Abstract
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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is among the most fatal of all malignancies[1]
Hmga2-deficient tumours formed in the pancreata of KP172CT;Hmga2CK/CK, KPHetCT;Hmga2CK/CK, and KPKOC;Hmga2CK/CK mice with similar rate and morphology and within a comparable time course as in control KP172CT, KPHetCT and KPKOC mice (Fig. 2)
Numerous in vitro studies across several different human cancer types have suggested a role for HMGA2 in controlling phenotypes associated with malignant transformation and metastasis[32,36,42,46,47]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is among the most fatal of all malignancies[1]. Pancreas-specific expression of oncogenic KrasG12D and Cre/loxP-based inactivation of the tumour suppressors that are frequently inactivated in human PDAC results in the development of murine PDAC that is histologically and molecularly similar to the human disease[18,19] These models recapitulate the entire course of the disease, from the development of preneoplastic lesions to invasive carcinomas and the development of widespread metastatic www.nature.com/scientificreports/. Using genetically engineered mouse models, we defined a transient, Hmga2-positive subpopulation of PDAC cells that has increased metastatic ability[13] It remains unclear whether Hmga[2] is a functionally important driver of the pro-metastatic properties of these cells or only a marker of this state. The absence of Hmga[2] did not dramatically alter the response of autochthonous PDAC to gemcitabine treatment
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