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An increased expression of oncogenic microRNA miR551b-3p (also known as miR551b) occurs in a subset of breast cancer due to genomic amplification of 3q26.2 locus. Using in silico and clinical sample analysis of breast cancer patient datasets, we identified that those breast cancer samples that encompass miR551b amplification express high levels of STAT3 mRNA and Oncostatin (OSM) family genes in triple-negative breast cancer (TNBC). Furthermore, high expression of Oncostatin family genes associates with poor outcome in estrogen receptor- negative breast cancer patients. In this study, we identified a previously unexplored mechanism that miR551b-3p promotes breast cancer progression and tumor growth by direct interaction of miR551b-3p with STAT3 promoter thereby activating STAT3 transcription. As a consequence, STAT3 upregulates a cytokine Oncostatin and its receptor Oncostatin M receptor (OSMR) and their interaction further induces STAT3 phosphorylation and an autocrine self-reinforcing loop in TNBC cells. In this study, we demonstrate that overexpression of miR551b-3p promoted proliferation, invasion and migration, epithelial to mesenchymal transition (EMT) and spheroid formation of breast cancer cells and its inhibition decreased the expression of miR551b-3p by inhibiting OSM, OSMR, IL6ST, IL31RA, phosphorylated and total STAT3 in breast cancer cells and reduced tumor cell growth. Overall, our results provide the first evidence that miR551b regulates OSM family gene expression by activating STAT3 and thereby promoting tumor cell growth and metastasis in breast cancer cells. Therefore, targeting miR-551b-3p-STAT3-OSMR axis and inhibiting their levels will provide an unprecedented therapeutic opportunity in breast cancer. Citation Format: Anjali Geethadevi, Deepak Parashar, Miriam Ragle Aure, Jasmine George, Changliang Chen, Jyotsna Mishra, Andliena Tahiri, Bindu Nair, Amadou Camara, Vessela N Kristensen, Sunila Pradeep, Pradeep Chaluvally Raghavan. miR551b-3p promotes Oncostatin M signaling in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-05-04.

BACKGROUND:Triple negative breast cancer (TNBC) has poor prognosis, lack of targeted therapies and are often refractory to conventional chemotherapy treatments. Therefore, finding new therapeutic targets for those tumours is an unmet need with high clinical impact. In this context, Oncostatin M receptor (OSMR) is a promising therapeutic target as it is over-expressed in this tumour subtype and its activation promotes invasiveness (Guo L, et al. 2013 Oncogene; West NR, et al.2014 Oncogene). We previously showed that OSMR is frequently copy-number gained and over-expressed in squamous cell carcinoma, where it induces migration, invasion and metastasis (Caffarel MM, et al 2013 Journal of Pathology; Caffarel MM, et al 2014 Journal of Pathology; Kucia-Tran JA, et al. 2016 Brit J Cancer; Kucia-Tran JA, et al 2018 Journal of Pathology). We now investigate the role of OSMR in breast cancer progression. METHODS: To address this issue we use a wide array of tools including in vitro cell cultures and in vivo models. The expression of OSMR pathway was analysed in FFPE samples and large datasets of publicly available breast cancer samples (METABRIC, n=1462; and TCGA, n=547). RESULTS: OSMR and its ligand Oncostatin M (OSM) are over-expressed in basal tumours, where they associate with shorter overall survival (p=0.015). While OSMR is expressed by breast cancer cells and cancer associated fibroblasts, the main source of OSM seems to be primarily macrophages. OSM treatment of breast cancer cells induces the expression of important mediators of angiogenesis and invasion. Importantly, OSMR activation accelerates tumour onset, tumour growth and metastasis in orthotopic xenografts in nude mice. CONCLUSIONS: Our results support that OSMR pathway may have an important role in the initiation and progression of breast cancer and that it could be a promising candidate for therapeutic targeting in TNBC. OSMR could be blocked by antibody based inhibition, strategy that has had a major impact on breast cancer. Citation Format: Alvarez I, Araujo A, Abaurrea A, Rezola R, Urruticoechea A, Lawrie C, Caffarel MM. New targets in triple negative breast cancer: Role of Oncostatin M receptor pathway [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-16.

