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Extracellular Matrix Regulates Fibroblast Heterogeneity and Tumorigenesis / Diana Avery.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Avery, Diana, author.
- Language:
- English
- Subjects (All):
- Pharmacology.
- Cellular biology.
- Oncology.
- Pharmacology--Penn dissertations.
- Penn dissertations--Pharmacology.
- Local Subjects:
- Pharmacology.
- Cellular biology.
- Oncology.
- Pharmacology--Penn dissertations.
- Penn dissertations--Pharmacology.
- Genre:
- Academic theses.
- Physical Description:
- 1 online resource (100 pages)
- Contained In:
- Dissertation Abstracts International 79-01B(E).
- Place of Publication:
- [Philadelphia, Pennsylvania]: University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2017.
- Language Note:
- English
- System Details:
- Mode of access: World Wide Web.
- text file
- Summary:
- Heterogeneous activated fibroblasts that deposit and remodel extracellular matrix (ECM) comprise desmoplasia, a key regulator of tumor development. The divergent outcomes in response to varied therapies targeting intratumoral desmoplasia underscore the pressing need to delineate the intricate role of a heterogeneous stroma in tumorigenesis. Fibroblast activation protein (FAP) and alpha-smooth muscle actin (?SMA) identify distinct, yet overlapping, activated fibroblast subsets in myriad tumor types, fibrosis, and wound healing. FAP Hi reactive fibroblasts and alphaSMAHi myofibroblasts can exert divergent influences on tumor progression. However, the factors that drive this phenotypic heterogeneity and the unique functional roles of these distinct phenotypes are not yet understood. By comparing fibroblast activation on fibronectin- and collagen I-coated hydrogels of varying stiffness, I demonstrated that a convergence of ECM composition, elasticity, and TGF-beta signaling governs activated fibroblast phenotypic heterogeneity. Furthermore, by characterizing gene expression signatures, I revealed potentially unique roles of activated fibroblast subsets in tissue remodeling.
- In addition to its utility as a marker of activated fibroblasts, FAP also constitutes a highly attractive drug target due to its selective expression in the tumor microenvironment and its pro-tumorigenic proteolytic activity. FAP-mediated proteolysis of collagen I and III fragments promotes collagen clearance. However, the potential mechanistic link between FAP's role in collagen proteolysis and tumorigenesis is not yet known. I investigated the role of FAP-dependent collagen proteolysis and ECM remodeling in tumorigenesis using both a spontaneous oncogenic Kras-driven lung tumor model and fibroblast-derived matrices. I found that Fap genetic deletion promotes intratumoral fibrillar collagen accumulation and attenuates lung tumor multiplicity, size, progression, and proliferation. Furthermore, I obtained preliminary evidence that Fap-/- lung fibroblasts produce ECM with enhanced fibrillar collagen accumulation, which directly impedes both tumor cell proliferation and motility. Taken together, my research underscores the essential role of ECM remodeling in regulating key aspects of tumorigenesis, such as intratumoral fibroblast heterogeneity, proliferation, and invasion.
- Notes:
- Source: Dissertation Abstracts International, Volume: 79-01(E), Section: B.
- Advisors: Ellen Pure; Committee members: Richard K. Assoian; Edna Cukierman; Sandra W. Ryeom; Rebecca G. Wells.
- Department: Pharmacology.
- Ph.D. University of Pennsylvania 2017.
- Local Notes:
- School code: 0175
- ISBN:
- 9780355183610
- Access Restriction:
- Restricted for use by site license.
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