Targeting S100A9-ALDH1A1-Retinoic Acid Signaling to Suppress Brain Relapse in EGFR-Mutant Lung Cancer.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib has significantly prolonged progression-free survival (PFS) in patients with EGFR-mutant lung cancer, including those with brain metastases. However, despite striking initial responses, osimertinib-treated patients eventually develop lethal metastatic relapse, often to the brain. Although osimertinib-refractory brain relapse is a major clinical challenge, its underlying mechanisms remain poorly understood. Using metastatic models of EGFR-mutant lung cancer, we show that cancer cells expressing high intracellular S100A9 escape osimertinib and initiate brain relapses. Mechanistically, S100A9 upregulates ALDH1A1 expression and activates the retinoic acid (RA) signaling pathway in osimertinib-refractory cancer cells. We demonstrate that the genetic repression of S100A9, ALDH1A1, or RA receptors (RAR) in cancer cells, or treatment with a pan-RAR antagonist, dramatically reduces brain metastasis. Importantly, S100A9 expression in cancer cells correlates with poor PFS in osimertinib-treated patients. Our study, therefore, identifies a novel, therapeutically targetable S100A9-ALDH1A1-RA axis that drives brain relapse. SIGNIFICANCE: Treatment with the EGFR TKI osimertinib prolongs the survival of patients with EGFR-mutant lung cancer; however, patients develop metastatic relapses, often to the brain. We identified a novel intracellular S100A9-ALDH1A1-RA signaling pathway that drives lethal brain relapse and can be targeted by pan-RAR antagonists to prevent cancer progression and prolong patient survival. This article is highlighted in the In This Issue feature, p. 873.

Upregulation of ZIP14 and Altered Zinc Homeostasis in Muscles in Pancreatic Cancer Cachexia.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer type in which the mortality rate approaches the incidence rate. More than 85% of PDAC patients experience a profound loss of muscle mass and function, known as cachexia. PDAC patients with this condition suffer from decreased tolerance to anti-cancer therapies and often succumb to premature death due to respiratory and cardiac muscle wasting. Yet, there are no approved therapies available to alleviate cachexia. We previously found that upregulation of the metal ion transporter, Zip14, and altered zinc homeostasis are critical mediators of cachexia in metastatic colon, lung, and breast cancer models. Here, we show that a similar mechanism is likely driving the development of cachexia in PDAC. In two independent experimental metastasis models generated from the murine PDAC cell lines, Pan02 and FC1242, we observed aberrant Zip14 expression and increased zinc ion levels in cachectic muscles. Moreover, in advanced PDAC patients, high levels of ZIP14 in muscles correlated with the presence of cachexia. These studies underscore the importance of altered ZIP14 function in PDAC-associated cachexia development and highlight a potential therapeutic opportunity for improving the quality of life and prolonging survival in PDAC patients.

Exploring the effect of hydroxylic and non-hydroxylic solvents on the reaction of [VIVO(ß-diketonate)2] with 2-aminobenzoylhydrazide in aerobic and anaerobic conditions.

