Abstract 3210: Oncostatin M modulates tumor-fibroblast crosstalk in pancreatic cancer without protecting against cachexia

Abstract Cancer cachexia is the involuntary loss of body weight, skeletal muscle, and adipose tissue associated with disease. Cachexia affects 85% of pancreatic cancer patients and patients suffer the greatest average weight loss among solid cancers. Inflammation is a key driver in cancer cachexia, specifically the Interleukin-6/GP130 family of cytokines that activate signaling of the JAK/STAT pathway. Among family members, Interleukin-6 (IL-6) and Leukemia Inhibitory Factor (LIF) promote cachexia and pancreatic cancer; however, less is known of the related Oncostatin M. Here we show cachexia and elevated circulating Osm coincide in the KrasG12D;Trp53R172H;Pdx1:Cre genetically engineered mouse model (KPC-GEMM) of pancreatic cancer and in mice bearing KPC cells implanted orthotopically. Osm expression was elevated in cardiac muscle and adipose tissue in KPC cachexia, while OSM receptor (Osmr) was elevated in cardiac and skeletal muscle and liver, indicating a systemic OSM circuit. Consistent with a feed-forward loop, KPC cells treated with OSM upregulated expression of OSMR. RNA-sequencing of OSM treated KPC and cancer-associated fibroblast (CAF) cell lines revealed activation of inflammation, fibrosis, and tumor progression pathways, including induction of IL-6. Functionally, exogenous OSM caused cardiac dysfunction, local muscle atrophy, fibrosis, and systemic bone loss in wildtype and Il6 null mice, suggesting OSM might mediate cachexia independent of IL-6. We hypothesized that deletion of OSM would be protective in cancer cachexia. Thus 14-week-old WT and Osm null mice were orthotopically implanted with KPC cells or underwent sham surgery; all groups were euthanized when one reached 5% fat mass. KPC tumors caused muscle weakness, body deconditioning and reduced activity as well as anemia and hematological inflammation. These findings were not genotype specific. There were also no differences in KPC-induced cardiac, skeletal muscle or fat wasting, nor in splenomegaly, organ wasting, or tumor size between WT and Osm null mice. Similarly, Osmr null mice showed no differences in KPC cachexia phenotypes versus wildtype mice. Nevertheless, tumors from Osm null mice showed alterations in the stromal compartment, including reduction in collagens I and III, decreased alpha smooth muscle actin staining, and altered mitochondrial metabolism and cellular composition by proteomics and RNAseq. Consistent with a role for OSM in modulating the stroma, excess OSM induced compaction of tumor cells and CAFs in 3D co-cultures. Together these data indicate that OSM signaling influences tumor-fibroblast crosstalk in the pancreatic cancer microenvironment but is not necessary for cachexia in the macroenvironment. Citation Format: Daenique H. Jengelley, Ashok Narasimhan, Joseph E. Rupert, Xiaoling Zhong, Andrew R. Young, Leonidas G. Koniaris, Teresa A. Zimmers. Oncostatin M modulates tumor-fibroblast crosstalk in pancreatic cancer without protecting against cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3210.