RESUMO
The role of epithelial-to-mesenchymal transition (EMT) in metastasis is a longstanding source of debate, largely owing to an inability to monitor transient and reversible EMT phenotypes in vivo. Here we establish an EMT lineage-tracing system to monitor this process in mice, using a mesenchymal-specific Cre-mediated fluorescent marker switch system in spontaneous breast-to-lung metastasis models. We show that within a predominantly epithelial primary tumour, a small proportion of tumour cells undergo EMT. Notably, lung metastases mainly consist of non-EMT tumour cells that maintain their epithelial phenotype. Inhibiting EMT by overexpressing the microRNA miR-200 does not affect lung metastasis development. However, EMT cells significantly contribute to recurrent lung metastasis formation after chemotherapy. These cells survived cyclophosphamide treatment owing to reduced proliferation, apoptotic tolerance and increased expression of chemoresistance-related genes. Overexpression of miR-200 abrogated this resistance. This study suggests the potential of an EMT-targeting strategy, in conjunction with conventional chemotherapies, for breast cancer treatment.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Metástase Neoplásica/patologia , Animais , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem da Célula , Proliferação de Células/efeitos dos fármacos , Rastreamento de Células , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Modelos Animais de Doenças , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Neoplasias Mamárias Experimentais/genética , Camundongos , MicroRNAs/genética , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/genética , Reprodutibilidade dos TestesRESUMO
Inflammation is inextricably associated with primary tumor progression. However, the contribution of inflammation to tumor outgrowth in metastatic organs has remained underexplored. Here, we show that extrinsic inflammation in the lungs leads to the recruitment of bone marrow-derived neutrophils, which degranulate azurophilic granules to release the Ser proteases, elastase and cathepsin G, resulting in the proteolytic destruction of the antitumorigenic factor thrombospondin-1 (Tsp-1). Genetic ablation of these neutrophil proteases protected Tsp-1 from degradation and suppressed lung metastasis. These results provide mechanistic insights into the contribution of inflammatory neutrophils to metastasis and highlight the unique neutrophil protease-Tsp-1 axis as a potential antimetastatic therapeutic target.
Assuntos
Neoplasias Pulmonares/metabolismo , Neutrófilos/metabolismo , Peptídeo Hidrolases/metabolismo , Pneumonia/metabolismo , Trombospondina 1/metabolismo , Animais , Western Blotting , Transplante de Medula Óssea , Catepsina G/metabolismo , Linhagem Celular Tumoral , Feminino , Citometria de Fluxo , Expressão Gênica , Elastase de Leucócito/metabolismo , Lipopolissacarídeos/administração & dosagem , Neoplasias Pulmonares/secundário , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/enzimologia , Proteólise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serina Proteases/metabolismo , Trombospondina 1/genéticaRESUMO
Physiological signal monitoring and driver behavior analysis have gained increasing attention in both fundamental research and applied research. This study involved the analysis of driving behavior using multimodal physiological data collected from 35 participants. The data included 59-channel EEG, single-channel ECG, 4-channel EMG, single-channel GSR, and eye movement data obtained via a six-degree-of-freedom driving simulator. We categorized driving behavior into five groups: smooth driving, acceleration, deceleration, lane changing, and turning. Through extensive experiments, we confirmed that both physiological and vehicle data met the requirements. Subsequently, we developed classification models, including linear discriminant analysis (LDA), MMPNet, and EEGNet, to demonstrate the correlation between physiological data and driving behaviors. Notably, we propose a multimodal physiological dataset for analyzing driving behavior(MPDB). The MPDB dataset's scale, accuracy, and multimodality provide unprecedented opportunities for researchers in the autonomous driving field and beyond. With this dataset, we will contribute to the field of traffic psychology and behavior.