Refluxing [VIVO(ß-diketonate)2], namely [VIVO(acetylacetonate)2] and [VIVO(benzoylacetonate)2], separately with an equivalent or excess amount of 2-aminobenzoylhydrazide (ah) in laboratory grade (LG) CH3OH in aerobic conditions afforded non-oxidovanadium(iv) and oxidovanadium(v) complexes of the type [VIV(L1)2] (1), [VVO(L1)(OCH3)]2 (3) and [VIV(L2)2] (2), and [VVO(L2)(OCH3)] (4), respectively. (L1)2- and (L2)2- represent the dianionic forms of 2-aminobenzoylhydrazone of acetylacetone (H2L1) and benzoylacetone (H2L2), respectively, (general abbreviation, H2L), which was formed by the in situ condensation of ah with the respective coordinated [ß-diketonate] in medium-to-good yield. The yield of different resulting products was dependent upon the ratio of ah to [VIVO(ß-diketonate)2]. For example, the yield of 1 and 2 complexes increased significantly associated with a decrease in the amount of 3 and 4 with an increase in the molar ratio of ah. Upon replacing CH3OH by a non-hydroxylic solvent, LG CHCl3, the above reaction yielded only oxidovanadium(v) complexes of the type [VVO(L1)(OH)]2 (5), [VVO(L2)(OH)] (6) and [VO3(L)2] (7, 8) whereas, upon replacing CHCl3 by another non-hydroxylic solvent, namely LG CH3CN, only the respective [VO3(L)2] (7, 8) complex was isolated in 72-78% yield. However, upon performing the above reactions in the absence of air using dry CH3OH or dry CHCl3, only the respective [VIV(L)2] complex was obtained, suggesting that aerial oxygen was the oxidising agent and the type of pentavalent product formed was dependent upon the nature of solvent used. Complexes 3 and 4 were converted, respectively, to 7 and 8 on refluxing in LG CHCl3via the respective unstable complex 5 and 6. The DFT calculated change in internal energy (ΔE) for the reactions 2[VVO(L2)(OCH3)] + 2H2O → 2[VVO(L2)(OH)] + 2CH3OH and 2[VVO(L2)(OH)] → [VO3(L2)2] + H2O was, respectively, +3.61 and -7.42 kcal mol-1, suggesting that the [VVO(L2)(OH)] species was unstable and readily transformed to the stable [VO3(L2)2] complex. Upon one-electron reduction at an appropriate potential, each of 7 and 8 generated mixed-valence [(L)VVO-(µ-O)-OVIV(L)]- species, which showed valence-delocalisation at room temperature and localisation at 77 K. Some of the complexes showed a wide range of toxicity in a dose-dependent manner against lung cancer cells comparable with that observed with cis-platin.

E2F1 responds to ultraviolet radiation by directly stimulating DNA repair and suppressing carcinogenesis.

In response to DNA damage, the E2F1 transcription factor is phosphorylated at serine 31 (serine 29 in mouse) by the ATM or ATR kinases, which promotes E2F1 protein stabilization. Phosphorylation of E2F1 also leads to the recruitment of E2F1 to sites of DNA damage, where it functions to enhance DNA repair. To study the role of this E2F1 phosphorylation event in vivo, a knock-in mouse model was generated, in which serine 29 was mutated to alanine. The S29A mutation impairs E2F1 stabilization in response to ultraviolet (UV) radiation and doxorubicin treatment, but has little effect on the expression of E2F target genes. The apoptotic and proliferative responses to acute UV radiation exposure are also similar between wild-type and E2f1(S29A/) (S29A) mice. As expected, the S29A mutation prevents E2F1 association with damaged DNA and reduces DNA repair efficiency. Moreover, E2f1(S29A/) (S29A) mice display increased sensitivity to UV-induced skin carcinogenesis. This knock-in mouse model thus links the ability of E2F1 to directly promote DNA repair with the suppression of tumor development.

Plasmodium falciparum uses gC1qR/HABP1/p32 as a receptor to bind to vascular endothelium and for platelet-mediated clumping.

The ability of Plasmodium falciparum-infected red blood cells (IRBCs) to bind to vascular endothelium, thus enabling sequestration in vital host organs, is an important pathogenic mechanism in malaria. Adhesion of P. falciparum IRBCs to platelets, which results in the formation of IRBC clumps, is another cytoadherence phenomenon that is associated with severe disease. Here, we have used in vitro cytoadherence assays to demonstrate, to our knowledge for the first time, that P. falciparum IRBCs use the 32-kDa human protein gC1qR/HABP1/p32 as a receptor to bind to human brain microvascular endothelial cells. In addition, we show that P. falciparum IRBCs can also bind to gC1qR/HABP1/p32 on platelets to form clumps. Our study has thus identified a novel host receptor that is used for both adhesion to vascular endothelium and platelet-mediated clumping. Given the association of adhesion to vascular endothelium and platelet-mediated clumping with severe disease, adhesion to gC1qR/HABP1/p32 by P. falciparum IRBCs may play an important role in malaria pathogenesis.