的治疗道路。
Nat Commun. 2021 Jan 18;12(1):432.
Dll1+ quiescent tumor stem cells drive chemoresistance in breast cancer through NF-κB survival pathway.
Sushil Kumar, Ajeya Nandi, Snahlata Singh, Rohan Regulapati, Ning Li, John W. Tobias, Christian W. Siebel, Mario Andres Blanco, Andres J. Klein-Szanto, Christopher Lengner, Alana L. Welm, Yibin Kang, Rumela Chakrabarti.
University of Pennsylvania, Philadelphia, PA, USA; Genentech Inc., South San Francisco, CA, USA; Fox Chase Cancer Center, Philadelphia, PA, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Princeton University, Princeton, NJ, USA.
Development of chemoresistance in breast cancer patients greatly increases mortality. Thus, understanding mechanisms underlying breast cancer resistance to chemotherapy is of paramount importance to overcome this clinical challenge. Although activated Notch receptors have been associated with chemoresistance in cancer, the specific Notch ligands and their molecular mechanisms leading to chemoresistance in breast cancer remain elusive. Using conditional knockout and reporter mouse models, we demonstrate that tumor cells expressing the Notch ligand Dll1 is important for tumor growth and metastasis and bear similarities to tumor-initiating cancer cells (TICs) in breast cancer. RNA-seq and ATAC-seq using reporter models and patient data demonstrated that NF-κB activation is downstream of Dll1 and is associated with a chemoresistant phenotype. Finally, pharmacological blocking of Dll1 or NF-κB pathway completely sensitizes Dll1+ tumors to chemotherapy, highlighting therapeutic avenues for chemotherapy resistant breast cancer patients in the near future.
DOI: 10.1038/s41467-020-20664-5