Abstract 243: Berberine eases inflammation in the anaplastic thyroid cancer microenvironment
Authors: Jarboe Tara , Kopec Kaci , DeSouza Nicole R. , Singh Sarnath , Moscatello Augustine , Geliebter Jan , Li Xiu-Min , Tiwari Raj K. 
Published: June 2022

Abstract
Only 2% of thyroid cancer (TC) cases are anaplastic thyroid cancer (ATC), but this rare, undifferentiated cancer with a highly inflamed tumor microenvironment (TME) presents universally as stage IV with a 5-year survival rate of 3%. Due to its loss of differentiation, ATC is resistant to radioiodine therapy, refractory to external beam radiation, and insufficiently treated by chemotherapy or immunotherapy. Berberine (BBR), a natural plant alkaloid, has vast pharmacological activities, including anti-inflammatory and anti-cancer roles. BBR blocks proliferation, induces cell cycle arrest, promotes apoptosis, and hinders invasion and metastasis. BBR may also inhibit cell proliferation through miRNA interactions and regulate the TME through its anti-inflammatory and antioxidant properties. Research in ATC using BBR is limited, specifically investigation on how BBR reprograms the inflammatory TME via altering miRNA cargo of secretory exosomes and polarization of tumor associated macrophages (TAMs). ATC tissues have extensive infiltration of a mixed TAM population. In ATC, infiltration with classically anti-tumorigenic, inflammatory M1 macrophages has a pro-tumorigenic role. We assessed the secretory profile of ATC cells and found a high expression of pro-inflammatory cytokines, such as TNFα, IL-6, IL-1, MCP-1/2, and MIP-1α/β in ATC conditioned media (CM), supporting the existence of an inflammatory TME. As this chronic inflammation is partially mediated by the presence of M1 TAMs in the TME, we activated monocyte cell line U937 with TPA and polarized with IFNγ and LPS into an M1 phenotype. In the presence of BBR at the activation and polarization stages, inflammatory mediators IL-1β, IL-6, IL-6R, CXCL9, MIP-1α/β, and TNFR1/2 were downregulated in the CM compared to M1 macrophages activated and polarized without BBR. BBR also appeared to prevent some level of activation and polarization of these cells into the M1 phenotype altogether. BBR may have an essential role in lessening the burden of inflammation in ATC through remodeling its tumor immune infiltrates, potentially priming it for greater success in combination therapy. Intervention prior to metastasis warrants secretome analysis to define ATC disease progression. Exosomal cargo, particularly miRNA, secreted by ATC cells was evaluated as exosomes have potential as biomarkers to detect ATC earlier improving prognosis, guide treatment, and avoid unneeded surgeries. Distinct miRNA expression from ATC-secreted exosomes compared to papillary thyroid cancer (PTC)-secreted exosomes revealed six miRNAs specifically downregulated in ATC-secreted exosomes that are known tumor suppressors. We are currently evaluating how BBR alters the miRNA profile of ATC- and PTC-secreted exosomes. The ability of BBR to alleviate inflammation in ATC and remodel its TME releases its chronic hold on ATC progression and may prime the tumor for increased responsiveness to therapy.
Citation Format: Tara Jarboe, Kaci Kopec, Nicole R. DeSouza, Sarnath Singh, Augustine Moscatello, Jan Geliebter, Xiu-Min Li, Raj K. Tiwari. Berberine eases inflammation in the anaplastic thyroid cancer microenvironment [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 243.