A team of researchers led by Jungwoo Lee, an assistant professor in the Chemical Engineering Department and an investigator in the Institute for Applied Life Sciences, has developed an implantable biomaterial that recruits rare tumor cells and enables long-term observation of their micro-environmental evolution, according to highlights in Science Translational Medicine and Nature Biomedical Engineering. The Science Translational Medicine highlight explained that this approach could offer a method for quantitative evaluation of therapeutics that target long-term suppression of metastasis.
The highlight concluded that “Other applications of this technology could include testing of therapeutics that target the mechanisms of immune escape and development of safer immunotherapies.”
The two highlights focused on an article originally published in in the prestigious journal Nature Biomedical Engineering and titled “Implantable pre-metastatic niches for the study of the microenvironmental regulation of disseminated human tumor cells” (or DCTs). The lead author of the Nature Biomedical Engineering article was Lee’s graduate student, Ryan A. Carpenter, and other co-authors were Lee, his undergraduate student Jun-Goo Kwak, and Chemical Engineering Professor Shelly R. Peyton.
As the authors wrote in that Nature Biomedical Engineering paper: “Implantable pre-metastatic niches provide a new opportunity to study DTC activation and evolution to lethal metastasis and could facilitate the development of effective anti-metastatic therapies.”
The Science Translational Medicine highlight also explained some background of this pioneering research. “The rules governing cancer metastasis to distant sites remain enigmatic. Of particular interest is the notion that disseminated tumor DTCs remain largely dormant, but the presence of a nourishing pre-metastatic niche can transform the quiescent circulating tumor cells into active cells.”
As the highlight added: “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 pre-metastatic niche that recruits circulating tumor cells and provides an opportunity to directly study DTC evolution to lethal metastasis.”
Lee and his research team also related that survivors of cancer often carry DTCs. However, these survivors don’t relapse from treatment owing to DTC dormancy.
“Understanding how the local microenvironment regulates the transition of DTCs from a quiescent state to active proliferation could suggest new therapeutic strategies to prevent or delay the formation of metastases,” explained Lee’s research team. “Here, we show that implantable biomaterial microenvironments incorporating human stromal cells, immune cells, and cancer cells can be used to examine the post-dissemination phase of tumor microenvironment evolution.”
Lee and his team went on to explain the lab procedure used. “After subdermal implantation in mice, porous hydrogel scaffolds seeded with human bone marrow stromal cells form a vascularized niche and recruit human circulating tumor cells released from an orthotopic prostate tumor xenograft. Systemic injection of human peripheral blood mononuclear cells slowed the progression of early metastatic niches. However, the rate of overt metastases did not change.”
The Science Translational Medicine highlight expanded on the technology of this procedure. 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 implanted scaffold recruited systemically injected human immune cells into the early-stage humanized DTC niches,” the highlight noted. “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.”
The importance and potential of this work was also detailed in the Nature Biomedical Engineering issue by Dr. David Lyden, a professor at the Weill Cornell Medical College, who first discovered the existence of pre-metastatic niches in 2005.
Dr. Lyden and his colleague Dr. Irina Matei wrote that “Besides better understanding of the factors and forces that control tumor outgrowth verses tumor dormancy at metastatic sites, Lee and colleagues’ humanized pre-metastatic niche should be of immediate interest to researchers who are studying drug-delivery modalities for metastasis prevention in animal models, as it enables a theranostic approach to identify druggable targets to hinder the transition from dormancy to metastasis.”
Moreover, wrote Lyden and Matei, “Because the humanized scaffold can combine the patient’s own tumor, stroma, and immune cells previously conditioned by the primary tumor, the scaffold should be an ideal system for the in vivo testing of responses to immunotherapies.”
Lee, in commenting about his groundbreaking research, also concluded that “The Institute of Applied Life Sciences provides an outstanding research infrastructure and support to independently carry out the cutting-edge interdisciplinary research. We are expecting many more exciting outcomes in the near future by leveraging the given privilege.” (January 2019)