RESUMEN
Cancer stem/tumor-initiating cells display stress tolerance and metabolic flexibility to survive in a harsh environment with limited nutrient and oxygen availability. The molecular mechanisms underlying this phenomenon could provide targets to prevent metabolic adaptation and halt cancer progression. Here, we showed in cultured cells and live human surgical biopsies of non-small cell lung cancer that nutrient stress drives the expression of the epithelial cancer stem cell marker integrin αvß3 via upregulation of the ß3 subunit, resulting in a metabolic reprogramming cascade that allows tumor cells to thrive despite a nutrient-limiting environment. Although nutrient deprivation is known to promote acute, yet transient, activation of the stress sensor AMP-activated protein kinase (AMPK), stress-induced αvß3 expression via Src activation unexpectedly led to secondary and sustained AMPK activation. This resulted in the nuclear localization of peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α) and upregulation of glutamine metabolism, the tricarboxylic acid cycle, and oxidative phosphorylation. Pharmacological or genetic targeting of this axis prevented lung cancer cells from evading the effects of nutrient stress, thereby blocking tumor initiation in mice following orthotopic implantation of lung cancer cells. These findings reveal a molecular pathway driven by nutrient stress that results in cancer stem cell reprogramming to promote metabolic flexibility and tumor initiation. SIGNIFICANCE: Upregulation of integrin αvß3, a cancer stem cell marker, in response to nutrient stress activates sustained AMPK/PGC1α signaling that induces metabolic reprogramming in lung cancer cells to support their survival. See related commentary by Rainero, p. 1543.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Integrina alfaVbeta3 , Neoplasias Pulmonares , Regulación hacia Arriba , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Animales , Integrina alfaVbeta3/metabolismo , Ratones , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Estrés Fisiológico , Nutrientes/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión GénicaRESUMEN
Tumor initiation at either primary or metastatic sites is an inefficient process in which tumor cells must fulfill a series of conditions. One critical condition involves the ability of individual tumor-initiating cells to overcome 'isolation stress', enabling them to survive within harsh isolating microenvironments that can feature nutrient stress, hypoxia, oxidative stress and the absence of a proper extracellular matrix (ECM). In response to isolation stress, tumor cells can exploit various adaptive strategies to develop stress tolerance and gain stemness features. In this Opinion, we discuss how strategies such as the induction of certain cell surface receptors and deposition of ECM proteins enable tumor cells to endure isolation stress, thereby gaining tumor-initiating potential. As examples, we highlight recent findings from our group demonstrating how exposure of tumor cells to isolation stress upregulates the G-protein-coupled receptor lysophosphatidic acid receptor 4 (LPAR4), its downstream target fibronectin and two fibronectin-binding integrins, α5ß1 and αvß3. These responses create a fibronectin-rich niche for tumor cells, ultimately driving stress tolerance, cancer stemness and tumor initiation. We suggest that approaches to prevent cancer cells from adapting to stress by suppressing LPAR4 induction, blocking its downstream signaling or disrupting fibronectin-integrin interactions hold promise as potential strategies for cancer treatment.
Asunto(s)
Fibronectinas , Integrinas , Fibronectinas/metabolismo , Adhesión Celular/fisiología , Regulación hacia Arriba , Integrinas/metabolismo , Integrina alfa5beta1/metabolismo , Matriz Extracelular/metabolismo , Integrina alfaVbeta3/metabolismoRESUMEN
While the tumor microenvironment is a critical contributor to cancer progression, early steps of tumor initiation and metastasis also rely on the ability of individual tumor cells to survive and thrive at locations where tumor stroma or immune infiltration has yet to be established. In this opinion article, we use the term 'isolation stress' to broadly describe the challenges that individual tumor cells must overcome during the initiation and expansion of the primary tumor beyond permissive boundaries and metastatic spread into distant sites, including a lack of cell-cell contact, adhesion to protumor extracellular matrix proteins, and access to nutrients, oxygen, and soluble factors that support growth. In particular, we highlight the ability of solitary tumor cells to autonomously generate a specialized fibronectin-enriched extracellular matrix to create their own pericellular niche that supports tumor initiation. Cancer cells that can creatively evade the effects of isolation stress not only become more broadly stress tolerant, they also tend to show enhanced stemness, drug resistance, tumor initiation, and metastasis.
