Metastatic progression is associated with dynamic changes in the local microenvironment

Nicole M. Aiello, David L. Bajor, Robert J. Norgard, Amine Sahmoud, Neha Bhagwat, Minh N. Pham, Toby C. Cornish, Christine A. Iacobuzio-Donahue, Robert H. Vonderheide () and Ben Z. Stanger ()
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Nicole M. Aiello: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania
David L. Bajor: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania
Robert J. Norgard: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania
Amine Sahmoud: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania
Neha Bhagwat: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania
Minh N. Pham: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania
Toby C. Cornish: Johns Hopkins University
Christine A. Iacobuzio-Donahue: Johns Hopkins University
Robert H. Vonderheide: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania
Ben Z. Stanger: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms12819

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