title: Metastatic progression is associated with dynamic changes in the local microenvironment.
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.
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Aiello
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Bajor
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Norgard
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Amine
authors.initials: A
authors.lastname: Sahmoud
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Neha
authors.initials: N
authors.lastname: Bhagwat
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Minh N
authors.initials: MN
authors.lastname: Pham
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland 21231, USA.
authors.forename: Toby C
authors.identifier: 0000-0002-1902-2109
authors.initials: TC
authors.lastname: Cornish
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland 21231, USA.
authors.forename: Christine A
authors.identifier: 0000-0002-4672-3023
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Ben Z
authors.initials: BZ
authors.lastname: Stanger
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary*; D019070:Cell Lineage; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents