Leucine-rich repeat kinase 2 (LRRK2) is a serine–threonine protein kinase belonging to the ROCO protein family. Within the kinase domain of LRRK2, a point mutation known as LRRK2 G2019S has emerged as the most prevalent variant associated with Parkinson’s disease. Recent clinical studies have indicated that G2019S carriers have an elevated risk of cancers, including colon cancer. Despite this observation, the underlying mechanisms linking LRRK2 G2019S to colon cancer remain elusive. In this study, employing a colitis-associated cancer (CAC) model and LRRK2 G2019S knock-in (KI) mouse model, we demonstrate that LRRK2 G2019S promotes the pathogenesis of colon cancer, characterized by increased tumor number and size in KI mice. Furthermore, LRRK2 G2019S enhances intestinal epithelial cell proliferation and inflammation within the tumor microenvironment. Mechanistically, KI mice exhibit heightened susceptibility to DSS-induced colitis, with inhibition of LRRK2 kinase activity ameliorating colitis severity and CAC progression. Our investigation also reveals that LRRK2 G2019S promotes inflammasome activation and exacerbates gut epithelium necrosis in the colitis model. Notably, GSDMD inhibitors attenuate colitis in LRRK2 G2019S KI mice. Taken together, our findings offer experimental evidence indicating that the gain-of-kinase activity in LRRK2 promotes colorectal tumorigenesis, suggesting LRRK2 as a potential therapeutic target in colon cancer patients exhibiting hyper LRRK2 kinase activity.

Eosinophilic esophagitis (EoE) is a progressive inflammatory disease of the esophagus. Untreated or uncontrolled disease over time can lead to the development of fibrosis and formation of strictures. Once the patient develops strictures, it is difficult to treat with the available medical therapies and will often require esophageal dilations. The Food and Drug Administration recently approved dupilumab for the treatment of EoE in patients older than 12 years. The clinical trials excluded patients with esophageal strictures. We describe a case of EoE with fibrostenotic stricture who had stricture resolution while on dupilumab therapy.

Obesity is strongly associated with triple-negative breast cancer (TNBC). A better understanding of the molecular mechanisms driving obesity-induced TNBC progression could facilitate the development of precision dietary intervention strategies. In this study, we used murine models of obesity induced by different high-fat diets (HFD) to examine their impact on TNBC progression. Compared with a low-fat diet, both cocoa butter and olive oil HFDs induced similar levels of obesity. However, only the olive oil HFD–induced obesity increased TNBC stemness and lung metastasis. Mechanistically, oleic acid (OA) in the olive oil HFD facilitated TNBC metastasis by activating the protein kinase C (PKC)–aldehyde dehydrogenase (ALDH) pathway. Furthermore, fatty acid–binding protein 5 (FABP5) in TNBC cells was identified as essential for OA-mediated PKC–ALDH pathway activation. FABP5 deficiency reduced TNBC metastasis in multiple mouse models, whereas higher FABP5 expression correlated with worse outcomes of TNBC in various human studies. These findings collectively suggest that the consumption of olive oil HFD promotes obesity-associated TNBC metastasis through OA/FABP5-driven oncogenic signaling. Significance: Comparison of obesity induced by different high-fat diets revealed that an olive oil-based diet promotes triple-negative breast cancer metastasis by activating FABP5/PKC/ALDH signaling, providing a target for the development of obesity-associated cancer therapeutics.

FABP5 Knockout suppresses tumor metastasis