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1.
Lancet Oncol ; 19(9): e470-e481, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30191851

RESUMO

Small-cell lung cancer (SCLC) is an aggressive tumour that seeds metastases early with dismal outcomes. As expected from a disease that is closely associated with smoking, mutation burden in SCLC is high. Intratumoral and intertumoral heterogeneity is a substantial obstacle to successful treatment and the SCLC genomic landscape reveals few targets that are readily druggable. Chemotherapy elicits responses in most patients with SCLC, but their effects are short lived. Multiple clinical trials have been unsuccessful in showing positive survival outcomes and biomarkers to select patients and monitor responses to novel targeted treatments have been lacking, not least because acquisition of tumour biopsies, especially during relapse after chemotherapy, is a substantial challenge. Liquid biopsies via blood sampling in SCLC, notably circulating tumour cells and circulating free tumour DNA can be readily and repeatedly accessed, and are beginning to yield promising data to inform SCLC biology and patient treatment. Primary cell cultures and preclinical mouse models can also be derived from the relatively plentiful SCLC circulating tumour cells providing a tractable platform for SCLC translational research and drug development.


Assuntos
DNA Tumoral Circulante/sangue , Biópsia Líquida , Neoplasias Pulmonares/diagnóstico , Células Neoplásicas Circulantes/química , Células Neoplásicas Circulantes/patologia , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Animais , DNA Tumoral Circulante/genética , Tomada de Decisão Clínica , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular , Estadiamento de Neoplasias , Seleção de Pacientes , Medicina de Precisão , Valor Preditivo dos Testes , Carcinoma de Pequenas Células do Pulmão/sangue , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/secundário
2.
Nature ; 475(7354): 106-9, 2011 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-21734707

RESUMO

Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer. Normally, ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors and is predominantly regulated by the transcription factor Nrf2 (also known as Nfe2l2) and its repressor protein Keap1 (refs 2-5). In contrast to the acute physiological regulation of Nrf2, in neoplasia there is evidence for increased basal activation of Nrf2. Indeed, somatic mutations that disrupt the Nrf2-Keap1 interaction to stabilize Nrf2 and increase the constitutive transcription of Nrf2 target genes were recently identified, indicating that enhanced ROS detoxification and additional Nrf2 functions may in fact be pro-tumorigenic. Here, we investigated ROS metabolism in primary murine cells following the expression of endogenous oncogenic alleles of Kras, Braf and Myc, and found that ROS are actively suppressed by these oncogenes. K-Ras(G12D), B-Raf(V619E) and Myc(ERT2) each increased the transcription of Nrf2 to stably elevate the basal Nrf2 antioxidant program and thereby lower intracellular ROS and confer a more reduced intracellular environment. Oncogene-directed increased expression of Nrf2 is a new mechanism for the activation of the Nrf2 antioxidant program, and is evident in primary cells and tissues of mice expressing K-Ras(G12D) and B-Raf(V619E), and in human pancreatic cancer. Furthermore, genetic targeting of the Nrf2 pathway impairs K-Ras(G12D)-induced proliferation and tumorigenesis in vivo. Thus, the Nrf2 antioxidant and cellular detoxification program represents a previously unappreciated mediator of oncogenesis.


Assuntos
Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Oncogenes/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Alelos , Animais , Antioxidantes/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Células Cultivadas , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibroblastos/metabolismo , Genes myc/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch , Sistema de Sinalização das MAP Quinases , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/deficiência , Fator 2 Relacionado a NF-E2/genética , Células NIH 3T3 , Oxirredução , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
3.
Gut ; 65(3): 465-75, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26347531

RESUMO

OBJECTIVES: Pancreatic cancer (PCa) is treatable by surgery when detected at an early stage. Non-invasive imaging methods able to detect both established tumours and their precursor lesions are needed to select patients for surgery. We investigated here whether pancreatic preneoplasia could be detected prior to the development of invasive cancers in genetically engineered mouse models of PCa using metabolic imaging. DESIGN: The concentrations of alanine and lactate and the activities of lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) were measured in extracts prepared from the pancreas of animals at different stages of disease progression; from pancreatitis, through tissue with predominantly low-grade and then high-grade pancreatic intraepithelial neoplasia and then tumour. (13)C magnetic resonance spectroscopic imaging ((13)C-MRSI) was used to measure non-invasively changes in (13)C labelling of alanine and lactate with disease progression, following injection of hyperpolarised [1-(13)C]pyruvate. RESULTS: Progressive decreases in the alanine/lactate concentration ratio and ALT/LDH activity ratio with disease progression were accompanied by a corresponding decrease in the [1-(13)C]alanine/[1-(13)C]lactate signal ratio observed in (13)C-MRSI images of the pancreas. CONCLUSIONS: Metabolic imaging with hyperpolarised [1-(13)C]pyruvate enables detection and monitoring of the progression of PCa precursor lesions. Translation of this MRI technique to the clinic has the potential to improve the management of patients at high risk of developing PCa.