Synovial sarcoma is a soft tissue malignancy of the muscle tissue which primarily affects adolescents. While it is a rare disease, little advancement has been made in the treatment of this cancer. With an overall survival rate of roughly 40%, the need for new treatments for synovial sarcoma is evident. Oncostatin M Receptor (OSMR) is a type I cytokine receptor and is overexpressed in metastatic synovial sarcoma. OSMR does not have high expression in normal tissues, making it an ideal target for cancer therapy. We hypothesize that by using an anti-OSMR monoclonal antibody conjugated to a radioactive Cu67 isotope, synovial sarcoma can be targeted at both primary and metastatic locations through systemic therapy. Copper 67 is a gamma radiation emitting isotope which is tissue damaging and able to induce cell death in cancer cells. By conjugating the chelating molecule p-SCN-Bn-NOTA to an anti-OSMR antibody, Cu67 was able to be captured to the antibody. Capture efficiency of Cu67 was measured through TLC and found to be 64 % efficient. Binding studies through Surface Plasmon Resonance (SPR) found that the conjugation did not interfere with the binding affinity of the antibody. This data suggests that targeting OSMR through radio-immune therapy is a viable treatment and indicates further testing in animal models. Citation Format: Sarah Luelling. Oncostatin M receptor as a therapeutic target of radio-immune therapy in metastatic synovial sarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 529.

Background: The emergence of molecular targeted therapies against driver mutations and gene fusions has resulted in significant therapeutic advances within a subset of non-small cell lung cancer (NSCLC) patients. However, even when targeted therapy is effective, patients eventually develop resistance and better therapies in this setting are still being sought. Preliminary studies, from the ongoing BATTLE-2 clinical trial in chemo-refractory NSCLC, identified a number of molecular candidates portending to targeted therapy resistance, including the oncostatin M (OSM) and leukemia inhibitory factor (LIF) receptors (OSMR, LIFR), both co-localized on a frequently amplified chromosome 5p region. In this study, we investigated the functional contribution of the OSM pathway to targeted therapy resistance in NSCLC. Materials and Methods: We analyzed OSM, OSMR, LIFR, and associated downstream pathways in a panel of OSMR-LIFR amplified (10) and diploid (10) NSCLC cell lines, in both mono- and co-culture experiments using human normal and lung cancer-associated fibroblasts (CAFs). We assessed the effect of OSM pathway stimulation and blockade on sensitivity to a variety of molecularly targeted agents. Further, we performed correlative studies using the BATTLE-2 molecular dataset. Results: OSM stimulation activated cell proliferation and survival pathways (AKT-mediated) through OSMR and LIFR. In addition, a dramatic JAK1/STAT3 pathway activation was predominant in OSMR amplified cells and was associated with EMT features. Co-culture experiments suggested a preferential paracrine activation of the OSM-STAT3 pathway, underscoring the importance of the microenvironment. Interestingly, OSM stimulation protected cells from drug-induced apoptosis in a STAT3-dependent manner. In the BATTLE-2 translational analysis, we also found that OSMR upregulation was significantly associated to STAT3 upregulation and EMT-gene expression signatures. Conclusions: Our data suggest that the OSM-OSMR/LIFR-STAT3 pathway causes EMT and contributes to molecular targeted therapy resistance in oncogene-addicted NSCLC cells, suggesting that this pathway could be a therapeutic target in NSCLC. Ongoing experiments are assessing therapeutic vulnerabilities and refining the signaling functionally involved. Supported by NIH-NCI CA155196 & 2P50CA070907-16A1 Citation Format: Kazuhiko Shien, Vassiliki A. Papadimitrakopoulou, Dennis Ruder, Nana E. Hanson, Neda Kalhor, J. Jack Lee, Waun Ki Hong, Ximing Tang, Roy S. Herbst, Luc Girard, John D. Minna, Jonathan M. Kurie, Ignacio I. Wistuba, Julie G. Izzo. Oncostatin M receptor activation leads to molecular targeted therapy resistance in non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 745. doi:10.1158/1538-7445.AM2015-745

