ELUCIDATING MECHANISMS OF METASTASIS WITH IMPLANTABLE BIOMATERIAL NICHES

Metastasis is the leading cause of cancer related deaths, yet it 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 observed in patients. Mouse models have been widely used to study cancer, however they are critically limited to study metastasis. Most models generate aggressive metastases in the lung without the use of unique cell lines or specialized injection techniques. This limits the ability to study disseminated tumor cells (DTCs) in other relevant metastasis prone tissues. Prolonged observation of the post-dissemination phase of cancer cell biology and the dormant-to-active transition are additional challenges to study in mouse models due to the rapid onset of actively growing primary and secondary tumors that shorten the experimental timeframe. These limitations have left a critical gap in the understanding of metastasis, specifically the long-term bi-directional crosstalk between DTCs and their local microenvironment. Previous findings have demonstrated that subcutaneously implanted inverted colloidal crystal (ICC) hydrogel scaffolds recruit circulating tumor cells and capture metastatic progression. Here, I introduce new implantable tissue engineered metastasis models that overcome the fundamental restrictions of existing mouse models and substantiate the role of the tumor niche in the reactivation of dormant DTCs with molecular and cellular detail. Throughout my dissertation work I engineered DTC niches leveraging ICC scaffolds to identify critical niche components that enable metastatic progression. Changing the anatomical location of the implant yielded unique microenvironments with varying levels of metastatic potential. In a secondary approach, I utilized the immunomodulatory properties of ICC scaffolds to assist the transplantation of adult lung and liver tissues into the subcutaneous space for prolonged study of metastasis-relevant tissues. Next, I leveraged the transplantable nature of scaffold niches to investigate DTC dormancy and potential triggers of metastatic relapse. I developed a fully humanized mouse model to explore local niche evolution as human DTCs progress from single cells to small colonies and overt metastases. The local vasculature and Ly6G+ cells were observed to play important roles during each step of the transition to aggressive proliferation. The effect of adjuvant chemotherapy and surgical disruption on DTCs and their niche was also explored by using a fully immunocompetent mouse model. Lastly, I improved the fabrication of ICC hydrogel scaffolds to make the process more scalable for widespread use. The use of expanded polystyrene beads enabled cheaper, faster, and safer production of ICC hydrogel scaffolds. Tissue engineering approaches to recreate in vivo DTC microenvironments represent an exciting opportunity to better understand metastasis. The presented models and techniques may be enabling tools to aid in the development of anti-metastasis therapies that significantly benefit patient health

Public priorities on locally-driven sea level rise planning on the East Coast of the United States

Sea level rise poses a substantial concern to communities worldwide. Increased inundation, storm surge, saltwater intrusion, and other impacts create challenges which will require considerable planning to address. Recognizing the broad and differing scope of sea level rise issues and the variability of policy options to address them, local planning frameworks are necessary in addition to tools and resources available from state and federal governments. To help assess priorities and preferences on sea level rise planning, a survey of 503 persons affiliated with coastal communities on the East Coast of the United States was conducted in December 2017. This survey studied key aspects locally-driven sea level rise plans, including planning priorities, funding options, methods to resolve conflict, and potential responses. Six key findings address these and other concerns to provide the foundation of a locally driven framework for public officials

An ALMA Constraint on the GSC 6214-210 B Circum-Substellar Accretion Disk Mass

We present Atacama Large Millimeter/submillimeter Array (ALMA) observations of GSC 6214-210 A and B, a solar-mass member of the 5-10 Myr Upper Scorpius association with a 15 $\pm$ 2 Mjup companion orbiting at $\approx$330 AU (2.2"). Previous photometry and spectroscopy spanning 0.3-5 $\mu$m revealed optical and thermal excess as well as strong H$\alpha$ and Pa~$\beta$ emission originating from a circum-substellar accretion disk around GSC 6214-210 B, making it the lowest mass companion with unambiguous evidence of a subdisk. Despite ALMA's unprecedented sensitivity and angular resolution, neither component was detected in our 880 $\mu$m (341 GHz) continuum observations down to a 3-$\sigma$ limit of 0.22 mJy/beam. The corresponding constraints on the dust mass and total mass are <0.15 Mearth and <0.05 Mjup, respectively, or <0.003% and <0.3% of the mass of GSC 6214-210 B itself assuming a 100:1 gas-to-dust ratio and characteristic dust temperature of 10-20 K. If the host star possesses a putative circum-stellar disk then at most it is a meager 0.0015% of the primary mass, implying that giant planet formation has certainly ceased in this system. Considering these limits and its current accretion rate, GSC 6214-210 B appears to be at the end stages of assembly and is not expected to gain any appreciable mass over the next few Myr.Comment: Accepted to ApJ