RESUMEN
Defining drivers of tumour initiation can provide opportunities to control cancer progression. Here we report that lysophosphatidic acid receptor 4 (LPAR4) becomes transiently upregulated on pancreatic cancer cells exposed to environmental stress or chemotherapy where it promotes stress tolerance, drug resistance, self-renewal and tumour initiation. Pancreatic cancer cells gain LPAR4 expression in response to stress by downregulating a tumour suppressor, miR-139-5p. Even in the absence of exogenous lysophosphatidic acid, LPAR4-expressing tumour cells display an enrichment of extracellular matrix genes that are established drivers of cancer stemness. Mechanistically, upregulation of fibronectin via an LPAR4/AKT/CREB axis is indispensable for LPAR4-induced tumour initiation and stress tolerance. Moreover, ligation of this fibronectin-containing matrix via integrins α5ß1 or αVß3 can transfer stress tolerance to LPAR4-negative cells. Therefore, stress- or drug-induced LPAR4 enhances cell-autonomous production of a fibronectin-rich extracellular matrix, allowing cells to survive 'isolation stress' and compensate for the absence of stromal-derived factors by creating their own tumour-initiating niche.
Asunto(s)
MicroARNs , Neoplasias Pancreáticas , Receptores Purinérgicos P2 , Humanos , Fibronectinas/genética , Fibronectinas/metabolismo , Neoplasias Pancreáticas/patología , Matriz Extracelular/metabolismo , Transformación Celular Neoplásica/metabolismo , Receptores Purinérgicos P2/metabolismo , MicroARNs/genética , Neoplasias PancreáticasRESUMEN
Zika virus (ZIKV) causes microcephaly by killing neural precursor cells (NPCs) and other brain cells. ZIKV also displays therapeutic oncolytic activity against glioblastoma (GBM) stem cells (GSCs). Here we demonstrate that ZIKV preferentially infected and killed GSCs and stem-like cells in medulloblastoma and ependymoma in a SOX2-dependent manner. Targeting SOX2 severely attenuated ZIKV infection, in contrast to AXL. As mechanisms of SOX2-mediated ZIKV infection, we identified inverse expression of antiviral interferon response genes (ISGs) and positive correlation with integrin αv (ITGAV). ZIKV infection was disrupted by genetic targeting of ITGAV or its binding partner ITGB5 and by an antibody specific for integrin αvß5. ZIKV selectively eliminated GSCs from species-matched human mature cerebral organoids and GBM surgical specimens, which was reversed by integrin αvß5 inhibition. Collectively, our studies identify integrin αvß5 as a functional cancer stem cell marker essential for GBM maintenance and ZIKV infection, providing potential brain tumor therapy.