Assuntos
Condução de Veículo , Movimentos Oculares , HumanosRESUMO
Single cell lineage tracing, essential for unraveling cellular dynamics in disease evolution is critical for developing targeted therapies. CRISPR-Cas9, known for inducing permanent and cumulative mutations, is a cornerstone in lineage tracing. The novel homing guide RNA (hgRNA) technology enhances this by enabling dynamic retargeting and facilitating ongoing genetic modifications. Charting these mutations, especially through successive hgRNA edits, poses a significant challenge. Our solution, LINEMAP, is a computational framework designed to trace and map these mutations with precision. LINEMAP meticulously discerns mutation alleles at single-cell resolution and maps their complex interrelationships through a mutation evolution network. By utilizing a Markov Process model, we can predict mutation transition probabilities, revealing potential mutational routes and pathways. Our reconstruction algorithm, anchored in the Markov model's attributes, reconstructs cellular lineage pathways, shedding light on the cell's evolutionary journey to the minutiae of single-cell division. Our findings reveal an intricate network of mutation evolution paired with a predictive Markov model, advancing our capability to reconstruct single-cell lineage via hgRNA. This has substantial implications for advancing our understanding of biological mechanisms and propelling medical research forward.
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Epithelial-to-mesenchymal transition (EMT) contributes significantly to chemotherapy resistance and remains a critical challenge in treating advanced breast cancer. The complexity of EMT, involving redundant pro-EMT signaling pathways and its paradox reversal process, mesenchymal-to-epithelial transition (MET), has hindered the development of effective treatments. In this study, we utilized a Tri-PyMT EMT lineage-tracing model and single-cell RNA sequencing (scRNA-seq) to comprehensively analyze the EMT status of tumor cells. Our findings revealed elevated ribosome biogenesis (RiBi) during the transitioning phases of both EMT and MET processes. RiBi and its subsequent nascent protein synthesis mediated by ERK and mTOR signalings are essential for EMT/MET completion. Importantly, inhibiting excessive RiBi genetically or pharmacologically impaired the EMT/MET capability of tumor cells. Combining RiBi inhibition with chemotherapy drugs synergistically reduced metastatic outgrowth of epithelial and mesenchymal tumor cells under chemotherapies. Our study suggests that targeting the RiBi pathway presents a promising strategy for treating patients with advanced breast cancer. Significance: This study uncovers the crucial involvement of ribosome biogenesis (RiBi) in the regulation of epithelial and mesenchymal state oscillations in breast cancer cells, which plays a major role in the development of chemoresistant metastasis. By proposing a novel therapeutic strategy targeting the RiBi pathway, the study offers significant potential to enhance treatment efficacy and outcomes for patients with advanced breast cancer. This approach could help overcome the limitations of current chemotherapy options and address the complex challenges posed by EMT-mediated chemoresistance.
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IRE1α-XBP1 signaling is emerging as a central orchestrator of malignant progression and immunosuppression in various cancer types. Employing a computational XBP1s detection method applied to TCGA datasets, we demonstrate that expression of the XBP1s mRNA isoform predicts poor survival in non-small cell lung cancer (NSCLC) patients. Ablation of IRE1α in malignant cells delays tumor progression and extends survival in mouse models of NSCLC. This protective effect is accompanied by alterations in intratumoral immune cell subsets eliciting durable adaptive anti-cancer immunity. Mechanistically, cancer cell-intrinsic IRE1α activation sustains mPGES-1 expression, enabling production of the immunosuppressive lipid mediator prostaglandin E2. Accordingly, restoring mPGES-1 expression in IRE1αKO cancer cells rescues normal tumor progression. We have developed an IRE1α gene signature that predicts immune cell infiltration and overall survival in human NSCLC. Our study unveils an immunoregulatory role for cancer cell-intrinsic IRE1α activation and suggests that targeting this pathway may help enhance anti-tumor immunity in NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Endorribonucleases , Neoplasias Pulmonares , Proteínas Serina-Treonina Quinases , Animais , Humanos , Camundongos , Carcinoma Pulmonar de Células não Pequenas/genética , Endorribonucleases/genética , Endorribonucleases/metabolismo , Neoplasias Pulmonares/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/metabolismoRESUMO
TCF1high progenitor CD8+ T cells mediate the efficacy of PD-1 blockade, however the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1high central memory-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2KO CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites, and increased PPP cycling as determined by 1,2 13C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8+ T cells towards a TCF1high population, generated a unique transcriptional landscape, enhanced tumor control in mice in combination with PD-1 blockade, and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state amenable to checkpoint blockade.
