Re-aligning patient prognosis: the role of collagen in establishing an immunosuppressive microenvironment and facilitating cancer cell dissemination in pancreatic ductal adenocarcinoma
2021-10
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Re-aligning patient prognosis: the role of collagen in establishing an immunosuppressive microenvironment and facilitating cancer cell dissemination in pancreatic ductal adenocarcinoma
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2021-10
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Abstract
Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer with particularly poor clinical outcomes, in part, because of a dramatically altered stromal
environment and striking immune dysfunction. Physical properties within tumors—
such as aligned fiber architectures—are fundamental to cancer progression and
invasion, and negatively correlate with survival in cancers like those of the breast.
However, the influence of aligned architectures in PDA remains unexplored. Here,
we elucidate the role extracellular matrix alignment has in establishing an
immunosuppressive, metastasis-conducive tumor microenvironment in early,
preinvasive PDA, as well as in precursory pancreatic inflammation. Using both
mouse and human samples, we demonstrate an inextricable link between
collagen, alignment, and 1) immunosuppressive macrophage localization,
phenotype, and function (Chapter 2); 2) epithelial cell extrusion and subsequent
invasion from intact ductal structures (Chapter 3). The contribution of alignment in
both driving macrophage polarization and tumor cell dissemination could be
attributed to altered focal adhesion dynamics, as targeting FAK in vivo resulted in
a concomitant decrease in aligned collagen architectures, disseminated tumor
cells, metastatic burden, and elongated, immunosuppressive macrophages. In
Chapter 4, we explore the interplay between macrophages, collagen, and cancer
cell extrusion using novel 3D microtissue co-cultures and human biopsies to reveal
contributions of macrophages to dissemination in vitro and in vivo. Importantly, we
show aligned collagen signatures and immunosuppressive macrophages are abundantly prevalent in pancreatitis, a known risk factor for PDA, suggesting that
pancreatic precursory disease may create stromal memory that is later conducive
to early immunosuppression and dissemination of PDA. This work highlights the
opportunity to utilize FAK inhibitors to target stromal immunity and architectures
and supports a model in which collagen architecture drives the early involution of
an immunosuppressive, malignant microenvironment. Further, this thesis
underscores the importance of targeting stromal matrices in precursor
inflammation, limit cancer progression, and “reprogram” stromal immunity.
Description
University of Minnesota Ph.D. dissertation. October 2021. Major: Biomedical Engineering. Advisor: Paolo Provenzano. 1 computer file (PDF); xv, 146 pages.
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Callaway, Mackenzie. (2021). Re-aligning patient prognosis: the role of collagen in establishing an immunosuppressive microenvironment and facilitating cancer cell dissemination in pancreatic ductal adenocarcinoma. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/259695.
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