Asunto(s)
Glioblastoma , Células-Madre Neurales , Infección por el Virus Zika , Virus Zika , Humanos , Receptores de Vitronectina , Factores de Transcripción SOXB1/genéticaRESUMEN
Tumor-associated macrophages (TAM) are highly expressed within the tumor microenvironment of a wide range of cancers, where they exert a protumor phenotype by promoting tumor cell growth and suppressing antitumor immune function. Here, we show that TAM accumulation in human and mouse tumors correlates with tumor cell expression of integrin αvß3, a known driver of epithelial cancer progression and drug resistance. A monoclonal antibody targeting αvß3 (LM609) exploited the coenrichment of αvß3 and TAMs to not only eradicate highly aggressive drug-resistant human lung and pancreas cancers in mice, but also to prevent the emergence of circulating tumor cells. Importantly, this antitumor activity in mice was eliminated following macrophage depletion. Although LM609 had no direct effect on tumor cell viability, it engaged macrophages but not natural killer (NK) cells to induce antibody-dependent cellular cytotoxicity (ADCC) of αvß3-expressing tumor cells despite their expression of the CD47 "don't eat me" signal. In contrast to strategies designed to eliminate TAMs, these findings suggest that anti-αvß3 represents a promising immunotherapeutic approach to redirect TAMs to serve as tumor killers for late-stage or drug-resistant cancers. SIGNIFICANCE: Therapeutic antibodies are commonly engineered to optimize engagement of NK cells as effectors. In contrast, LM609 targets αvß3 to suppress tumor progression and enhance drug sensitivity by exploiting TAMs to trigger ADCC.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Integrina alfaVbeta3/inmunología , Macrófagos/inmunología , Neoplasias Glandulares y Epiteliales/inmunología , Animales , Antineoplásicos/farmacología , Progresión de la Enfermedad , Humanos , Ratones , Neoplasias Glandulares y Epiteliales/patología , Fagocitosis/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
While molecular subtypes of glioblastoma (GBM) are defined using gene expression and mutation profiles, we identify a unique subpopulation based on addiction to the high-affinity glucose transporter, Glut3. Although Glut3 is a known driver of a cancer stem cell phenotype, direct targeting is complicated by its expression in neurons. Using established GBM lines and patient-derived stem cells, we identify a subset of tumors within the "proneural" and "classical" subtypes that are addicted to aberrant signaling from integrin αvß3, which activates a PAK4-YAP/TAZ signaling axis to enhance Glut3 expression. This defined subpopulation of GBM is highly sensitive to agents that disrupt this pathway, including the integrin antagonist cilengitide, providing a targeted therapeutic strategy for this unique subset of GBM tumors.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Transportador de Glucosa de Tipo 3/metabolismo , Integrina alfaVbeta3/metabolismo , Transcriptoma , Animales , Antineoplásicos/farmacología , Neoplasias Encefálicas/mortalidad , Línea Celular Tumoral , Perfilación de la Expresión Génica , Glioblastoma/mortalidad , Humanos , Estimación de Kaplan-Meier , Ratones , Ratones Desnudos , Transducción de Señal , Venenos de Serpiente/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Identifying the molecular basis for cancer cell dependence on oncogenes such as KRAS can provide new opportunities to target these addictions. Here, we identify a novel role for the carbohydrate-binding protein galectin-3 as a lynchpin for KRAS dependence. By directly binding to the cell surface receptor integrin αvß3, galectin-3 gives rise to KRAS addiction by enabling multiple functions of KRAS in anchorage-independent cells, including formation of macropinosomes that facilitate nutrient uptake and ability to maintain redox balance. Disrupting αvß3/galectin-3 binding with a clinically active drug prevents their association with mutant KRAS, thereby suppressing macropinocytosis while increasing reactive oxygen species to eradicate αvß3-expressing KRAS-mutant lung and pancreatic cancer patient-derived xenografts and spontaneous tumors in mice. Our work reveals galectin-3 as a druggable target for KRAS-addicted lung and pancreas cancers, and indicates integrin αvß3 as a biomarker to identify susceptible tumors.Significance: There is a significant unmet need for therapies targeting KRAS-mutant cancers. Here, we identify integrin αvß3 as a biomarker to identify mutant KRAS-addicted tumors that are highly sensitive to inhibition of galectin-3, a glycoprotein that binds to integrin αvß3 to promote KRAS-mediated activation of AKT. Cancer Discov; 7(12); 1464-79. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1355.
