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1. A deficiency screen of the X chromosome for Rap1 GTPase dominant interacting genes in Drosophila border cell migration

   https://doi.org/10.1093/g3journal/jkaf040  

   Messer, C Luke; Burghardt, Emily; McDonald, Jocelyn A (February 2025, G3: Genes, Genomes, Genetics)

   Bergstralh, D (Ed.)

   Abstract Collective cell migration is critical to embryonic development, wound healing, and the immune response, but also drives tumor dissemination. Understanding how cell collectives coordinate migration in vivo has been a challenge, with potential therapeutic benefits that range from addressing developmental defects to designing targeted cancer treatments. The small GTPase Rap1 has emerged as a regulator of both embryogenesis and cancer cell migration. How active Rap1 coordinates downstream signaling functions required for coordinated collective migration is poorly understood. Drosophila border cells undergo a stereotyped and genetically tractable in vivo migration within the developing egg chamber of the ovary. This group of 6–8 cells migrates through a densely packed tissue microenvironment and serves as an excellent model for collective cell migration during development and disease. Rap1, like all small GTPases, has distinct activity state switches that link extracellular signals to organized cell behaviors. Proper regulation of Rap1 activity is essential for successful border cell migration yet the signaling partners and other downstream effectors are poorly characterized. Using the known requirement for Rap1 in border cell migration, we conducted a dominant suppressor screen for genes whose heterozygous loss modifies the migration defects observed upon constitutively active Rap1V12 expression. Here, we identified 7 genomic regions on the X chromosome that interact with Rap1V12. We mapped three genomic regions to single Rap1-interacting genes, frizzled 4, Ubiquitin-specific protease 16/45, and strawberry notch. Thus, this unbiased screening approach identified multiple new candidate regulators of Rap1 activity with roles in collective border cell migration. 

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2. Fusobacterium nucleatum host-cell binding and invasion induces IL-8 and CXCL1 secretion that drives colorectal cancer cell migration

   https://doi.org/10.1126/scisignal.aba9157  

   Casasanta, Michael A.; Yoo, Christopher C.; Udayasuryan, Barath; Sanders, Blake E.; Umaña, Ariana; Zhang, Yao; Peng, Huaiyao; Duncan, Alison J.; Wang, Yueying; Li, Liwu; et al (July 2020, Science Signaling)

   Fusobacterium nucleatumis implicated in accelerating colorectal cancer (CRC) and is found within metastatic CRC cells in patient biopsies. Here, we found that bacterial invasion of CRC cells and cocultured immune cells induced a differential cytokine secretion that may contribute to CRC metastasis. We used a modified galactose kinase markerless gene deletion approach and found thatF. nucleatuminvaded cultured HCT116 CRC cells through the bacterial surface adhesin Fap2. In turn, Fap2-dependent invasion induced the secretion of the proinflammatory cytokines IL-8 and CXCL1, which are associated with CRC progression and promoted HCT116 cell migration. Conditioned medium fromF. nucleatum–infected HCT116 cells caused naïve cells to migrate, which was blocked by depleting CXCL1 and IL-8 from the conditioned medium. Cytokine secretion from HCT116 cells and cellular migration were attenuated by inhibitingF. nucleatumhost-cell binding and entry using galactose sugars,l-arginine, neutralizing membrane protein antibodies, orfap2deletion.F. nucleatumalso induces the mobilization of immune cells in the tumor microenvironment. However, in neutrophils and macrophages, the bacterial-induced secretion of cytokines was Fap2 independent. Thus, our findings show thatF. nucleatumboth directly and indirectly modulates immune and cancer cell signaling and migration. Because increased IL-8 and CXCL1 production in tumors is associated with increased metastatic potential and cell seeding, poor prognosis, and enhanced recruitment of tumor-associated macrophages and fibroblasts, we propose that inhibition of host-cell binding and invasion, potentially through vaccination or novel galactoside compounds, could be an effective strategy for reducingF. nucleatum–associated CRC metastasis. 

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3. On the role of myosin-induced actin depolymerization during cell migration

   https://doi.org/10.1091/mbc.E22-10-0494  

   Yao, Lingxing; Mori, Yoichiro; Sun, Sean X.; Li, Yizeng (May 2023, Molecular Biology of the Cell)

   Mogilner, Alex (Ed.)

