RESUMO
Cellular locomotion is required for survival, fertility, proper embryonic development, regeneration, and wound healing. Cell migration is a major component of metastasis, which accounts for two-thirds of all solid tumor deaths. While many studies have demonstrated increased energy requirements, metabolic rates, and migration of cancer cells compared with normal cells, few have systematically compared normal and cancer cell migration as well as energy requirements side by side. Thus, we investigated how non-malignant and malignant cells migrate, utilizing several cell lines from the breast and lung. Initial screening was performed in an unbiased high-throughput manner for the ability to migrate/invade on collagen and/or Matrigel. We unexpectedly observed that all the non-malignant lung cells moved significantly faster than cells derived from lung tumors regardless of the growth media used. Given the paradigm-shifting nature of our discovery, we pursued the mechanisms that could be responsible. Neither mass, cell doubling, nor volume accounted for the individual speed and track length of the normal cells. Non-malignant cells had higher levels of intracellular ATP at premigratory-wound induction stages. Meanwhile, cancer cells also increased intracellular ATP at premigratory-wound induction, but not to the levels of the normal cells, indicating the possibility for further therapeutic investigation.
RESUMO
Identifying the cell(s) of origin for lung cancer including detecting their expansion during "field cancerization" and understanding how to therapeutically target them for beneficial chemoprevention is an urgent need. In this issue of Cancer Research, Yin and colleagues provide new and potentially controversial information to this question using Gprc5a knockout genetically engineered mouse models of lung adenocarcinoma. Prior research identified several different cell types including resident lung stem/progenitor such as alveolar type II cells as well as terminally differentiated cells as candidates for the cancer-initiating cell. Yin and colleagues provide new information that the cancer-initiating cell in this model is the bronchioalveolar stem cell. See related article by Yin et al., p. 1025.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Animais , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Camundongos , Receptores Acoplados a Proteínas G , Células-Tronco/metabolismoRESUMO
Discovered as a proto-oncogene 40 years ago, mutations in KRAS exist in â¼30% of all human cancers. In this issue of Cell Stem Cell,Dost et al. (2020) combine the power of analyzing organoid cultures, patient samples, and mouse models with scRNA-seq to elucidate early events occurring with oncogenic KRAS activation.
Assuntos
Proteínas Proto-Oncogênicas , Proteínas ras , Humanos , Pulmão/metabolismo , Mutação/genética , Organoides/metabolismo , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Células-Tronco/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
Increased expression of zinc finger E-box binding homeobox 1 (ZEB1) is associated with tumor grade and metastasis in lung cancer, likely due to its role as a transcription factor in epithelial-to-mesenchymal transition (EMT). Here, we modeled malignant transformation in human bronchial epithelial cells (HBECs) and determined that EMT and ZEB1 expression are early, critical events in lung cancer pathogenesis. Specific oncogenic mutations in TP53 and KRAS were required for HBECs to engage EMT machinery in response to microenvironmental (serum/TGF-ß) or oncogenetic (MYC) factors. Both TGF-ß- and MYC-induced EMT required ZEB1, but engaged distinct TGF-ß-dependent and vitamin D receptor-dependent (VDR-dependent) pathways, respectively. Functionally, we found that ZEB1 causally promotes malignant progression of HBECs and tumorigenicity, invasion, and metastases in non-small cell lung cancer (NSCLC) lines. Mechanistically, ZEB1 expression in HBECs directly repressed epithelial splicing regulatory protein 1 (ESRP1), leading to increased expression of a mesenchymal splice variant of CD44 and a more invasive phenotype. In addition, ZEB1 expression in early stage IB primary NSCLC correlated with tumor-node-metastasis stage. These findings indicate that ZEB1-induced EMT and associated molecular changes in ESRP1 and CD44 contribute to early pathogenesis and metastatic potential in established lung cancer. Moreover, TGF-ß and VDR signaling and CD44 splicing pathways associated with ZEB1 are potential EMT chemoprevention and therapeutic targets in NSCLC.
Assuntos
Transição Epitelial-Mesenquimal , Receptores de Hialuronatos/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Ligação a RNA/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/metabolismo , Linhagem Celular , Transformação Celular Neoplásica , Feminino , Humanos , Neoplasias Pulmonares/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Microcirculação , Invasividade Neoplásica , Metástase Neoplásica , Fenótipo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores de Calcitriol/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genéticaRESUMO
Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumour suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. Here we show, however, that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN messenger RNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma development with broad implications for cancer pathogenesis.