An important feature of cervical squamous carcinogenesis is genomic instability caused by deregulated expression of HPV oncogenes in proliferating epithelial cells. A genomic imbalance that is commonly selected in advanced cervical squamous cell carcinoma (SCC) is copy number gain of chromosome 5p. One gene that is likely to drive selection of this abnormality is the oncostatin-M receptor (OSMR; located at 5p13.1), which is commonly up-regulated in cervical SCC and produces a significantly worse clinical outcome when over-expressed. Cervical SCC cells that over-expressed OSMR showed enhanced responsiveness to the major ligand OSM, which induced multiple pro-malignant effects, including increased cell migration and invasiveness. We now show that transglutaminase-2 (TGM2) is an important mediator of the ligand-dependent phenotypic effects of OSMR over-expression in cervical carcinoma cells. TGM2 expression correlated with disease progression and with OSMR levels in clinical samples of SCC of the cervix and head and neck. TGM2 depletion in cervical SCC cells abrogated the increased migration and invasiveness induced by OSM. TGM2 was shown to interact with integrin-α5β1 and fibronectin in cervical SCC cells, with OSM treatment strengthening the interaction. Importantly, integrin-α5β1 and fibronectin were over-expressed in cervical SCC samples, where levels correlated with those of OSMR. We conclude that an OSMR-TGM2-integrin-α5β1 pathway is of biological significance in cervical SCC and a candidate for therapeutic targeting. Citation Format: Maria M. Caffarel, Anasuya Chattopadhyay, Cinzia G. Scarpini, Nicholas Coleman. Transglutaminase-2 mediates the pro-malignant effects of oncostatin-M receptor overexpression in cervical squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4383. doi:10.1158/1538-7445.AM2013-4383

Brain metastasis affects an estimated 10% of cancer patients with metastatic disease, a major cause of morbidity and mortality in these patients. The most common primary tumors causing brain metastasis are adenocarcinoma of the lung or breast. While recent studies have demonstrated the genetic basis of such metastases, the molecular cause(s) of brain metastases remains largely elusive. Signal transducer and activator of transcription 3 (STAT3) has been shown to control various cellular functions and regulates the immune response. STAT3 is activated in various aggressive carcinomas. We hypothesize that STAT3 may play a role in metastatic brain tumors. Metastatic brain tumors were analyzed for expression of activated STAT3Tyr705 by immunohistochemical analysis. Gene expression profiling (17,000 gene chip) was performed in metastatic tumor samples, and STAT3 regulated genes were evaluated. Functional analysis such as cell motility and proliferation were investigated by chemotactic migration and MTT assay, respectively. The results of this study showed that a significant number of metastatic tumors to brain (75%) demonstrated nuclear expression of pSTAT3Tyr705. A significant number of these tumors also expressed mutant-p53 and activated MAPK. Gene expression analysis demonstrated that 32 STAT3-associated genes were significantly altered. Upregulated genes included stathmin-1 and stathmin-like 3 that control mictotubule dynamics in migrating cells and are associated with STAT3-related migration. The upregulation of stathmin-like 3 (also called SCG10-like-protein or SCLIP) also interacts with STAT3 in the maintenance of cellular dynamics involved in cell-cell attachment. The gp130-related interleukin 6 signal transducer gene, which is generally involved in STAT3-dependent glial fibrillary acidic protein (GFAP) induction during nerve regeneration, was inhibited. The suppression of STAT3-regulated gene oncostatin M receptor, which regulates metastasis, was observed. Furthermore, protein inhibitor of activated STAT3 (PIAS3), that suppresses activated STAT3 levels, was downregulated. Functional analysis revealed that cell proliferation of breast cancer cells (MCF7 cells) was enhanced in an astrocytic environment. Chemotactic analysis showed that breast cancer cells migrated toward astrocytic media. In addition, co-culture analysis demonstrated that astrocytes and tumor cells have an affinity for each other and make genuine cell-cell contact. These results indicate that STAT3 activation plays a significant role in brain metastasis by itself as well as by altering downstream target genes that regulate various cellular functions. Furthermore, the astrocytic milieu promotes the metastatic potential of tumor cells. Therefore, the activation of STAT3 promotes metastasis to brain, and may serve as a target for therapeutic intervention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3399.