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The role of RAC1 in resistance to targeted therapies in cancer

Small GTPases 2024年第1期15卷 1-14页

作者： Cristina Uribe-Alvarez Jonathan Chernoff Cancer Signaling & Microenvironment Program Fox Chase Cancer Center Philadelphia PA USA.

RAC1 is a small 21 kDa RHO GTPase that plays a pivotal role in regulating actin cytoskeletal dynamics and cell growth. Alterations in the activity of RAC1 are implicated in a range of diseases, including cancer. Increased RAC1 activity, due to overexpression and/or activating mutations, drives transcriptional upregulation, reactive oxygen species production, mesenchymal-to-epithelial transition, membrane ruffling, and uncontrolled cell proliferation, which are hallmarks of an oncogenic phenotype. While RAC1-activating mutations alone do not appear sufficient to transform cells, their combination with other common mutations, such as BRAF, NRAS, or NF1, have been linked to drug resistance and significantly worsen patient prognosis and hinder treatment responses. The precise mechanisms underlying drug resistance, and the regulation of splicing remain poorly understood. RAC1 is a challenging therapeutic target due to its ubiquitous presence and essential cellular functions. To date, there are no established standard treatments for cancers that harbour an additional RAC1 mutation or for RAC1-mediated drug resistance. Current experimental strategies aim to target RAC1 localization, its activators (. guanine nucleotide exchange factors) and downstream effectors. Regulating RAC1 expression by targeting epigenetic regulators, and direct targeting of RAC1 itself, may also be possible in the near future.

关键词： RAC1 RHO GTPases Signal transduction cancer drug resistance

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Impact of radiation therapy on the immunological tumor microenvironment

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Cell Chemical Biology 2025年第5期32卷 678-693页

作者： Guilbaud, Emma Naulin, Flavie Meziani, Lydia Deutsch, Eric Galluzzi, Lorenzo Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA United States Department of Radiotherapy Gustave Roussy Cancer Campus Villejuif France INSERM RAMO-IT U1030 Villejuif France Faculty of Medicine University of Paris-Saclay Bicêtre Le Kremlin France

External beam radiation therapy (RT) is a cornerstone of modern cancer management, being utilized in both curative and palliative settings due to its safety, efficacy, and widespread availability. A primary biological effect of RT is DNA damage, which leads to significant cytostatic and cytotoxic effects. Importantly, malignant cells possess a limited capacity for DNA repair compared to normal cells, and when combined with irradiation techniques that minimize damage to healthy tissues, this creates an advantageous therapeutic window. However, the clinical effectiveness of RT also appears to involve both direct and indirect interactions between RT and non-transformed components of the tumoral ecosystem, particularly immune cells. In this review, we describe the molecular and cellular mechanisms by which irradiated cancer cells modify the immunological tumor microenvironment and how such changes ultimately impact tumor growth. © 2025 Elsevier Ltd

关键词： CD8+ cytotoxic T lymphocytes CGAS/STING signaling dendritic cells immune checkpoint inhibitors PD-1 tumor-associated macrophages

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A macrophage-neutrophil program drives mammary carcinogenesis

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Trends in cancer 2025年第5期11卷 427-429页

作者： Lukas Bolini Simon R V Knott Lorenzo Galluzzi Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA USA. Department of Biomedical Sciences Cedars-Sinai Medical Center Los Angeles CA USA. Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA USA. Electronic address: deadoc80@***.

The molecular and cellular pathways through which breast cancer evades immunosurveillance remain poorly understood. Recent data from Camargo et al. demonstrate that - on recruitment to the tumor microenvironment by ductal macrophages - a heterogeneous population of neutrophils can establish physical contacts with malignant cells within spatial niches that sustain mammary oncogenesis.

关键词： CCL3 MMTV-PyMT angiogenesis endothelial cells three Cs γδ T cells

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Challenges and Opportunities Modeling the Dynamic Tumor Matrisome

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Biomedical Engineering Frontiers 2023年第1期4卷 239-246页

作者： Shelly R.Peyton Manu O.Platt Edna Cukierman Department of Chemical Engineering University of Massachusetts AmherstAmherstMAUSA Coulter Department of Biomedical Engineering Georgia Institute of Technology and Emory UniversityAtlantaGAUSA Cancer Signaling&Microenvironment Program Marvin and Concetta Greenberg Pancreatic Cancer Institute.Fox Chase Cancer CenterTemple HealthPhiladelphiaPAUSA

