Term | Value | Language |
---|---|---|
dc.contributor.advisor | McCurdy, Dr., Carrie | |
dc.contributor.author | Bhaskar, Mayurika | |
dc.date.accessioned | 2024-08-30T19:09:29Z | |
dc.date.available | 2024-08-30T19:09:29Z | |
dc.date.issued | 2024 | |
dc.identifier.uri | https://scholarsbank.uoregon.edu/xmlui/handle/1794/29886 | |
dc.description | 47 pages | |
dc.description.abstract | The most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), is one of the most fatal cancers worldwide with an 11.5% 5-year survival rate. Cancer cachexia, defined as a loss in skeletal muscle and fat mass that cannot be regained with nutritional supplementation, is a common morbidity that impacts over 80% of patients with PDAC. Cachexia makes it challenging for patients to receive life-extending treatments and decreases their quality of life. Prior research has shown interleukin 6 (IL6), a pro-inflammatory cytokine, is associated with cancer cachexia development. IL6 acts within its target cells by activating the IL6/JAK2/STAT3 pathway, a signaling pathway that transmits signals from the extracellular environment to the nucleus, leading to changes in gene transcription. In cancer cachexia models, phosphorylation of STAT3 activates skeletal muscle and is a common feature of skeletal muscle wasting. However, we are still unaware of the specific mechanisms by which IL6 causes muscle wasting. I hypothesized that IL6 is sufficient and necessary to induce muscle wasting by acting directly on skeletal muscle. For my honors thesis, I chose to study the potential mechanisms and pathways of IL6 in in vitro C2C12 myotube models and IL6 knock-out (IL6 – KO) and WT mouse models. In the mouse models, PDAC tumors derived from tumors that grow spontaneously in the transgenic KPC mouse that either did (KPC – IL6 OE) or did not over-express IL6 (KPC – parental) were implanted orthotopically, and myofiber atrophy was documented by measuring the diameter of myofibers and skeletal muscle mass from the harvested gastrocnemius muscle. In vitro, C2C12 myotubes were treated with conditioned media from these cancer cell lines, recombinant IL6 (rIL6), or hyper-IL6 (hIL6, the bound IL6 and IL6-R complex), and myotube atrophy was similarly measured via minimum feret diameter. Activation of the IL6/JAK2/STAT3 pathway by IL6 was measured by quantifying phosphorylated STAT3 in western blot procedures and Socs3 (an indicator of IL6 signaling) product in qPCR using different conformations of IL6. We report that (1) IL6 is necessary and sufficient to drive skeletal muscle mass loss in our mouse models, (2) rIL6 does not induce wasting or activate STAT3 signaling in vitro, and (3) neither rIL6 nor hIL6 is sufficient to drive muscle wasting in vitro, despite activating IL6/JAK2/STAT3 signaling. These results indicate that while IL6 is both sufficient and necessary to induce muscle atrophy in vivo, it does not act directly on the skeletal muscle. Therefore, we conclude that IL6 causes muscle wasting through an indirect signaling mechanism involving other effector cells. | en_US |
dc.language.iso | en_US | |
dc.publisher | University of Oregon | |
dc.rights | CC BY-NC-ND 4.0 | |
dc.subject | Pancreatic Cancer | en_US |
dc.subject | Cancer Cachexia | en_US |
dc.subject | IL6 | en_US |
dc.subject | Cancer Biology | en_US |
dc.subject | Cancer | en_US |
dc.title | Sufficiency and Necessity of Tumor-Derived IL6 on Skeletal Muscle in PDAC-Associated Muscle Atrophy | |
dc.type | Thesis/Dissertation | |
dc.identifier.orcid | 0009-0009-2322-6700 |