Metastatic progression is associated with dynamic changes in the local microenvironment. Nat Commun 2016 Sep 15;7:12819
Date
09/16/2016Pubmed ID
27628423Pubmed Central ID
PMC5027614DOI
10.1038/ncomms12819Scopus ID
2-s2.0-84987786814 (requires institutional sign-in at Scopus site) 103 CitationsAbstract
Most cancer-associated deaths result from metastasis. However, it remains unknown whether the size, microenvironment or other features of a metastatic lesion dictate its behaviour or determine the efficacy of chemotherapy in the adjuvant (micrometastatic) setting. Here we delineate the natural history of metastasis in an autochthonous model of pancreatic ductal adenocarcinoma (PDAC), using lineage tracing to examine the evolution of disseminated cancer cells and their associated microenvironment. With increasing size, lesions shift from mesenchymal to epithelial histology, become hypovascular and accumulate a desmoplastic stroma, ultimately recapitulating the primary tumours from which they arose. Moreover, treatment with gemcitabine and nab-paclitaxel significantly reduces the overall number of metastases by inducing cell death in lesions of all sizes, challenging the paradigm that PDAC stroma imposes a critical barrier to drug delivery. These results illuminate the cellular dynamics of metastatic progression and suggest that adjuvant chemotherapy affords a survival benefit by directly targeting micrometastases.
Author List
Aiello NM, Bajor DL, Norgard RJ, Sahmoud A, Bhagwat N, Pham MN, Cornish TC, Iacobuzio-Donahue CA, Vonderheide RH, Stanger BZAuthor
Toby Charles Cornish MD, PhD Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AgedAnimals
Antineoplastic Agents
Carcinoma, Pancreatic Ductal
Cell Lineage
Female
Humans
Liver
Liver Neoplasms
Male
Mice
Middle Aged
Neoplasm Metastasis
Pancreatic Neoplasms
Tumor Microenvironment
