Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most devastating human malignancies with poor survival rate owing to chemoresistance and relapse. Small population of Tumor Initiating Cells (TIC) are considered major players driving these traits. Recent literature has demonstrated the importance of microenvironment “niche” in enrichment of these TIC populations. The desmoplastic stroma in pancreatic cancer comprising of stromal cells and immune cells are instrumental in pathogenesis and progression of PDAC. Among many cytokines, IL-6 a pro-inflammatory cytokine plays a major role in it. In this study, we show that stromal cell secreted IL6 altered metabolic reprogramming and increased cancer stemness in PDAC cells. PDAC cells cultured with pancreatic stellate cells condition media (PSC-CM) or recombinant IL6 and stem ness markers expression were investigated. Cytometry Bead Array (CBA) were used for cytokine profiling. Metabolic alteration along with TIC gene expression were measured using flow cytometry and Seahorse. PDAC cells when cultured with PSC-CM exhibited increase glucose uptake along with an enrichment of CD133+ population. An analysis of the conditioned media using CBA reveled that PSC-CM is enriched with cytokine IL-6 and TNF-α. Treatment of PDAC cells with recombinant IL-6 increased expression of self-renewal genes SOX2, OCT4, Nanog along with biochemical marker ALDH. In addition, TIC marker CD133 and invasion marker gene MMP7 expression also increased upon IL6 induction. Moreover, IL6 treatment increased glucose uptake and lactate secretion. Small molecule inhibitor Stattic (inhibitor of STAT3) inhibit glucose uptake and stemness gene expression.Our study shows that stromal IL6 altered metabolic reprogramming in cancer cells as well as increased cancer stemness and invasion. In future, the underlying mechanisms of IL-6 driven metabolic alteration and its impact on stemness and metastasis will be investigated.

Citation Format: Kousik K. Kesh, Vineet K. Gupta, Nikita Sharma, Roey Hadad, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee. Stroma drive metabolic reprogramming and induces stemness properties in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4353.