Abstract 3748: Implantable tumor attracting niche models to study disseminated tumor cell biology
Authors: Carpenter Ryan , Lee Jungwoo 
Published: August 2019

Metastasis is the leading cause of death in cancer but remains the most poorly understood aspect of tumor biology. This can be attributed to the lack of relevant experimental models that can recapitulate the complex and lengthy progression of metastatic relapse. Mouse models have been widely used to study metastasis, however they are limited for prolonged investigation of the post-dissemination phase of cancer cell biology due to the rapid onset of actively growing primary and secondary tumors. This limitation has left a critical gap in understanding the long-term bi-directional crosstalk between DTCs and their local microenvironment due to the relatively short experimental timeframe. Here we introduce an implantable tissue engineered metastasis model that can overcome the fundamental restrictions of existing mouse models and substantiate the role of the tumor microenvironment in the reactivation of dormant DTCs with molecular and cellular detail.

Subcutaneous implantation of porous collagen-coated acrylamide scaffolds, fabricated as previously described (1-3), modulate the foreign body response to induce the formation of a robust vascularized tissue. During tissue formation and local inflammation, the scaffold generates a pre-metastatic niche, characterized by the recruitment of circulating tumor cells and given time, the formation of overt metastases. However, mice became moribund before meaningful investigation of dormant tumor cell biology could occur due to increasing tumor burden. We addressed this limitation via intact transplantation of the DTC microenvironment to tumor-free mice. Scaffolds have been maintained in secondary mice for up to 10 weeks. Compared to transplanted DTC-bearing lung tissue, scaffolds maintained an inactive phenotype for longer periods. At the end of this period, transplanted scaffolds captured three distinct DTC phenotypes: dormant, early colonization, and overt metastasis. Multiplex immunohistostaining was used to dissect the local microenvironment during the transition from single DTCs to overt metastasis. The local vasculature and Ly6G+ cells were observed to have differential roles during metastatic development. These experiments have been demonstrated in humanized NSG mouse models capable of generating scaffold niches containing human stromal, tumor (PC-3), and immune cells, as well as a spontaneous tumor model (MMTV-PyMT) with an intact immune system.

Our results demonstrate the potential of a tissue engineering approach to generate pre-metastatic niches and investigate the transient activity of the DTC niche during tumor cell awakening and subsequent metastasis. We envision that implantable microenvironments will be an enabling tool to study DTC biology and aid in the development of anti-metastatic therapies.

References: Carpenter R. Nat. Biomed. Eng, 2018. (2) Lee J. PNAS, 109(48), 19638-43, 2012. (3) Bersani F. Cancer Research, 74(24), 7229-38, 2014.

Citation Format: Ryan Carpenter, Jungwoo Lee. Implantable tumor attracting niche models to study disseminated tumor cell biology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3748.