Asunto(s)
Galectina 3/genética , Neoplasias Pulmonares/genética , Proteínas ras/genética , Animales , Galectina 3/metabolismo , Humanos , Neoplasias Pulmonares/patología , Ratones , Transducción de SeñalRESUMEN
Rather than targeting tumour cells directly, elements of the tumour microenvironment can be modulated to sensitize tumours to the effects of therapy. Here we report a unique mechanism by which ectopic microRNA-103 can manipulate tumour-associated endothelial cells to enhance tumour cell death. Using gain-and-loss of function approaches, we show that miR-103 exacerbates DNA damage and inhibits angiogenesis in vitro and in vivo. Local, systemic or vascular-targeted delivery of miR-103 in tumour-bearing mice decreased angiogenesis and tumour growth. Mechanistically, miR-103 regulation of its target gene TREX1 in endothelial cells governs the secretion of pro-inflammatory cytokines into the tumour microenvironment. Our data suggest that this inflammatory milieu may potentiate tumour cell death by supporting immune activation and inducing tumour expression of Fas and TRAIL receptors. Our findings reveal miR-mediated crosstalk between vasculature and tumour cells that can be exploited to improve the efficacy of chemotherapy and radiation.
Asunto(s)
Exodesoxirribonucleasas/genética , MicroARNs/metabolismo , Neoplasias/genética , Neovascularización Patológica/genética , Fosfoproteínas/genética , Microambiente Tumoral/genética , Animales , Línea Celular Tumoral , Regulación hacia Abajo , Exodesoxirribonucleasas/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/administración & dosificación , MicroARNs/genética , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapia , Neovascularización Patológica/patología , Neovascularización Patológica/radioterapia , Fosfoproteínas/metabolismo , ARN Interferente Pequeño/metabolismo , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Microambiente Tumoral/efectos de la radiación , Ensayos Antitumor por Modelo de Xenoinjerto , Receptor fas/metabolismoRESUMEN
Although oncology therapy regimens commonly include radiation and genotoxic drugs, tumour cells typically develop resistance to these interventions. Here we report that treatment of tumours with ionizing radiation or genotoxic drugs drives p21-activated kinase 1 (PAK1)-mediated phosphorylation of CRAF on Serine 338 (pS338) triggering a kinase-independent mechanism of DNA repair and therapeutic resistance. CRAF pS338 recruits CHK2, a cell cycle checkpoint kinase involved in DNA repair, and promotes CHK2 phosphorylation/activation to enhance the tumour cell DNA damage response. Accordingly, a phospho-mimetic mutant of CRAF (S338D) is sufficient to induce the CRAF/CHK2 association enhancing tumour radioresistance, while an allosteric CRAF inhibitor sensitizes tumour cells to ionizing radiation or genotoxic drugs. Our findings establish a role for CRAF in the DNA damage response that is independent from its canonical function as a kinase.
Asunto(s)
Quinasa de Punto de Control 2/efectos de la radiación , Daño del ADN/efectos de la radiación , Proteínas Proto-Oncogénicas c-raf/efectos de la radiación , Tolerancia a Radiación/genética , Radiación Ionizante , Quinasas p21 Activadas/efectos de la radiación , Animales , Línea Celular Tumoral , Quinasa de Punto de Control 2/metabolismo , Daño del ADN/genética , Técnica del Anticuerpo Fluorescente , Células HCT116 , Humanos , Immunoblotting , Inmunoprecipitación , Ratones , Mutación , Trasplante de Neoplasias , Fosforilación/efectos de la radiación , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-raf/genética , Serina/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasas p21 Activadas/genéticaRESUMEN
Integrin αvß3 has been implicated as a driver of aggressive and metastatic disease, and is upregulated during glioblastoma progression. Here, we demonstrate that integrin αvß3 allows glioblastoma cells to counteract senescence through a novel tissue-specific effector mechanism involving recruitment and activation of the cytoskeletal regulatory kinase PAK4. Mechanistically, targeting either αvß3 or PAK4 led to emergence of a p21-dependent, p53-independent cell senescence phenotype. Notably, glioblastoma cells did not exhibit a similar requirement for either other integrins or additional PAK family members. Moreover, αvß3/PAK4 dependence was not found to be critical in epithelial cancers. Taken together, our findings established that glioblastomas are selectively addicted to this pathway as a strategy to evade oncogene-induced senescence, with implications that inhibiting the αvß3-PAK4 signaling axis may offer novel therapeutic opportunities to target this aggressive cancer.
