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, Ben Z. Stanger

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number12819
JournalNature Communications
Volume7
DOIs
StatePublished - Sep 15 2016

Fingerprint

Chemotherapy
metastasis
gemcitabine
progressions
lesions
chemotherapy
Adjuvant Chemotherapy
Neoplasm Metastasis
death
Histology
Adenocarcinoma
Cell death
cancer
Drug delivery
Tumors
Neoplasms
Neoplasm Micrometastasis
histology
Cells
tracing

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Aiello, N. M., Bajor, D. L., Norgard, R. J., Sahmoud, A., Bhagwat, N., Pham, M. N., ... Stanger, B. Z. (2016). Metastatic progression is associated with dynamic changes in the local microenvironment. Nature Communications, 7, [12819]. https://doi.org/10.1038/ncomms12819

Metastatic progression is associated with dynamic changes in the local microenvironment. / Aiello, Nicole M.; Bajor, David L.; Norgard, Robert J.; Sahmoud, Amine; Bhagwat, Neha; Pham, Minh N.; Cornish, Toby C.; Iacobuzio-Donahue, Christine A.; Vonderheide, Robert H.; Stanger, Ben Z.

In: Nature Communications, Vol. 7, 12819, 15.09.2016.

Research output: Contribution to journalArticle

Aiello, NM, Bajor, DL, Norgard, RJ, Sahmoud, A, Bhagwat, N, Pham, MN, Cornish, TC, Iacobuzio-Donahue, CA, Vonderheide, RH & Stanger, BZ 2016, 'Metastatic progression is associated with dynamic changes in the local microenvironment', Nature Communications, vol. 7, 12819. https://doi.org/10.1038/ncomms12819
Aiello NM, Bajor DL, Norgard RJ, Sahmoud A, Bhagwat N, Pham MN et al. Metastatic progression is associated with dynamic changes in the local microenvironment. Nature Communications. 2016 Sep 15;7. 12819. https://doi.org/10.1038/ncomms12819
Aiello, Nicole M. ; Bajor, David L. ; Norgard, Robert J. ; Sahmoud, Amine ; Bhagwat, Neha ; Pham, Minh N. ; Cornish, Toby C. ; Iacobuzio-Donahue, Christine A. ; Vonderheide, Robert H. ; Stanger, Ben Z. / Metastatic progression is associated with dynamic changes in the local microenvironment. In: Nature Communications. 2016 ; Vol. 7.
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