Biomaterial Scaffolds Recruit an Aggressive Population of Metastatic Tumor Cells In Vivo

Abstract

For most cancers, metastasis is the point at which clinical treatment shifts from curative intent to extending survival. Biomaterial implants acting as a synthetic premetastatic niche recruit metastatic cancer cells and provide a survival advantage, and their use as a diagnostic platform requires assessing their relevance to disease progression. Here, we showed that scaffold-captured tumor cells (SCAF) were 30 times more metastatic to the lung than primary tumor (PT) cells, similar to cells derived from lung micrometastases (LUNG). SCAF cells were more aggressive in vitro, demonstrated higher levels of migration, invasion, and mammosphere formation, and had a greater proportion of cancer stem cells than PT. SCAF cells were highly enriched for gene expression signatures associated with metastasis and had associated genomic structural changes, including globally enhanced entropy. Collectively, our findings demonstrate that SCAF cells are distinct from PT and more closely resemble LUNG, indicating that tumor cells retrieved from scaffolds are reflective of cells at metastatic sites.

Microporous scaffolds loaded with immunomodulatory lentivirus to study the contribution of immune cell populations to tumor cell recruitment in vivo

“…PCL scaffolds have been employed as a synthetic premetastatic niche (Aguado et al, ; Bushnell et al, ; Rao et al, ), and here, we investigated the ability to deliver lentivirus to achieve sustained transgene expression as outlined in the experimental platform and timeline in Figure . Transgene expression was analyzed after implantation into the fat pad via delivery of FLUC lentivirus and bioluminescence imaging (Figure a).…”

“…Second, strategies to probe the premetastatic niche have often employed genetic modifications that impact the entire organism, typically with off-target effects on primary tumor development (Peinado et al, 2011). Biomaterial scaffolds have recently emerged as tools to investigate tumor cell abundance in predefined sites and to alter the local microenvironment without altering the primary tumor cells or host organism (Aguado, Bushnell, Rao, Jeruss, & Shea, 2017;Aguado et al, 2016;Aguado et al, 2018;Aguado et al, 2015;Azarin et al, 2015;Bersani et al, 2014;Bushnell et al, 2019;Ko et al, 2012;J. Lee et al, 2012;Rao et al, 2016).…”

Cargo-free scaffold implant recruits metastatic cancer cells via lung-mimicking myeloid cell S100A8/A9 axis

“…Our attempts to isolate and expand 4T1 cells directly from diseased lung and scaffold tissue for validation of these results in vivo were unsuccessful due to technical limitations. However, we were able to isolate cancer cells from diseased lung and scaffold using MDA-MB-231BR human breast cancer cells 21 . Both the diseased lung and scaffold isolated cancer cell lines aligned with the lung-tropic gene expression signature, but not the bone-tropic signature, demonstrating the lung-like recruitment mechanism towards the cargo-free scaffold implants in vivo (Fig.…”

Precision health for breast cancer metastasis: biomaterial scaffolds as an engineered metastatic niche to define, study, and monitor metastatic progression

“…These platforms robustly recruit tumor cells across several mouse models of metastasis [1]. Tumor cells recruited to the synthetic niche are representative of metastasis to other organs, and reflect an aggressive population; similar in metastatic ability, behavior in vitro, and transcriptome to breast cancer cells that spontaneously metastasized to the lung [2]. These findings suggest that tumor cells recruited to a synthetic niche could provide a surrogate for tumor cells in occult or relatively inaccessible locations.…”

“…Additionally, the synthetic niche platform has potential benefits beyond enumeration of circulating tumor cells (CTCs) or disseminated tumor cells (DTCs), which has been performed as part of clinical research for more than two decades yet has not been routinely applied in clinical decision making. The presence of an easily accessible metastatic site would facilitate analysis of cells proven to be capable of metastasis [2], which distinguish them from the majority of CTCs and DTCs. Additionally, the analysis of CTCs and DTCs does not account for the microenvironment that tumor cells occupy and co-opt during the metastatic cascade.…”