   Mammalian cell migration in open spaces requires F-actin polymerization and myosin contraction. While many studies have focused on myosin’s coupling to focal adhesion and stress fibers, the indirect effect of myosin contraction on cell migration through actin depolymerization is not well studied. In this work, we quantified how cell velocity and effective power output are influenced by the rate of actin depolymerization, which is affected by myosin contraction. In addition, we derived scaling laws to provide physical insights into cell migration. Model analysis shows that the cell migration velocity displays a biphasic dependence on the rate of actin depolymerization and myosin contraction. Our model further predicts that the effective cell energy output depends not only on the cell velocity but also on myosin contractility. The work has implications on in vivo processes such as immune response and cancer metastasis, where cells overcome barriers imposed by the physical environment. 

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4. Multifunctional Superparamagnetic Copper Iron Oxide Nanoparticles for Synergistic Cancer Therapy via Magnetic Hyperthermia, Oxidative Stress and Immune Reprogramming

   https://doi.org/10.1002/adfm.202425286  

   Cai, Yuxin; Kang, Xuejia; Zhou, Lang; Wu, Shuai; Wang, Chuanyu; Wu, Siqi; Huang, Chunghui; Wang, Qi; Chang, Ya; Babu, R_Jayachandra; et al (March 2025, Advanced Functional Materials)

   Abstract Aggressive cancers, characterized by high metastatic potential and resistance to conventional therapies, present a significant challenge in oncology. Current treatments often fail to effectively target metastasis, recurrence, and the immunosuppressive tumor microenvironment, while causing significant off‐target toxicity. Here, superparamagnetic copper iron oxide nanoparticles (SCIONs) as a multifunctional platform that integrates magnetic hyperthermia therapy, immune modulation, and targeted chemotherapeutic delivery, aiming to provide a more comprehensive cancer treatment is presented. Specifically, SCIONs generate localized hyperthermia under an alternating magnetic field while delivering a copper‐based anticancer agent, resulting in a synergistic anticancer effect. The hyperthermia induced by SCIONs caused ER stress and ROS production, leading to significant tumor cell death, while the copper complex further enhanced oxidative stress, ferroptosis, and apoptosis. Beyond direct cytotoxicity, SCIONs disrupted the tumor microenvironment by inhibiting cancer‐associated fibroblasts, downregulating epithelial‐mesenchymal transition markers, and reducing cell migration and invasion, thereby limiting metastasis. Additionally, SCION‐based therapy reprogrammed the immune microenvironment by inducing immunogenic cell death and enhancing dendritic cell activation, resulting in increased CD8+ T cell infiltration and amplified antitumor immunity. This integrated approach targets primary and metastatic tumors while mitigating immunosuppression, offering a promising next‐generation therapy for combating cancer with enhanced efficacy and reduced side effects. 

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5. Regulation of the Hippo-YAP Signaling by Cytokines in Prostate Cancer Cell Lines

   Seymour, Demaiya; Boston, Ava; Cinar, Bekir (April 2020, Presented at Virtual Research Day in Spelman College; April 16-17, 2020; Atlanta, Georgia)

   The transcriptional co-activator YAP1 (yes-associated protein 1), a crucial effector of the Hippo pathway in mammals, regulates cell growth, cell motility, cell migration, and carcinogenesis. The STK4/Hippo kinase phosphorylates Ser127 and inactivate YAP1 activity in mammalian cells. Cytokines such as receptor activator of nuclear factor Kappa B (RANKL) regulate the immune system and bone remodeling. Similarly, stroma-cell derived factor 1 alpha (SDF1α) produced by the bone marrow stromal cell, is directly linked to cell migration and metastasis. We hypothesize that RANKL/SDF1α attenuates phospho-Ser127 and enhances YAP nuclear localization. We conducted immunological assays to evaluate the effects of SDF1α or RANKL on YAP1 in the LNCaP prostate cancer cell line. We showed that SDF1α and RANKL modulate phospho-Ser127 and total YAP1 protein in a time-dependent manner, as demonstrated by western blotting. We also showed that SDF1α exposure promoted YAP1 nuclear localization, as revealed by immunofluorescence imaging with confocal microscopy. These findings suggest that cytokines positively regulate YAP1 activity, possibly by counteracting with the STK4/Hippo signaling. The results of this study imply that cytokines secreted by the tumor cell environment promote an invasive cancer cell phenotype by modulating the Hippo-YAP1 pathway. 

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