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- Creators: Harrington Bioengineering Program
Description
The objective of this research was to create a 3D in vitro model to mimic the native breast tumor microenvironment. Polydimethylsiloxane (PDMS) stamps and micromolding techniques were utilized to develop collagen based 3D tumor model. Geometrical design was optimized for the PDMS stamp to compartmentalize the tumor and stromal region of the 3D model. Addition of tumor and stromal cells into the platform further demonstrated the successful fabrication of the 3D model which will be used to investigate the role of stromal components on tumor growth and progression. Atomic force microscopy will also be utilized to access stromal remodeling during active invasion.
ContributorsAssefa, Eyerusalem Dibaba (Author) / Nikkhah, Mehdi (Thesis director) / Saini, Harpinder (Committee member) / Harrington Bioengineering Program (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
Description
Breast and other solid tumors exhibit high and varying degrees of intra-tumor heterogeneity resulting in targeted therapy resistance and other challenges that make the management and treatment of these diseases rather difficult. Due to the presence of admixtures of non-neoplastic cells with polyclonal cell populations, it is difficult to define cancer genomes in patient samples. By isolating tumor cells from normal cells, and enriching distinct clonal populations, clinically relevant genomic aberrations that drive disease can be identified in patients in vivo. An in-depth analysis of clonal architecture and tumor heterogeneity was performed in a stage II chemoradiation-naïve breast cancer from a sixty-five year old patient. DAPI-based DNA content measurements and DNA content-based flow sorting was used to to isolate nuclei from distinct clonal populations of diploid and aneuploid tumor cells in surgical tumor samples. We combined DNA content-based flow cytometry and ploidy analysis with high-definition array comparative genomic hybridization (aCGH) and next-generation sequencing technologies to interrogate the genomes of multiple biopsies from the breast cancer. The detailed profiles of ploidy, copy number aberrations and mutations were used to recreate and map the lineages present within the tumor. The clonal analysis revealed driver events for tumor progression (a heterozygous germline BRCA2 mutation converted to homozygosity within the tumor by a copy number event and the constitutive activation of Notch and Akt signaling pathways. The highlighted approach has broad implications in the study of tumor heterogeneity by providing a unique ultra-high resolution of polyclonal tumors that can advance effective therapies and clinical management of patients with this disease.
ContributorsLaughlin, Brady Scott (Author) / Ankeny, Casey (Thesis director) / Barrett, Michael (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor) / School for the Science of Health Care Delivery (Contributor)
Created2015-05
Description
Stromal cells play an important role in facilitating disease progression of ductal carcinoma. Cancer associated fibroblasts (CAFs) are an important component of the extracellular matrix (ECM) which constitutes the microenvironment of breast tumor cells. They are known to participate in chemotherapeutic drug resistance by modulating various biochemical and biophysical factors that contribute to increased matrix stiffness and collagen I density of the tumor-adjacent stroma. To address these issues in terms of patient treatment, anti-cancer drug regimes have been assembled to incorporate both chemotherapeutic as well as anti-fibrotic drugs to both target tumor cells while also diminishing the elastic modulus of the microenvironment by targeting CAFs. The quantitative assessment of these drug regimes on tumor progression is missing in terms of CAFs role alone.
A high density 3D tumor model was utilized to recapitulate the tumor microenvironment of ductal carcinoma in vitro. The tumor model consisted of MDA-MB-231 tumors seeded within micromolded collagen wells, chemically immobilized upon a surface treated PDMS substrate. CAFs were seeded within the greater collagen structure from which the microwells were formed. The combinatorial effect of anti-fibrotic drug (Tranilast) and chemotherapy drug (Doxorubicin) were studied within 3D co culture conditions. Specifically, the combinatorial effects of the drugs on tumor cell viability, proliferation, and invasion were examined dynamically upon coculture with CAFs using the microengineered model.
The results of the study showed that the combinatorial effects of Tranilast and Doxorubicin significantly decreased the proliferative ability of tumor cells, in addition to significantly decreasing the ability of tumor cells to remain viable and invade their surrounding stroma, compared to control conditions.
A high density 3D tumor model was utilized to recapitulate the tumor microenvironment of ductal carcinoma in vitro. The tumor model consisted of MDA-MB-231 tumors seeded within micromolded collagen wells, chemically immobilized upon a surface treated PDMS substrate. CAFs were seeded within the greater collagen structure from which the microwells were formed. The combinatorial effect of anti-fibrotic drug (Tranilast) and chemotherapy drug (Doxorubicin) were studied within 3D co culture conditions. Specifically, the combinatorial effects of the drugs on tumor cell viability, proliferation, and invasion were examined dynamically upon coculture with CAFs using the microengineered model.
The results of the study showed that the combinatorial effects of Tranilast and Doxorubicin significantly decreased the proliferative ability of tumor cells, in addition to significantly decreasing the ability of tumor cells to remain viable and invade their surrounding stroma, compared to control conditions.
ContributorsSilva, Casey Rudolph (Author) / Nikkhah, Mehdi (Thesis director) / Saini, Harpinder (Committee member) / Harrington Bioengineering Program (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2019-05