RESUMO
Radiation therapy (RT) in combination with immune checkpoint inhibitor (ICI) represents a promising regimen for non-small cell lung cancer (NSCLC), however, the underlying mechanisms are poorly characterized. We identified a specific dose of RT that conferred tumor regression and improved survival in NSCLC models when combined with ICI. The immune-modulating functions of RT was ascribed to activated lung-resident Scgb1a1+ club cells. Importantly, mice with club cell-specific knockout of synaptosome-associated protein 23 failed to benefit from the combination treatment, indicating a pivotal role of club cell secretome. We identified 8 club cells secretory proteins, which inhibited immunosuppressive myeloid cells, reduced pro-tumor inflammation, and enhanced anti-tumor immunity. Notably, CC10, a member of club cell secretome was increased in plasma of NSCLC patients responding to the combination therapy. By revealing an immune-regulatory role of club cells, our studies have the potential to guide future clinical trials of ICI in NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Uteroglobina/uso terapêuticoRESUMO
Copper serves as a co-factor for a host of metalloenzymes that contribute to malignant progression. The orally bioavailable copper chelating agent tetrathiomolybdate (TM) has been associated with a significant survival benefit in high-risk triple negative breast cancer (TNBC) patients. Despite these promising data, the mechanisms by which copper depletion impacts metastasis are poorly understood and this remains a major barrier to advancing TM to a randomized phase II trial. Here, using two independent TNBC models, we report a discrete subpopulation of highly metastatic SOX2/OCT4+ cells within primary tumors that exhibit elevated intracellular copper levels and a marked sensitivity to TM. Global proteomic and metabolomic profiling identifies TM-mediated inactivation of Complex IV as the primary metabolic defect in the SOX2/OCT4+ cell population. We also identify AMPK/mTORC1 energy sensor as an important downstream pathway and show that AMPK inhibition rescues TM-mediated loss of invasion. Furthermore, loss of the mitochondria-specific copper chaperone, COX17, restricts copper deficiency to mitochondria and phenocopies TM-mediated alterations. These findings identify a copper-metabolism-metastasis axis with potential to enrich patient populations in next-generation therapeutic trials.
Assuntos
Cobre/metabolismo , Mitocôndrias/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Linhagem Celular Tumoral , Proteínas de Transporte de Cobre/genética , Proteínas de Transporte de Cobre/metabolismo , Feminino , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/genética , Metástase Neoplásica , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Fosforilação Oxidativa , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Emerging evidence indicates that bone marrow (BM)-derived endothelial progenitor cells (EPCs) contribute to angiogenesis-mediated growth of certain tumors in mice and human. EPCs regulate the angiogenic switch via paracrine secretion of proangiogenic growth factors and by direct luminal incorporation into sprouting nascent vessels. While the contributions of EPCs to neovessel formation in spontaneous and transplanted tumors and to the metastatic transition have been reported to be relatively low, remarkably, specific EPC ablation in vivo has resulted in severe angiogenesis inhibition and impaired primary and metastatic tumor growth. The existence of a BM reservoir of EPCs, and the selective involvement of EPCs in neovascularization, have attracted considerable interest because these cells represent novel target for therapeutic intervention. In addition, EPCs are also being used as pharmacodynamic surrogate markers for monitoring cancer progression, as well as for optimizing efficacy of anti-angiogenic therapies in the clinic. This review will focus primarily on recent advances and emerging concepts in the field of EPC biology and discuss ongoing debates involving the role of EPCs in tumor neovascularization. For detailed information on the in vitro characterization of EPCs contribution to non-tumor pathologies, the reader is directed towards several excellent reviews and publications [F. Bertolini, Y. Shaked, P. Mancuso and R.S. Kerbel, Nat. Rev., Cancer 6 (2006) 835-845. [1]] [J.M. Hill, T. Finkel and A.A. Quyyumi, Vox Sang. 87 Suppl 2 (2004) 31-37. [2]] [A.Y. Khakoo and T. Finkel, Annu. Rev. Med. 56 (2005) 79-101. [3]] [H.G. Kopp, C.A. Ramos and S. Rafii, Curr. Opin. Hematol. 13 (2006) 175-181. [4]; K.K. Hirschi, D.A. Ingram and M.C. Yoder, Arterioscler. Thromb. Vasc. Biol. 28 (2008) 1584-1595. [5]; F. Timmermans, J. Plum, M.C. Yoder, D.A. Ingram, B. Vandekerckhove and J. Case, J. Cell. Mol. Med. 13 (2009) 87-102. [6]] and reviews by Bertolini, Voest and Yoder in this issue.