We need novel strategies to target the complexity of cancer and,particularly,of metastatic *** an example of this complexity,certain tissues are particularly hospitable environments for metastases,whereas others do not contain fertile microenvironments to support cancer cell *** evidence that the extracellular matrix(ECM)of tissues is one of a host of factors necessary to support cancer cell growth at both primary and secondary tissue sites is *** on cancer metastasis has largely been focused on the molecular adaptations of tumor cells in various cytokine and growth factor environments on 2-dimensional tissue culture polystyrene *** imaging,conversely,has transformed our ability to watch,in real time,tumor cell invasion,intravasation,extravasation,and *** the interstitial ECM that supports all cells in the tumor microenvironment changes over time scales outside the possible window of typical intravital imaging,bioengineers are continuously developing both simple and sophisticated in vitro controlled environments to study tumor(and other)cell interactions with this *** this perspective,we focus on the cellular unit responsible for upholding the pathologic homeostasis of tumor-bearing organs,cancer-associated fibroblasts(CAFs),and their selfgenerated *** latter,together with tumoral and other cell secreted factors,constitute the“tumor matrisome”.We share the challenges and opportunities for modeling this dynamic CAF/ECM unit,the tools and techniques available,and how the tumor matrisome is remodeled(e.g.,via ECM proteases).We posit that increasing information on tumor matrisome dynamics may lead the field to alternative strategies for personalized medicine outside genomics.

关键词： invasion organs environments

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Novel metabolic routes to cancer immune evasion

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Trends in cancer 2025年

作者： Ayoub Jaa Aitziber Buque Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA USA. Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA USA. Electronic address: abuquemartinez@***.

The tumor microenvironment (TME) comprises heterogeneous cell types that closely interact with each other. Crosstalk among the TME components determines antitumor immune responses and their sensitivity to therapies such as immunotherapy. Recent studies published in cancer Cell by Tang et al. and Zhu et al. identify two novel metabolic adaptations that tumors use to facilitate immune evasion. These targetable mechanisms suggest new avenues to improve antitumor immune responses.

关键词： amino acids arginine breast cancer immunology metabolism tryptophan tumor microenvironment

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A novel anti-FGFR1 monoclonal antibody OM-RCA-01 exhibits potent antitumor activity and enhances the efficacy of immune checkpoint inhibitors in lung cancer models

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Immuno-Oncology and Technology 2024年 23卷 100725-100725页

作者： Tsimafeyeu, I. Makhov, P. Ovcharenko, D. Smith, J. Khochenkova, Y. Olshanskaya, A. Khochenkov, D. Bureau for Cancer Research - BUCARE New York Program in Cancer Signaling and Microenvironment Fox Chase Cancer Center Philadelphia Altogen Labs Austin United States N.N. Blokhin National Medical Research Center of Oncology Moscow Clinical Oncology Hospital No. 1 Moscow Center for Medicinal Chemistry Togliatti State University Togliatti Russian Federation

Background: Fibroblast growth factor receptor 1 (FGFR1) plays a crucial role in carcinogenesis. Exploring the combination of the novel humanized monoclonal anti-FGFR1 antibody OM-RCA-01 and immunotherapy was intriguing due to involvement of FGFR1 in mechanisms of resistance to checkpoint inhibitors. Materials and methods: Lung cancer A549, exhibiting distinct levels of FGFR1 expression, were cultured in basic FGF medium with OM-RCA-01 supplementation. The efficacy of antibody monotherapy was validated in a lung cancer xenograft study. To investigate whether OM-RCA-01 could enhance the efficacy of immunotherapy in vitro and in vivo, mixed lymphocyte reaction/Staphylococcal enterotoxin B assays and FGFR1/programmed death-ligand 1-positive patient-derived xenograft model were established. Results: The antibody effectively suppressed receptor phosphorylation, resulting in inhibited cell proliferation. OM-RCA-01 led to a substantial delay in tumor growth compared to non-specific immunoglobulin G in a xenograft study. The median tumor volume was 1048.5 mm³ and 2174 mm³ in the study and vehicle groups, respectively, representing a twofold difference in favor of the anti-FGFR1 antibody. In vitro, the combination of nivolumab and OM-RCA-01 resulted in higher levels of interferon gamma and interleukin-2 release compared with nivolumab alone. In vivo, pembrolizumab in combination with OM-RCA-01 produced a greater inhibitory effect on tumor growth compared with vehicle and pembrolizumab alone. The curve plateaued, indicating minimal tumor growth from day 16 onwards in the combination group. The OM-RCA-01 demonstrated no toxicity, even at therapeutic doses or higher doses. Conclusions: Our preclinical studies demonstrate that OM-RCA-01 exhibits robust activity with minimal toxicity. Combining an anti-FGFR1 antibody with a checkpoint inhibitor may enhance the efficacy of both drugs. However, further studies are needed to elucidate the mechanism of this inter

关键词： anti-FGFR1 monoclonal antibody fibroblast growth factor receptor 1 immune checkpoint inhibitors immunotargeted therapy

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DACIT: Device for Axon - cancer Cell Interaction Testing in 2D & 3D

SSRN

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SSRN 2025年

作者： Velazquez-Quesada, Ines Alizadeh, Vahid Allison, Kara Belova, Elizaveta Kallogjerovic, Svetllana Hesketh, Natasha Zhang, Xiaotian Thomas, Gareth Tuzel, Erkan Gligorijevic, Bojana Temple University Hospital United States Bioengineering Department Temple University PhiladelphiaPA19122 United States Lewis Katz School of Medicine Temple University PhiladelphiaPA19140 United States Cancer Signaling and Microenvironment Program Fox Chase Cancer Center PhiladelphiaPA19111 United States Fels Cancer Institute for Personalized Medicine Lewis Katz School of Medicine Temple University PhiladelphiaPA19140 United States

