Indiana University-Purdue University Indianapolis (IUPUI) / Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancerrelated
deaths with a five-year survival rate of 11%. PDAC tumors are characterized by a
dense desmoplastic stromal microenvironment, mediated in part through local cytokine
production. PDAC tumors also elicit a systemic inflammatory response in the host; this,
combined with a loss of body weight due to muscle and fat wasting, is characteristic of
cachexia. Understanding the molecular mechanisms that drive malignant inflammation is
critical to improve PDAC therapy and increase patient survival. Oncostatin M (OSM)
belongs to the IL-6/GP130 family of cytokines, members of which have been shown to
promote PDAC tumor development, inflammation, and cachexia. Much less is known of
OSM. My central hypothesis was that OSM promotes pancreatic cancer and cachexia by
inducing local and systemic inflammation, fibrosis, and wasting via OSM signaling
through the receptor, OSM receptor (OSMR). We investigated effects of exogenous OSM
administration in wildtype and IL-6 null mice without cancer. OSM induced systemic
fibrosis, bone loss, local muscle wasting, and cardiac dysfunction in presence and absence
of IL-6. We further defined the roles of OSM/OSMR in the pancreatic cancer
microenvironment and macroenvironment. OSM activated genes involved in
inflammation, fibrosis, and tumor progression in both tumor cells and fibroblasts and
altered the tumor microenvironment, promoting a dense compaction of tumor cells and
cancer associated fibroblasts. Loss of systemic OSM signaling altered tumor metabolism
and reduced the stromal compartment without affecting tumor size. Loss of OSMR signaling in tumor cells reduced tumor size and promoted survival.
However, systemic loss of OSM or OSMR in host cells did not halt effects of cachexia
including muscle dysfunction, atrophy, or inflammation/anemia. Overall, OSM/OSMR
signaling in the microenvironment is necessary in modulating tumor phenotype and
promoting survival in PDAC but may not be necessary for pancreatic cancer cachexia. / 2024-08-02
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/29728 |
| Date | 07 1900 |
| Creators | Jengelley, Daenique Heather Andrene |
| Contributors | Zimmers, Teresa A., Goebl, Mark G., Mayo, Lindsey D., Nakshatri, Harikrishna, Ostrowski, Michael C. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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