Assuntos
Células Endoteliais/fisiologia , Neoplasias/patologia , Células-Tronco/fisiologia , Medula Óssea , Proliferação de Células , Previsões , Humanos , Proteína 1 Inibidora de Diferenciação/fisiologia , Metástase Neoplásica , Neoplasias/irrigação sanguínea , Neovascularização PatológicaRESUMO
The versatility of Ca2+ as a second messenger lies in the complex manner in which Ca2+ signals are generated. How information contained within the Ca2+ code is interpreted underlies cell function. Recently, we identified CAPRI and RASAL as related Ca2+-triggered Ras GTPase-activating proteins. RASAL tracks agonist-stimulated Ca2+ oscillations by repetitively associating with the plasma membrane, yet CAPRI displays a long-lasting Ca2+-triggered translocation that is refractory to cytosolic Ca2+ oscillations. CAPRI behavior is Ca2+- and C2 domain-dependent but sustained recruitment is predominantly Ca2+ independent, necessitating integration of Ca2+ by the C2 domains with agonist-evoked plasma membrane interaction sites for the pleckstrin homology domain. Using an assay to monitor Ras activity in real time, we correlate the spatial and temporal translocation of CAPRI with the deactivation of H-Ras. CAPRI seems to low-pass filter the Ca2+ signal, converting different intensities of stimulation into different durations of Ras activity in contrast to the preservation of Ca2+ frequency information by RASAL, suggesting sophisticated modes of Ca2+-regulated Ras deactivation.
Assuntos
Sinalização do Cálcio/fisiologia , Proteínas Ativadoras de ras GTPase/metabolismo , Proteínas ras/fisiologia , Animais , Células CHO , Cálcio/metabolismo , Membrana Celular/metabolismo , Cricetinae , Cricetulus , Genes ras , Proteínas de Fluorescência Verde/genética , Células HeLa , Humanos , Estrutura Terciária de Proteína , Transporte Proteico , Sistemas do Segundo Mensageiro/fisiologia , Proteínas Ativadoras de ras GTPase/genética , Proteínas ras/genéticaRESUMO
Metastases are responsible for the majority of breast cancer-associated deaths. The contribution of epithelial-to-mesenchymal transition (EMT) in the establishment of metastases is still controversial. To obtain in vivo evidence of EMT in metastasis, we established an EMT lineage tracing (Tri-PyMT) model, in which tumor cells undergoing EMT would irreversibly switch their fluorescent marker from RFP+ to GFP+ due to mesenchymal-specific Cre expression. Surprisingly, we found that lung metastases were predominantly derived from the epithelial compartment of breast tumors. However, concerns were raised on the fidelity and sensitivity of RFP-to-GFP switch of this model in reporting EMT of metastatic tumor cells. Here, we evaluated Tri-PyMT cells at the single-cell level using single-cell RNA-sequencing and found that the Tri-PyMT cells exhibited a spectrum of EMT phenotypes, with EMT-related genes concomitantly expressed with the activation of GFP. The fluorescent color switch in these cells precisely marked an unequivocal change in EMT status, defining the pre-EMT and post-EMT compartments within the tumor. Consistently, the pre-EMT cells played dominant roles in metastasis, while the post-EMT cells were supportive in promoting tumor invasion and angiogenesis. Importantly, the post-EMT (GFP+) cells in the Tri-PyMT model were not permanently committed to the mesenchymal phenotype; they were still capable of reverting to the epithelial phenotype and giving rise to secondary tumors, suggesting their persistent EMT plasticity. Our study addressed major concerns with the Tri-PyMT EMT lineage tracing model, which provides us with a powerful tool to investigate the dynamic EMT process in tumor biology. SIGNIFICANCE: These findings confirm the fidelity and sensitivity of the EMT lineage tracing (Tri-PyMT) model and highlight the differential contributions of pre- and post-EMT tumor cells in breast cancer metastasis.See related commentary by Bunz, p. 153.
