The Role of Oncostatin M in the PDAC tumor microenvironment and macroenvironment

项目总结/文摘

Project Summary/Abstract Pancreatic adenocarcinoma (PDAC) carries a 90% 5-year mortality due to the treatment refractory, highly metastatic nature of the tumor and frequent, severe cachexia or unintentional weight loss induced by tumor. Tumor cells interact with host cells locally to specify a highly desmoplastic microenvironment, but also induce systemic changes in the macroenvironment, including wasting of fat and muscle. Inflammatory cytokines, such as members of the Interleukin-6/GP130 family including IL-6 and LIF, contribute to both the microenvironment and macroenvironment in PDAC. IL-6 and LIF promote tumor inflammation and progression, and both have been implicated in cachexia. However, less is known about the other IL-6 family of cytokines, including Oncostatin M (OSM). Preliminary studies support a central role for OSM in PDAC. OSM and its receptor, OSMR, are expressed in human and murine tumors. High tumor expression of OSMR correlates with poor survival for PDAC patients. OSM was elevated in plasma of mice with PDAC tumors. In vitro, OSM increased expression of OSMR in human and murine tumor cells and stromal cells demonstrating feed-forward regulation. OSM induced compaction of tumor spheroids in tumor cell/fibroblast co-cultures. In contrast, deletion of OSM but not OSMR, from hosts decreased collagen deposition in the tumor microenvironment. While skeletal muscle wasting, was unaffected, deletion of OSM/OSMR from the host accelerated cardiac wasting and cardiac dysfunction and reduced overall activity in mice with PDAC tumors. These data demonstrate that OSM/OSMR signaling modulates both the tumor microenvironment and macroenvironment in PDAC. Here we will test the following hypotheses in two Aims: 1) OSM signaling on tumor cells through fibroblasts promotes the desmoplastic phenotype in PDAC. 2) OSM signaling in the heart is protective of cardiac mass and function in PDAC cachexia. For AIM 1, Osm signaling will be manipulated in monoculture and co-cultures studies using human and murine tumor and fibroblast cells; mice deleted for OSM or OSMR will be orthotopically implanted with pancreatic cancer cells; tumor cells deleted for OSMR will be implanted in wildtype mice; all will be evaluated by cell and molecular analysis. For AIM 2, OSM and OSMR knockout mice will be implanted with PDAC tumor cells and evaluated for body weight change, body composition, strength/function, cardiac function, and organ wasting. Muscle and heart will be harvested for histomorphometry and molecular analysis. The training plan will provide the applicant with skills in CRISPR, single cell sequencing, interpretation of omics data, immunophenotyping of tissues, cancer modeling, cardiac dysfunction and oral and written communication. Training will take place at Indiana University School of Medicine, a highly collaborative and resourced institution, under the direct advisement of Dr. Teresa Zimmers, a well-published cancer cachexia researcher. Summarily, the trainee will grow as an independent investigator within the training environment.