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Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of kidney cancer, accounting for 70-80% of the cases. While surgical resection of early-stage tumors remains the standard care for patients, advanced ccRCC, metastatic or recurrent, portends a 5-year survival rate of only 12%, primarily due to insensitivity toward conventional chemotherapy. ccRCC is identifiable histologically by its dramatic lipid storage phenotype, similar to adipocytes; yet the role of lipid metabolism in ccRCC is poorly understood. One of the well-established risk factors for ccRCC is obesity and given that adipose tissue is known to produce a variety of pro-adipogenic signaling molecules (called adipokines), we hypothesized that adipokine signaling might be involved in the etiology of ccRCC. We recently identified a pro-tumorigenic adipokine protein, chemerin (RARRES2), that is positively correlated with tumor aggressiveness. Suppression of chemerin via either monoclonal antibody or siRNA led to reduction in lipid storage and significant tumor growth impairment in both in vitro and in vivo models by inducing ferroptosis. We next investigated the signaling mechanisms of chemerin and have found that chemerin drives downstream cellular activities and lipid deposition through either of the two receptors, GPR1 and CMKRL1. We further demonstrated that chemerin signals to both receptors to drive the expression adipose triglyceride lipase (ATGL) that frees up fatty acid from lipid depositions. In addition, Chemerin/CMKLR1 signaling axis further drives the activation of SREBP-mediated lipogenesis pathway. By using a small molecule antagonist specific for CMKRL1, α-NETA, we could suppress ccRCC tumor growth by inhibiting intracellular lipid droplet formation both in vitro and in vivo through the activation of ATGL-mediated lipolysis pathway and suppression of SREBP-mediated lipogenesis pathway. We have therefore shown the possibility of targeting Chemerin/CMKLR1 axis both genetically and pharmacologically to suppress the growth of ccRCC by increasing ferroptosis. Overall, our studies have identified chemerin/CMKLR1 axis as a promising therapeutic target that weakens ccRCC by modulating its lipid metabolic profiles and validated such vulnerability by using a more clinically relevant PDX orthotopic model. Further mechanistic investigations revealed overlapping yet distinct pathways downstream of chemerin that could potentially yield combinational strategies to treat ccRCC patients. Citation Format: Dazhi Wang, Scott Welford, James Brugarolas, Sze K. Tan. Harnessing chemerin signaling as a novel therapeutic vulnerability in ccRCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 275.

Background. We identified 12 patients with Clostridium difficile infection between July 2011 and March 2012 from whom an unusual C. difficile strain was isolated. This strain had a single-nucleotide deletion of the tcdC gene at position 117 and binary toxin genes, which are characteristic of the hypervirulent ribotype (RT) 027 strain.Methods. A retrospective cohort study of 12 patients infected with C. difficile RT244 and 24 patients infected with non-RT244/non-RT027 strains matched for place of diagnosis and time of collection of specimen was performed. We performed whole-genome sequencing to understand the relationship of the RT244 strain to other C. difficile strains and further understand its virulence potential.Results. Clostridium difficile RT244 was associated with more severe disease and a higher mortality rate. Phylogenomic analysis using core genome single-nucleotide polymorphisms showed that RT244 is in the same genetic clade (clade 2) as RT027 but is distinct from all RT027 strains. The pathogenicity locus of the RT244 strain encodes a variant toxin B, and this was confirmed by demonstration of Clostridium sordellii-like cytopathic effect on Vero cells. Toxin B production in culture supernatants was lower than that seen with a RT027 strain.Conclusions. Our findings demonstrate the pathogenic potential of this RT244 C. difficile strain and emphasize the importance of ongoing surveillance for emergent strains.