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Amplificação de Genes/genética , MicroRNAs/genética , Neuroblastoma/genética , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Proteínas de Ligação a RNA/genética , Regiões 3' não Traduzidas/genética , Animais , Deleção Cromossômica , Feminino , Deleção de Genes , Genes Neoplásicos/genética , Humanos , Camundongos , MicroRNAs/metabolismo , Modelos Genéticos , Proteína Proto-Oncogênica N-Myc , Neuroblastoma/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Small cell lung carcinoma (SCLC) is a high-grade pulmonary neuroendocrine tumor. The transcription factors ASCL1 and NEUROD1 play crucial roles in promoting malignant behavior and survival of human SCLC cell lines. Here, we find that ASCL1 and NEUROD1 identify heterogeneity in SCLC, bind distinct genomic loci, and regulate mostly distinct genes. ASCL1, but not NEUROD1, is present in mouse pulmonary neuroendocrine cells, and only ASCL1 is required in vivo for tumor formation in mouse models of SCLC. ASCL1 targets oncogenic genes including MYCL1, RET, SOX2, and NFIB while NEUROD1 targets MYC. ASCL1 and NEUROD1 regulate different genes that commonly contribute to neuronal function. ASCL1 also regulates multiple genes in the NOTCH pathway including DLL3. Together, ASCL1 and NEUROD1 distinguish heterogeneity in SCLC with distinct genomic landscapes and distinct gene expression programs.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Camundongos , Células Neuroendócrinas/metabolismo , Oncogenes/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Cigarette smoking is a major risk factor for acquisition of small cell lung cancer (SCLC). A role has been demonstrated for the basic helix-loop-helix transcription factor NeuroD1 in the pathogenesis of neural and neuroendocrine lung cancer, including SCLC. In the present study we investigate the possible function of NeuroD1 in established tumors, as well as actions early on in pathogenesis, in response to nicotine. We demonstrate that nicotine up-regulates NeuroD1 in immortalized normal bronchial epithelial cells and a subset of undifferentiated carcinomas. Increased expression of NeuroD1 subsequently leads to regulation of expression and function of the nicotinic acetylcholine receptor subunit cluster of α3, α5, and ß4. In addition, we find that coordinated expression of these subunits by NeuroD1 leads to enhanced nicotine-induced migration and invasion, likely through changes in intracellular calcium. These findings suggest that aspects of the pathogenesis of neural and neuroendocrine lung cancers may be affected by a nicotine- and NeuroD1-induced positive feedback loop.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Movimento Celular/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Nicotina/farmacologia , Subunidades Proteicas/metabolismo , Receptores Nicotínicos/metabolismo , Brônquios/patologia , Cálcio/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células Clonais , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Neoplasias Pulmonares/patologia , Modelos Biológicos , Mutação , Invasividade Neoplásica , Receptor trkB/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Small-cell lung cancer and other aggressive neuroendocrine cancers are often associated with early dissemination and frequent metastases. We demonstrate that neurogenic differentiation 1 (NeuroD1) is a regulatory hub securing cross talk among survival and migratory-inducing signaling pathways in neuroendocrine lung carcinomas. We find that NeuroD1 promotes tumor cell survival and metastasis in aggressive neuroendocrine lung tumors through regulation of the receptor tyrosine kinase tropomyosin-related kinase B (TrkB). Like TrkB, the prometastatic signaling molecule neural cell adhesion molecule (NCAM) is a downstream target of NeuroD1, whose impaired expression mirrors loss of NeuroD1. TrkB and NCAM may be therapeutic targets for aggressive neuroendocrine cancers that express NeuroD1.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Movimento Celular/fisiologia , Sobrevivência Celular/fisiologia , Neoplasias Pulmonares/fisiopatologia , Moléculas de Adesão de Célula Nervosa/metabolismo , Receptor trkB/metabolismo , Carcinoma de Pequenas Células do Pulmão/fisiopatologia , Análise de Variância , Animais , Carbazóis , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Primers do DNA/genética , Furanos , Humanos , Immunoblotting , Imunoprecipitação , Luciferases , Neoplasias Pulmonares/metabolismo , Camundongos , Análise em Microsséries , Plasmídeos/genética , Reação em Cadeia da Polimerase em Tempo Real , Carcinoma de Pequenas Células do Pulmão/metabolismoRESUMO
The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade is the prototype mammalian mitogen-activated protein kinase (MAPK) signaling cascade that regulates a number of processes, including proliferation, differentiation, survival, migration, stress responses and apoptosis. How this seemingly linear cascade is modulated to achieve a specific cellular function has been a main focus of the field. In this review, we describe new as well as old findings in the regulation of the ERK1/2 pathway in normal and disease states via MAP3Ks.