Doctor of Philosophy (PhD)
Michael A. Hollingsworth
This work addresses two understudied elements of inflammation and malignancy—namely, (1) neurolymphatic remodeling during transitions in microenvironmental inflammatory status and (2) the systemic paraneoplastic inflammatory syndrome cancer-associated cachexia in the context of pancreatic adenocarcinoma (PDAC). Lymphatic vessels undergo dramatic phenotypic changes in initial inflammation, wound recovery, and recurrent inflammation. We identified complementary novel neuroremodeling behaviors under these conditions and hypothesized that both nerve and lymphatic remodeling were directed by a tissue remodeling factor with overlapping functions. We found that nerve growth factor (NGF) influenced not only nerves but also lymphatics. NGF stimulated lymphangiogenesis, inhibited lymphatic vessel regression during wound recovery, and increased nociception. NGF induced VEGF-C protein expression, and ablation of VEGFR-2/3 signaling abrogated NGF-mediated lymphangiogenesis, supporting a hierarchical model of NGF-VEGF signaling with NGF functioning upstream of the VEGF family. We next studied neurolymphatic remodeling in the context of malignancy using a novel murine live imaging platform. Lyve1CreERT2tdT mice inducibly express tdTomato fluorescent protein in Lyve-1+ cells. We implanted fluorescently-labeled tumor cells into cornea and pinna and identified tumor-specific neurolymphatic architecture signatures that are distinct from those associated with nonmalignant inflammation, including disorganized hypersprouting nascent lymphatic vessels and a shift in nerve morphology to a phenotype previously associated only with wound recovery. We also found that manipulating the timing of establishment of inflammation affected tumor cell persistence in tissue. In the final portion of this work, we studied cancer-associated inflammation in a broader context—i.e. the paraneoplastic syndrome cancer-associated cachexia. We sought to address discrepancies in the literature regarding cachexia gene expression with a unique set of PDAC skeletal muscle samples harvested at rapid autopsy and stratified based on severity of cachexia. We found differential expression of a number of candidate targets in PDAC samples compared to cancer-free controls including FAP-α, CAMKIIβ, FBXO32, TIE-1, and TRIM63 and challenged some previous findings. In summary, we defined a novel role for NGF signaling in lymphatics, identified microenvironment-specific neurolymphatic architecture signatures, and highlighted the complexity of cancer-associated cachexia while providing new data about this syndrome in the context of PDAC.
Fink, Darci M., "Inflammation- and Cancer-Associated Neurolymphatic Remodeling and Cachexia in Pancreatic Ductal Adenocarcinoma" (2016). Theses & Dissertations. 104.
Available for download on Sunday, April 29, 2018