Asunto(s)
Neoplasias Encefálicas/genética , Senescencia Celular/genética , Glioblastoma/genética , Integrina alfaVbeta3/genética , Quinasas p21 Activadas/genética , Animales , Neoplasias Encefálicas/patología , Proliferación Celular/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Femenino , Glioblastoma/patología , Humanos , Integrina alfaVbeta3/metabolismo , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Interferencia de ARN , ARN Interferente Pequeño , Transducción de Señal/genética , Esferoides Celulares , Trasplante Heterólogo , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/genética , Vitronectina/metabolismo , Quinasas p21 Activadas/metabolismoRESUMEN
Interactions between cancer cells and their surroundings can trigger essential signaling cues that determine cell fate and influence the evolution of the malignant phenotype. As the primary receptors involved in cell-matrix adhesion, integrins present on the surface of tumor and stromal cells have a profound impact on the ability to survive in specific locations, but in some cases, these receptors can also function in the absence of ligand binding to promote stemness and survival in the presence of environmental and therapeutic stresses. Understanding how integrin expression and function is regulated in this context will enable the development of new therapeutic approaches to sensitize tumors to therapy and suppress their metastatic phenotype.
Asunto(s)
Resistencia a Medicamentos/efectos de los fármacos , Integrinas/metabolismo , Metástasis de la Neoplasia/terapia , Neoplasias/metabolismo , Células Madre/metabolismo , Adhesión Celular , Humanos , Neoplasias/terapia , Transducción de Señal , Células del EstromaAsunto(s)
Resistencia a Antineoplásicos , Receptores ErbB/antagonistas & inhibidores , Integrina beta3/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas/metabolismo , Proteínas de Unión al GTP ral/metabolismo , Proteínas ras/metabolismo , Animales , Femenino , HumanosRESUMEN
Recently in Cell Reports, Goel et al. (2014) identified mechanisms underlying cellular heterogeneity in triple negative breast cancer. They find that expression of α6 integrin and its splice variants differs between epithelial and mesenchymal tumor cell subpopulations, the latter of which relies on VEGF signaling to promote cancer stem cell function.
Asunto(s)
Integrina alfa6/metabolismo , Células Madre Neoplásicas/metabolismo , Empalme del ARN/fisiología , Femenino , HumanosRESUMEN
Tumour cells, with stem-like properties, are highly aggressive and often show drug resistance. Here, we reveal that integrin α(v)ß3 serves as a marker of breast, lung and pancreatic carcinomas with stem-like properties that are highly resistant to receptor tyrosine kinase inhibitors such as erlotinib. This was observed in vitro and in mice bearing patient-derived tumour xenografts or in clinical specimens from lung cancer patients who had progressed on erlotinib. Mechanistically, α(v)ß3, in the unliganded state, recruits KRAS and RalB to the tumour cell plasma membrane, leading to the activation of TBK1 and NF-κB. In fact, α(v)ß3 expression and the resulting KRAS-RalB-NF-κB pathway were both necessary and sufficient for tumour initiation, anchorage independence, self-renewal and erlotinib resistance. Pharmacological targeting of this pathway with bortezomib reversed both tumour stemness and erlotinib resistance. These findings not only identify α(v)ß3 as a marker/driver of carcinoma stemness but also reveal a therapeutic strategy to sensitize such tumours to RTK inhibition.
Asunto(s)
Resistencia a Antineoplásicos , Receptores ErbB/antagonistas & inhibidores , Integrina beta3/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas/metabolismo , Proteínas de Unión al GTP ral/metabolismo , Proteínas ras/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos Clínicos Fase II como Asunto , Resistencia a Antineoplásicos/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib , Femenino , Humanos , Integrina alfaVbeta3/metabolismo , Integrina beta3/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Terapia Molecular Dirigida , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Fenotipo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-rel/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-rel/metabolismo , Proteínas Proto-Oncogénicas p21(ras) , Quinazolinas/uso terapéutico , Interferencia de ARN , Ensayos Clínicos Controlados Aleatorios como Asunto , Transducción de Señal/efectos de los fármacos , Esferoides Celulares , Factores de Tiempo , Transfección , Carga Tumoral/efectos de los fármacos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas de Unión al GTP ral/genética , Proteínas ras/genéticaRESUMEN
Disseminated tumour cells (DTCs) can adopt a state of long-term dormancy. However, when and why they emerge from quiescence has remained unclear. Distinct microvascular niches are now shown to regulate this process. Mature blood vessels produce signals that sustain tumour cell quiescence, whereas sprouting microvasculature provides stimuli that reactivate DTCs, leading to metastatic relapse.
