<p>Metastasis of primary
mammary tumors to vital secondary organs is the primary cause of breast cancer-associated
death, with no effective treatment. Metastasis is a highly selective process
that requires cancer cells to overcome multiple barriers to escape the primary
tumor, survive in circulation, and eventually colonize distant secondary
organs. One of the important aspects of metastatic cancers is the ability to
undergo epithelial-mesenchymal transition (EMT) and the reverse process
mesenchymal-epithelial transition (MET) process. Constant interconversion of
tumor cells between these phenotypes creates epithelial-mesenchymal heterogeneity
(EMH) and interaction between these tumor cell types and the stromal cell
compartment is clearly important to metastasis. In healthy tissues, stromal
cells maintain the composition and structure of the tissue through the production
of extracellular matrix (ECM) proteins and paracrine signaling with epithelial
cells. However, little is known about how EMH
promotes changes in the ECM to promote breast cancer progression and
metastasis. Cancer cells also secret exosomes, nano-size extracellular
vesicles, to establish intercellular communication with distant organs in order
to induce metastasis. These exosomes contain a plethora of different proteins
including extracellular matrix proteins and matrix crosslinking enzymes.
Fibronectin, an important ECM protein, plays an active role in tumor
progression and is often crosslinked by tissue transglutaminase 2 (TGM2) to
promote fibrosis in cancer. Both FN and TGM2 exist in exosomes and are
expressed by heterogenous breast tumors. Although FN and TGM2 have been
reported to play essential roles in cancer, their involvement in metastasis
remains unclear. This work utilizes a variety of approaches to investigate the
role of tumor heterogeneity and ECM proteins in promoting breast cancer
metastasis. In this dissertation, we establish that mesenchymal cells
expressing intracellular FN are held in a stable non-metastatic mesenchymal
phenotype and produce cellular fibrils containing functionalized FN capable of
supporting the growth of metastatic competent epithelial cells. We introduce a
novel 3D culture system consisting of a tessellated scaffold which is capable
of recapitulating cellular and matrix phenotypes <i>in vivo. </i>Further, we
also demonstrate breast tumor cells secrete exosomes containing TGM2
crosslinked FN fibrils to promote premetastatic niche formation and induction
of metastasis.<i> </i>Using genetic approaches, we establish TGM2 is essential
and sufficient to drive metastasis. Finally, we demonstrate pharmacological
inhibition of TGM2 offers a potential therapeutic strategy to treat metastatic
breast cancer. Altogether, our research provides insights into the mechanism
through which TGM2 promotes metastatic breast cancer. This work will help in
developing new drugs to target TGM2 aimed at reducing breast cancer metastasis.<br></p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/7952360 |
| Date | 10 June 2019 |
| Creators | Aparna B. Shinde (5930267) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/Role_Of_Tumor_Microenvironment_in_Breast_Cancer_Metastasis/7952360 |
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