Shannon Stott, PhD
Assistant Professor of Medicine
The Stott laboratory is comprised of bioengineers and chemists focused on translating technological advances to relevant applications in clinical medicine. Specifically, we are interested in using microfluidics and imaging technologies to create tools that increase understanding of cancer biology and of the metastatic process. In collaboration with the Toner, Haber and Maheswaran laboratories, we have developed a microfluidic device that can isolate extraordinary rare circulating tumor cells (CTCs) from the blood of cancer patients. We are striving to employ new imaging modalities to extract as much information as possible from these rare cells while pushing the technology further for early cancer detection. Ultimately, we hope that by working in close partnership with the molecular and cell biologist at the Mass General Cancer Center, we can create new tools that directly impact patient care.
Shannon Stott, PhD
*co-directed with Mehmet Toner, PhD
Rapid technological advances in microfluidics, imaging and digital gene-expression profiling are converging to present new capabilities for blood, tissue and single-cell analysis. Our laboratory is interested in taking these advances and creating new technologies to help build understanding of the metastatic process. Our research focus is on 1) the development and application of microfluidic devices for the isolation and characterization of CTCs, 2) novel imaging strategies to characterize cancer cells and the dynamics of metastasis, and 3) the enrichment and analysis of exosomes and microvesicles using microfluidics.
Microfluidics for Circulating Tumor Cell Analysis
One of the proposed mechanisms of cancer metastasis is the dissemination of tumor cells from the primary organ into the blood stream. A cellular link between the primary malignant tumor and the peripheral metastases has been established in the form of CTCs in peripheral blood. While extremely rare (1 in 10 billion cells), these cells provide a potentially accessible source for early detection, characterization and monitoring of cancers that would otherwise require invasive serial biopsies. The emerging fields of medical technology and microfluidics offer a radically different approach to rare cell detection, which is particularly relevant to the isolation of CTCs. Working in collaboration with Drs. Mehmet Toner, Shyamala Maheswaran and Daniel Haber, we have designed a high throughput microfluidic device, the CTC-Chip, that allows the isolation and characterization of CTCs from the peripheral blood of cancer patients. The chip design was centered on the concept of passive mixing of blood through the generation of microvortices, ultimately improving the capture of rare cells by dramatically increasing the number of interactions between the target CTCs and the antibody-coated substrate. Using blood from patients with metastatic and localized cancer, we have demonstrated the ability to isolate, enumerate and molecularly characterize putative CTCs with high sensitivity and specificity. Additionally, microclusters of CTCs have been captured in a rare number of patient samples. These clusters of CTCs present an intriguing phenomenon; however their significance has yet to be determined. Ongoing projects include translating the technology for early cancer detection, exploring these clusters of CTCs, increasing capture sensitivity through amplification of cell surface antigens, and the design of biomaterials for the release of the rare cells from the device surface.
High-content and high-throughput imaging of cancer cells
Cancer cells can be highly heterogeneous, with rare metastasis precursors capable of giving rise to a metastatic lesion mixed in with other tumor cells undergoing apoptosis. Thus, due to this heterogeneity, quantitative, robust analysis for individual cells may be critical for determining a particular cancer cells’ their clinical relevance in different disease contexts. Due to limitations in the number of distinct spectra that can be used in wide-field fluorescence imaging, high throughput characterization of cells and tissue is traditionally done with three to four colors. Our lab is exploring alternative imaging modalities, such as multi-spectral imaging (MSI), to enable quantitative analysis of multiple (8+) markers on a single cell. Our interest in MSI is driven by the technology’s capability to image as many colors as distinct antibodies available and by dramatic reductions in sample autofluorescence. We are also interested in using this technology to develop an automated system to quantitatively analyze RNA-ISH and FISH signals in cells and tissue.
Microvesicle and Exosome Characterization
Microvesicles have been implicated in promoting tumor progression by manipulating the surrounding microenvironment. Researchers have hypothesized that microvesicles shed from the membranes of tumors transport RNA and proteins that promote tumor growth, and studies have shown that microvesicles are present in the serum of patients with glioblastoma. Ongoing work in my lab, performed in collaboration with Dr. Xandra Breakefield of the Mass General Neurogenetics Unit, is exploring the use of microfluidics to purify microvesicles from serum and use of their RNA content as a biomarker, specifically the expression of epithelial growth factor receptor (EGFRvIII).