There is increasing interest in studying the role of peripheral innervation in tumor growth and metastasis. However, in vitro studies of interactions between cancer cells and axonal projections are technically challenging. To address this, we have developed a microfluidic Device for Axon-cancer cell Interaction Testing in 2D and 3D (DACIT). We show that DACIT successfully separates neuronal soma from the axons and cancer cells into two compartments, which can be exposed to similar, or different growth conditions, depending on the experimental needs. We compare neoaxonogenesis using either the PC-12 cell line or primary embryonic or adult sensory neurons, demonstrating superior neurite growth in primary cells. Additionally, we show that DACIT can accommodate assessing growth and 3D invasion of tumor spheroids, due to its unique height profile. Hence, DACIT can be used to analyze cancer cell interactions with axons in most typical cell biology assays such as proliferation, invasion, and calcium activity which we demonstrate on examples of imaging transients in GCaMP6-labeled neurons, invadopodia assay, and 3D cancer spheroid invasion. © 2025, The Authors. All rights reserved.

关键词： cancer cells

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Targeting CDK2 to circumvent treatment resistance in HR+ breast cancer

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Trends in molecular medicine 2024年

作者： Leire Arrizabalaga Esmeralda García-Torralba Lorenzo Galluzzi Aitziber Buqué Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA USA Program of Immunology and Immunotherapy Cima Universidad de Navarra Pamplona Spain Navarra Institute for Health Research (IDISNA) Pamplona Spain. Department of Medical Oncology Hospital Universitario Morales Meseguer Murcia Spain Department of Medicine Medical School University of Murcia Murcia Spain IMIB-Arrixaca Murcia Spain. Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA USA. Electronic address: deadoc80@***. Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA USA. Electronic address: abuquemartinez@***.

Genetic and epigenetic defects of the p53 system have previously been associated with resistance to CDK4/6 inhibitors in women with HR breast cancer. Recent data from Kudo et al. demonstrate that CDK2-targeting agents may offer an effective strategy to circumvent such resistance by enforcing cellular senescence downstream of RBL2 dephosphorylation.

关键词： DREAM complex MDM2 RB1 immune checkpoint inhibitors non-oncogene addiction type I interferon

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Defeating kinases that promote tumorigenesis through non-catalytic functions with PROTACs - PIM kinase as an example

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Emerging Therapeutic Targets 2025年第4-5期29卷

作者： Pedro Torres-Ayuso John Brognard a Department of Cancer and Cellular Biology Lewis Katz School of Medicine Temple University Philadelphia PA USAb Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA USA c Laboratory of Cell and Developmental Signaling National Cancer Institute National Institutes of Health Frederick MD USA

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Acetyl-NPKY of integrin-β1 binds KINDLIN2 to control endothelial cell proliferation and junctional integrity

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iScience 2024年第6期27卷 110129页

作者： Sidibé, Adama Mykuliak, Vasyl V. Zhang, Pingfeng Hytönen, Vesa P. Wu, Jinhua Wehrle-Haller, Bernhard Department of Cell Physiology and Metabolism University of Geneva Centre Médical Universitaire Rue Michel-Servet 1 Geneva CH-1211 Switzerland Faculty of Medicine and Health Technology Tampere University Arvo Ylpön katu 34 Tampere FI-33520 Finland Cancer Signaling and Microenvironment Program Fox Chase Cancer Center 333 Cottman Avenue Philadelphia 19111 PA United States Fimlab Laboratories Biokatu 4 Tampere FI-33520 Finland

Integrin-dependent crosstalk between cell-matrix adhesions and cell-cell junctions is critical for controlling endothelial permeability and proliferation in cancer and inflammatory diseases but remains poorly understood. Here, we investigated how acetylation of the distal NPKY-motif of Integrin-β1 influences endothelial cell physiology and barrier function. Expression of an acetylation-mimetic β1-K794Q-GFP mutant led to the accumulation of immature cell-matrix adhesions accompanied by a transcriptomic reprograming of endothelial cells, involving genes associated with cell adhesion, proliferation, polarity, and barrier function. β1-K794Q-GFP induced constitutive MAPK signaling, junctional impairment, proliferation, and reduced contact inhibition at confluence. Structural analysis of Integrin-β1 interaction with KINDLIN2, biochemical pulldown assay, and binding energy determination by using molecular dynamics simulation showed that acetylation of K794 and the K794Q-mutant increased KINDLIN2 binding affinity to the Integrin-β1. Thus, enhanced recruitment of KINDLIN2 to Lysine-acetylated Integrin-β1 and resulting modulation of barrier function, offers new therapeutic possibilities for controlling vascular permeability and disease conditions. © 2024 The Author(s)

关键词： Cell Cell biology Structural biology

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