Assuntos
Neoplasias da Mama , Neoplasias Pulmonares , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Humanos , FenótipoRESUMO
Epigenetic changes are increasingly being appreciated as key events in breast cancer progression. However, breast cancer subtype-specific epigenetic regulation remains poorly investigated. Here we report that EZH2 is a leading candidate of epigenetic modulators associated with the TNBC subtype and that it predicts poor overall survival in TNBC patients. We demonstrate that specific pharmacological or genetic inhibition of EZH2 catalytic activity impairs distant metastasis. We further define a specific EZH2high population with enhanced invasion, mammosphere formation, and metastatic potential that exhibits marked sensitivity to EZH2 inhibition. Mechanistically, EZH2 inhibition differentiates EZH2high basal cells to a luminal-like phenotype by derepressing GATA3 and renders them sensitive to endocrine therapy. Furthermore, dissection of human TNBC heterogeneity shows that EZH2high basal-like 1 and mesenchymal subtypes have exquisite sensitivity to EZH2 inhibition compared with the EZH2low luminal androgen receptor subtype. These preclinical findings provide a rationale for clinical development of EZH2 as a targeted therapy against TNBC metastasis.
Assuntos
Biocatálise , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Sequência de Bases , Compartimento Celular , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Epigênese Genética , Feminino , Fator de Transcrição GATA3/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Camundongos SCID , Proteínas Mutantes/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Fator 3 de Transcrição de Octâmero/metabolismo , Fenótipo , Fatores de Transcrição SOXB1/metabolismo , Neoplasias de Mama Triplo Negativas/genéticaRESUMO
Experimental evidence accumulated over decades has implicated epithelial-mesenchymal plasticity (EMP), which collectively encompasses epithelial-mesenchymal transition and the reverse process of mesenchymal-epithelial transition, in tumour metastasis, cancer stem cell generation and maintenance, and therapeutic resistance. However, the dynamic nature of EMP processes, the apparent need to reverse mesenchymal changes for the development of macrometastases and the likelihood that only minor cancer cell subpopulations exhibit EMP at any one time have made such evidence difficult to accrue in the clinical setting. In this Perspectives article, we outline the existing preclinical and clinical evidence for EMP and reflect on recent controversies, including the failure of initial lineage-tracing experiments to confirm a major role for EMP in dissemination, and discuss accumulating data suggesting that epithelial features and/or a hybrid epithelial-mesenchymal phenotype are important in metastasis. We also highlight strategies to address the complexities of therapeutically targeting the EMP process that give consideration to its spatially and temporally divergent roles in metastasis, with the view that this will yield a potent and broad class of therapeutic agents.
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Plasticidade Celular , Transição Epitelial-Mesenquimal , Metástase Neoplásica/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Células-Tronco Neoplásicas/patologia , Animais , Linhagem Celular Tumoral , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Humanos , Imunoterapia , Camundongos , Invasividade Neoplásica , Células-Tronco Neoplásicas/metabolismo , Fenótipo , RatosRESUMO
Lung cancer is a major global health problem, as it is the leading cause of cancer-related deaths worldwide. Major advances in the identification of key mutational alterations have led to the development of molecularly targeted therapies, whose efficacy has been limited by emergence of resistance mechanisms. US Food and Drug Administration (FDA)-approved therapies targeting angiogenesis and more recently immune checkpoints have reinvigorated enthusiasm in elucidating the prognostic and pathophysiological roles of the tumour microenvironment in lung cancer. In this Review, we highlight recent advances and emerging concepts for how the tumour-reprogrammed lung microenvironment promotes both primary lung tumours and lung metastasis from extrapulmonary neoplasms by contributing to inflammation, angiogenesis, immune modulation and response to therapies. We also discuss the potential of understanding tumour microenvironmental processes to identify biomarkers of clinical utility and to develop novel targeted therapies against lung cancer.