Asunto(s)
Neoplasias de la Médula Ósea/secundario , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/patología , Endotelio Vascular/patología , Neoplasias Pulmonares/secundario , Neoplasia Residual/patología , Neovascularización Patológica , Pericitos/patología , Animales , Femenino , HumanosRESUMEN
Vascular cell adhesion molecule-1 (VCAM-1) plays important roles in development and inflammation. Tumor necrosis factor-α (TNF-α) and focal adhesion kinase (FAK) are key regulators of inflammatory and integrin-matrix signaling, respectively. Integrin costimulatory signals modulate inflammatory gene expression, but the important control points between these pathways remain unresolved. We report that pharmacological FAK inhibition prevented TNF-α-induced VCAM-1 expression within heart vessel-associated endothelial cells in vivo, and genetic or pharmacological FAK inhibition blocked VCAM-1 expression during development. FAK signaling facilitated TNF-α-induced, mitogen-activated protein kinase activation, and, surprisingly, FAK inhibition resulted in the loss of the GATA4 transcription factor required for TNF-α-induced VCAM-1 production. FAK inhibition also triggered FAK nuclear localization. In the nucleus, the FAK-FERM (band 4.1, ezrin, radixin, moesin homology) domain bound directly to GATA4 and enhanced its CHIP (C terminus of Hsp70-interacting protein) E3 ligase-dependent polyubiquitination and degradation. These studies reveal new developmental and anti-inflammatory roles for kinase-inhibited FAK in limiting VCAM-1 production via nuclear localization and promotion of GATA4 turnover.
Asunto(s)
Núcleo Celular/metabolismo , Quinasa 1 de Adhesión Focal/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismo , Transporte Activo de Núcleo Celular , Animales , Células Cultivadas , Embrión de Mamíferos/metabolismo , Activación Enzimática , Quinasa 1 de Adhesión Focal/genética , Factor de Transcripción GATA4/metabolismo , Regulación del Desarrollo de la Expresión Génica , Humanos , Ratones , Ratones Transgénicos , Factor de Necrosis Tumoral alfa/metabolismo , UbiquitinaciónRESUMEN
Receptor tyrosine kinases and integrins play an essential role in tumor cell invasion and metastasis. We previously showed that EGF and other growth factors induce human carcinoma cell invasion and metastasis mediated by integrin αvß5 that is prevented by Src blockade. MUC1, a transmembrane glycoprotein, is expressed in most epithelial tumors as a heterodimer consisting of an extracellular and a transmembrane subunit. The MUC1 cytoplasmic domain of the transmembrane subunit (MUC1.CD) translocates to the nucleus where it promotes the transcription of a metastatic gene signature associated with epithelial to mesenchymal transition. Here, we demonstrate a requirement for MUC1 in carcinoma cell metastasis dependent on EGFR and Src without affecting primary tumor growth. EGF stimulates Src-dependent MUC1 cleavage and nuclear localization leading to the expression of genes linked to metastasis. Moreover, expression of MUC1.CD results in its nuclear localization and is sufficient for transcription of the metastatic gene signature and tumor cell metastasis. These results demonstrate that EGFR and Src activity contribute to carcinoma cell invasion and metastasis mediated by integrin αvß5 in part by promoting proteolytic cleavage of MUC1 and highlight the ability of MUC1.CD to promote metastasis in a context-dependent manner. Our findings may have implications for the use and future design of targeted therapies in cancers known to express EGFR, Src, or MUC1.