Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Sci Rep. 2018 Sep 18;8(1):14008. doi: 10.1038/s41598-018-32159-x.
Expression of the chromatin-associated protein HMGA2 correlates with progression, metastasis and therapy resistance in pancreatic ductal adenocarcinoma (PDAC). Hmga2 has also been identified as a marker of a transient subpopulation of PDAC cells that has increased metastatic ability. Here, we characterize the requirement for Hmga2 during growth, dissemination, and metastasis of PDAC in vivo using conditional inactivation of Hmga2 in well-established autochthonous mouse models of PDAC. Overall survival, primary tumour burden, presence of disseminated tumour cells in the peritoneal cavity or circulating tumour cells in the blood, and presence and number of metastases were not significantly different between mice with Hmga2-wildtype or Hmga2-deficient tumours. Treatment of mice with Hmga2-wildtype and Hmga2-deficient tumours with gemcitabine did not uncover a significant impact of Hmga2-deficiency on gemcitabine sensitivity. Hmga1 and Hmga2 overlap in their expression in both human and murine PDAC, however knockdown of Hmga1 in Hmga2-deficient cancer cells also did not decrease metastatic ability. Thus, Hmga2 remains a prognostic marker which identifies a metastatic cancer cell state in primary PDAC, however Hmga2 has limited if any direct functional impact on PDAC progression and therapy resistance.
染色质相关蛋白 HMGA2 的表达与胰腺导管腺癌 (PDAC) 的进展、转移和治疗耐药性相关。Hmga2 也被确定为 PDAC 细胞短暂亚群的标志物，该亚群具有增加的转移能力。在这里，我们使用在已建立的 PDAC 自发模型中条件性失活 Hmga2 来表征 HMGA2 在 PDAC 体内生长、扩散和转移中的需求。在 Hmga2 野生型或 Hmga2 缺失型肿瘤小鼠中，总体存活率、原发性肿瘤负担、腹腔内播散性肿瘤细胞的存在或血液中循环肿瘤细胞的存在以及转移的存在和数量均无显著差异。用吉西他滨治疗 Hmga2 野生型和 Hmga2 缺失型肿瘤的小鼠并未发现 Hmga2 缺失对吉西他滨敏感性有显著影响。Hmga1 和 Hmga2 在人类和鼠 PDAC 中的表达存在重叠，但在 Hmga2 缺失型癌细胞中敲低 Hmga1 也不会降低转移能力。因此，HMGA2 仍然是一个预后标志物，它在原发性 PDAC 中识别出一种转移性癌细胞状态，但 Hmga2 对 PDAC 进展和治疗耐药性的直接功能影响有限，如果有的话。
