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.

The role of stromal cancer-associated fibroblasts in pancreatic cancer

“…Unique and dynamic features of stromal components of the metastatic lesions themselves are also beginning to be described [33, 39, 43]. Aiello et al characterized stroma within metastatic lesions in an autochthonous model of PDAC.…”

“…They showed that myofibroblasts appear when metastases are as small as 6–7 cells and that cell populations within these lesions become more epithelial during growth. They found that stromal volume, including cellular and extracellular components, eventually reaches levels similar to primary lesions [43]. Heeg et al found that overexpression of transcription factor ETV1 drastically increased the incidence and volume of micro- and macrometastasis in mouse models.…”

“…Most recently, Aiello et al demonstrated in mouse models a widespread reduction in metastases with chemotherapy administration both in lesions with minimal and dense stroma. Little is known though about the character and function of stroma within PDAC metastases [43]. Zechner et al did find that, within primary tumors treated with a combination of metformin and gemcitabine, metformin better inhibited cancer cells near the desmoplastic stroma, whereas gemcitabine inhibited proliferation in cells distant to the stroma [48].…”

Cancer Manipulation of Host Physiology: Lessons from Pancreatic Cancer

“…For example, in both murine and human PDAC, the metastatic liver has been shown to exhibit significant alterations in its microarchitecture that are evident even with isolated tumor cells [70, 76]; these include the deposition of various ECM proteins (such as HA, collagen I and fibronectin), and activation of myofibroblast-like cells, as well as infiltrating immune cells [70, 76]. These changes are remarkable in that they have been shown to promote the engraftment of pancreatic cancer cells in mouse models and thus, constitute a defining characteristic of the hepatic premetastatic niche [77, 78].…”

“…These changes are remarkable in that they have been shown to promote the engraftment of pancreatic cancer cells in mouse models and thus, constitute a defining characteristic of the hepatic premetastatic niche [77, 78]. Successful treatment of liver metastases in mice leads to regression of metastasis-associated ECM changes, attesting to the addiction of pancreatic cancer cells to desmoplasia [76]. …”