Abstract B023: Oncostatin M induces HIF1A-dependent collective cell migration in mammary epithelial cells
Authors: McLean Ian C. 
Published: January 2023

Over 40,000 deaths due to breast cancer occur annually in the United States, and metastatic status is the most important determinant in prognosis. The metastatic potential of cancer cells is strongly influenced by interactions with the tumor microenvironment, which are mediated in large part by growth factors and cytokines that can modulate cellular phenotype. One such ligand is Oncostatin M (OSM), a cytokine produced by macrophages in breast cancer tumors. An emerging body of literature suggests that OSM is capable of shifting cancer cells into a metastatic cell state, however the mechanistic relationship between OSM signaling and cancer progression remains unclear. Gaining a better understanding of the molecular and microenvironmental factors that promote metastasis is critical for design of therapeutic strategies that can mitigate metastasis for patients with breast cancer. In previous studies, we found that MCF10A mammary epithelial cells exposed to OSM form multicellular clusters that migrate collectively, a process termed collective cell migration (CCM). This migratory phenotype has been linked to an increase in metastatic potential in breast cancer and provides an explanation for the association between OSM and cancer progression. Understanding the mechanism that underlies OSM-induced CCM may reveal how this phenotype contributes to metastasis. Toward this goal, we performed RNAseq and proteomic profiling of OSM-treated MCF10A cells, which revealed broad changes in molecular activity. Notably, OSM induced upregulation of transcription factors associated with migration (e.g., CEBPB, HIF1A) as well as a set of transcripts that contribute to cell junction formation (e.g., CDH3, GJA1). Network analysis revealed key nodes that may be associated with the phenotypic response, and functional screening with siRNA knock-down identified HIF1A as an essential mediator of OSM-induced CCM. Cellular activation of HIF1A is typically observed in response to hypoxia, a microenvironmental condition commonly found in human breast tumors, and patients with increased HIF1A expression have been found to be at a greater risk of metastasis. Our findings suggest that OSM released from tumor infiltrating myeloid cells may offer an alternative hypoxia-independent pathway to induce tumor cell upregulation of HIF1A and activation of metastatic cascades. Single-cell RNA-seq will be utilized to identify the transcriptional programs regulated by HIF1A in OSM-treated MCF10A cells. To further explore this hypothesis, we have performed additional experiments investigating the HIF1A signaling axis using organoids derived from MMTV-PyMT mice, cultured ex vivo in collagen gels. Initial results indicate that exposure to OSM increase cancer cell invasion in this mouse model of breast cancer. Future experiments will explore the relationship between HIF1A activation and MMTV-PyMT invasion and dissemination. Collectively, these results demonstrate an important connection between OSM, HIF1A, and CCM and help clarify the signaling consequences of OSM on cancer cell invasion.

Citation Format: Ian C. McLean. Oncostatin M induces HIF1A-dependent collective cell migration in mammary epithelial cells [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B023.