Assuntos
Proliferação de Células/fisiologia , Neoplasias Pulmonares/patologia , Metástase Neoplásica/patologia , Microambiente Tumoral/fisiologia , Animais , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Neoplasias Pulmonares/metabolismo , Processos Neoplásicos , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , PrognósticoRESUMO
BACKGROUND: Metastasis is the primary cause of mortality in cancer patients. Therefore, elucidating the genetics and epigenetics of metastatic tumor cells and the mechanisms by which tumor cells acquire metastatic properties constitute significant challenges in cancer research. OBJECTIVE: To summarize the current understandings of the specific genotype and phenotype of the metastatic tumor cells. METHOD AND RESULT: In-depth genetic analysis of tumor cells, especially with advances in the next-generation sequencing, have revealed insights of the genotypes of metastatic tumor cells. Also, studies have shown that the cancer stem cell (CSC) and epithelial to mesenchymal transition (EMT) phenotypes are associated with the metastatic cascade. CONCLUSION: In this review, we will discuss recent advances in the field by focusing on the genomic instability and phenotypic dynamics of metastatic tumor cells.
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Success of immune checkpoint inhibitors in advanced non-small-cell lung cancer (NSCLC) has invigorated their use in the neoadjuvant setting for early-stage disease. However, the cellular and molecular mechanisms of the early immune responses to therapy remain poorly understood. Through an integrated analysis of early-stage NSCLC patients and a Kras mutant mouse model, we show a prevalent programmed cell death 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) axis exemplified by increased intratumoral PD-1+ T cells and PD-L1 expression. Notably, tumor progression was associated with spatiotemporal modulation of the immune microenvironment with dominant immunosuppressive phenotypes at later phases of tumor growth. Importantly, PD-1 inhibition controlled tumor growth, improved overall survival, and reprogrammed tumor-associated lymphoid and myeloid cells. Depletion of T lymphocyte subsets demonstrated synergistic effects of those populations on PD-1 inhibition of tumor growth. Transcriptome analyses revealed T cell subset-specific alterations corresponding to degree of response to the treatment. These results provide insights into temporal evolution of the phenotypic effects of PD-1/PD-L1 activation and inhibition and motivate targeting of this axis early in lung cancer progression.
Assuntos
Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/imunologia , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Receptor de Morte Celular Programada 1/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Imunoterapia , Pulmão/patologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas p21(ras) , Linfócitos T , Microambiente Tumoral/imunologiaRESUMO
Molecularly targeted therapies benefit approximately 15-20% of non-small cell lung cancer (NSCLC) patients carrying specific drug-sensitive mutations. Thus, there is a clinically unmet need for the identification of novel targets for drug development. Here, we performed RNA-deep sequencing to identify altered gene expression between malignant and non-malignant lung tissue. Matrix Metalloproteinase 14 (MMP14), a membrane-bound proteinase, was significantly up-regulated in the tumor epithelial cells and intratumoral myeloid compartments in both mouse and human NSCLC. Overexpression of a soluble dominant negative MMP14 (DN-MMP14) or pharmacological inhibition of MMP14 blocked invasion of lung cancer cells through a collagen I matrix in vitro and reduced tumor incidence in an orthotopic K-RasG12D/+p53-/- mouse model of lung cancer. Additionally, MMP14 activity mediated proteolytic processing and activation of Heparin-Binding EGF-like Growth Factor (HB-EGF), stimulating the EGFR signaling pathway to increase proliferation and tumor growth. This study highlights the potential for development of therapeutic strategies that target MMP14 in NSCLC with particular focus on MMP14-HB-EGF axis.