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Browsing by Author "Ostrowski, Michael C."
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Item Cancer Cachexia: Involvement of an Expanding Macroenvironment(Elsevier, 2023) Pryce, Benjamin R.; Wang, David J.; Zimmers, Teresa A.; Ostrowski, Michael C.; Guttridge, Denis C.; Surgery, School of MedicineAdvanced cancers often present with the cachexia syndrome that impacts peripheral tissues, leading to involuntary weight loss and reduced prognosis. The central tissues undergoing depletion are skeletal muscle and adipose, but recent findings reveal an expanding tumor macroenvironment involving organ crosstalks that underlie the cachectic state.Item Musculoskeletal Effects of Oncostatin M in Pancreatic Cancer Cachexia(2022-07) Jengelley, Daenique Heather Andrene; Zimmers, Teresa A.; Goebl, Mark G.; Mayo, Lindsey D.; Nakshatri, Harikrishna; Ostrowski, Michael C.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.Item STAT3 in tumor fibroblasts promotes an immunosuppressive microenvironment in pancreatic cancer(Cold Spring Harbor Laboratory, 2022-07-08) Lefler, Julia E.; MarElia-Bennett, Catherine B.; Thies, Katie A.; Hildreth, Blake E., III.; Sharma, Sudarshana M.; Pitarresi, Jason R.; Han, Lu; Everett, Caroline; Koivisto, Christopher; Cuitino, Maria C.; Timmers, Cynthia D.; O'Quinn, Elizabeth; Parrish, Melodie; Romeo, Martin J.; Linke, Amanda J.; Hobbs, G. Aaron; Leone, Gustavo; Guttridge, Denis C.; Zimmers, Teresa A.; Lesinski, Gregory B.; Ostrowski, Michael C.; Anatomy, Cell Biology and Physiology, School of MedicinePancreatic ductal adenocarcinoma (PDAC) is associated with an incredibly dense stroma, which contributes to its recalcitrance to therapy. Cancer-associated fibroblasts (CAFs) are one of the most abundant cell types within the PDAC stroma and have context-dependent regulation of tumor progression in the tumor microenvironment (TME). Therefore, understanding tumor-promoting pathways in CAFs is essential for developing better stromal targeting therapies. Here, we show that disruption of the STAT3 signaling axis via genetic ablation of Stat3 in stromal fibroblasts in a Kras G12D PDAC mouse model not only slows tumor progression and increases survival, but re-shapes the characteristic immune-suppressive TME by decreasing M2 macrophages (F480+CD206+) and increasing CD8+ T cells. Mechanistically, we show that loss of the tumor suppressor PTEN in pancreatic CAFs leads to an increase in STAT3 phosphorylation. In addition, increased STAT3 phosphorylation in pancreatic CAFs promotes secretion of CXCL1. Inhibition of CXCL1 signaling inhibits M2 polarization in vitro. The results provide a potential mechanism by which CAFs promote an immune-suppressive TME and promote tumor progression in a spontaneous model of PDAC.