Browsing by Author "Guttridge, Denis C."

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    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 Medicine
    Advanced 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.
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    Circulating monocyte chemoattractant protein-1 (MCP-1) is associated with cachexia in treatment-naïve pancreatic cancer patients
    (Wiley, 2018-04) Talbert, Erin E.; Lewis, Heather L.; Farren, Matthew R.; Ramsey, Mitchell L.; Chakedis, Jeffery M.; Rajasekera, Priyani; Haverick, Ericka; Sarna, Angela; Bloomston, Mark; Pawlik, Timothy M.; Zimmers, Teresa A.; Lesinski, Gregory B.; Hart, Phil A.; Dillhoff, Mary E.; Schmidt, Carl R.; Guttridge, Denis C.; Surgery, School of Medicine
    Cancer-associated wasting, termed cancer cachexia, has a profound effect on the morbidity and mortality of cancer patients but remains difficult to recognize and diagnose. While increases in circulating levels of a number of inflammatory cytokines have been associated with cancer cachexia, these associations were generally made in patients with advanced disease and thus may be associated with disease progression rather than directly with the cachexia syndrome. Thus, we sought to assess potential biomarkers of cancer-induced cachexia in patients with earlier stages of disease. METHODS: A custom multiplex array was used to measure circulating levels of 25 soluble factors from 70 pancreatic cancer patients undergoing attempted tumour resections. A high-sensitivity multiplex was used for increased sensitivity for nine cytokines. RESULTS: Resectable pancreatic cancer patients with cachexia had low levels of canonical pro-inflammatory cytokines including interleukin-6 (IL-6), interleukin-1β (IL-1β), interferon-γ (IFN-γ), and tumour necrosis factor (TNF). Even in our more sensitive analysis, these cytokines were not associated with cancer cachexia. Of the 25 circulating factors tested, only monocyte chemoattractant protein-1 (MCP-1) was increased in treatment-naïve cachectic patients compared with weight stable patients and identified as a potential biomarker for cancer cachexia. Although circulating levels of leptin and granulocyte-macrophage colony-stimulating factor (GM-CSF) were found to be decreased in the same cohort of treatment-naïve cachectic patients, these factors were closely associated with body mass index, limiting their utility as cancer cachexia biomarkers. CONCLUSIONS: Unlike in advanced disease, it is possible that cachexia in patients with resectable pancreatic cancer is not associated with high levels of classical markers of systemic inflammation. However, cachectic, treatment-naïve patients have higher levels of MCP-1, suggesting that MCP-1 may be useful as a biomarker of cancer cachexia.
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    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 Medicine
    Pancreatic 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.