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.
Highlights
epithelialmesenchymal transition (EMT) is believed to play a role in the dissemination of carcinoma cells, it has been observed that metastases tend to exhibit the epithelial histology of their parent primary tumours[7,8,9]
We found that the rate of Ki67 positivity was not significantly different between primary tumours (2.1±1.9), gross metastases (5.4±5.6) and micro-metastases (3.1±5.9), similar to what we observed in mouse pancreatic ductal adenocarcinoma (PDAC)
Most animal studies of metastasis have relied on transplantation of tumour cell lines into recipient animals
Summary
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. We show that treatment with gemcitabine and nab-paclitaxel results in killing of metastatic tumour cells despite the presence of an ostensibly protective microenvironment These results provide insight into the process of metastatic colonization and challenge the hypothesis that stroma acts as a physical barrier to drug delivery
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