Editors' ChoiceCancer

Charting the course of metastatic cells

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Science Translational Medicine  14 Nov 2018:
Vol. 10, Issue 467, eaav9142
DOI: 10.1126/scitranslmed.aav9142


An implantable biomaterial recruits rare tumor cells and enables long-term observation of microenvironmental evolution.

The rules governing cancer metastasis to distant sites remain enigmatic. Of particular interest is the notion that disseminated tumor cells (DTCs) remain largely dormant, but the presence of a nourishing premetastatic niche can transform the quiescent circulating tumor cells into active cells. Immunocompromised mouse models have elucidated key stromal-tumor interactions; however, they are limited in that they always induce both active and dormant DTCs simultaneously. Moreover, metastatic relapse in these mouse models becomes evident only after reactivated DTCs establish a clinically detectable tumor mass. Importantly, current experimental metastasis models are unable to capture the microenvironment-DTC interactions that are critical to the functioning and therapeutic response of tumors. Now, Carpenter et al. report a humanized, implantable biomaterial-based premetastatic niche that recruits circulating tumor cells and provides an opportunity to directly study DTC evolution to lethal metastasis.

The team used a porous hydrogel scaffold that induced vascularized, pro-inflammatory tissue microenvironments upon implantation. These niches were humanized with human bone marrow stromal cell scaffolds and enabled recruitment of tumor cells released from tumor xenografts. The experimental metastasis model recapitulated tumor cell–receptive and supportive functions of the premetastatic niche. The implanted scaffold recruited systemically injected human immune cells into the early-stage humanized DTC niches. The engineered scaffolds allowed for long-term monitoring of DTC niche evolution via serial transplantation, as well as demonstrated that human immune cells can suppress DTC growth. The authors used multiplex imaging to characterize the heterogeneity in metastatic niches, revealing that the tumor microenvironment evolves during the progression to an overt tumor, with the mesenchymal transformation of tumor cells and a continual recruitment of immune cells.

Although in its early stages, the approach could offer a method for quantitative evaluation of therapeutics that target long-term suppression of metastasis. A notable caveat of the current approach is that the extent to which this material induces chronic inflammation is still unknown. This is an important limitation because functional premetastatic niches share pro-inflammatory features observed during implantation and wound healing. Therefore, any material-based inflammation could potentially influence the development of metastatic niche. Other applications of this technology could include testing of therapeutics that target the mechanisms of immune escape and development of safer immunotherapies.

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