Assuntos
Espectroscopia de Ressonância Magnética Nuclear de Carbono-13/métodos , Carcinoma Ductal Pancreático/diagnóstico , Pâncreas/metabolismo , Neoplasias Pancreáticas/diagnóstico , Lesões Pré-Cancerosas/diagnóstico , Animais , Biomarcadores/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Progressão da Doença , Camundongos , Camundongos Transgênicos , Pâncreas/patologia , Neoplasias Pancreáticas/metabolismo , Pancreatite/diagnóstico , Pancreatite/metabolismo , Lesões Pré-Cancerosas/metabolismo , Ácido Pirúvico
4.
Nat Rev Cancer ; 7(9): 645-58, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17687385

RESUMO

Animal models of cancer provide an alternative means to determine the causes of and treatments for malignancy, thus representing a resource of immense potential for cancer medicine. The sophistication of modelling cancer in mice has increased to the extent that investigators can both observe and manipulate a complex disease process in a manner impossible to perform in patients. However, owing to limitations in model design and technology development, and the surprising underuse of existing models, only now are we realising the full potential of mouse models of cancer and what new approaches are needed to derive the maximum value for cancer patients from this investment.


Assuntos
Modelos Animais de Doenças , Modelos Animais , Neoplasias , Animais , Animais Geneticamente Modificados , Genes Supressores de Tumor , Humanos , Oncologia/tendências , Camundongos , Camundongos Transgênicos , Transplante de Neoplasias , Neoplasias/genética , Oncogenes
5.
Proc Natl Acad Sci U S A ; 110(30): 12325-30, 2013 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-23836645

RESUMO

Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant desmoplasia and poor tissue perfusion. These features are proposed to limit the access of therapies to neoplastic cells and blunt treatment efficacy. Indeed, several agents that target the PDA tumor microenvironment promote concomitant chemotherapy delivery and increased antineoplastic response in murine models of PDA. Prior studies could not determine whether chemotherapy delivery or microenvironment modulation per se were the dominant features in treatment response, and such information could guide the optimal translation of these preclinical findings to patients. To distinguish between these possibilities, we used a chemical inhibitor of cytidine deaminase to stabilize and thereby artificially elevate gemcitabine levels in murine PDA tumors without disrupting the tumor microenvironment. Additionally, we used the FG-3019 monoclonal antibody (mAb) that is directed against the pleiotropic matricellular signaling protein connective tissue growth factor (CTGF/CCN2). Inhibition of cytidine deaminase raised the levels of activated gemcitabine within PDA tumors without stimulating neoplastic cell killing or decreasing the growth of tumors, whereas FG-3019 increased PDA cell killing and led to a dramatic tumor response without altering gemcitabine delivery. The response to FG-3019 correlated with the decreased expression of a previously described promoter of PDA chemotherapy resistance, the X-linked inhibitor of apoptosis protein. Therefore, alterations in survival cues following targeting of tumor microenvironmental factors may play an important role in treatment responses in animal models, and by extension in PDA patients.


Assuntos
Anticorpos Monoclonais/imunologia , Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Fator de Crescimento do Tecido Conjuntivo/antagonistas & inibidores , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Anticorpos Monoclonais Humanizados , Antineoplásicos/administração & dosagem , Apoptose , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Fator de Crescimento do Tecido Conjuntivo/imunologia , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Neoplasias Hepáticas/secundário , Camundongos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Análise de Sobrevida , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Gencitabina
6.
Gut ; 63(6): 974-83, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24067278

RESUMO

DESIGN: Pharmacokinetic and pharmacodynamic parameters of cremophor-paclitaxel, nab-paclitaxel (human-albumin-bound paclitaxel, Abraxane) and a novel mouse-albumin-bound paclitaxel (m-nab-paclitaxel) were evaluated in genetically engineered mouse models (GEMMs) by liquid chromatography-tandem mass spectrometry (LC-MS/MS), histological and biochemical analysis. Preclinical evaluation of m-nab-paclitaxel included assessment by three-dimensional high-resolution ultrasound and molecular analysis in a novel secreted protein acidic and rich in cysteine (SPARC)-deficient GEMM of pancreatic ductal adenocarcinoma (PDA). RESULTS: nab-Paclitaxel exerted its antitumoural effects in a dose-dependent manner and was associated with less toxicity compared with cremophor-paclitaxel. SPARC nullizygosity in a GEMM of PDA, Kras(G12D);p53(flox/-);p48Cre (KPfC), resulted in desmoplastic ductal pancreas tumours with impaired collagen maturation. Paclitaxel concentrations were significantly decreased in SPARC null plasma samples and tissues when administered as low-dose m-nab-paclitaxel. At the maximally tolerated dose, SPARC deficiency did not affect the intratumoural paclitaxel concentration, stromal deposition and the immediate therapeutic response. CONCLUSIONS: nab-Paclitaxel accumulates and acts in a dose-dependent manner. The interaction of plasma SPARC and albumin-bound drugs is observed at low doses of nab-paclitaxel but is saturated at therapeutic doses in murine tumours. Thus, this study provides important information for future preclinical and clinical trials in PDA using nab-paclitaxel in combination with novel experimental and targeted agents.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacocinética , Osteonectina/metabolismo , Paclitaxel/farmacocinética , Neoplasias Pancreáticas/tratamento farmacológico , Veículos Farmacêuticos/farmacocinética , Paclitaxel Ligado a Albumina , Albuminas/farmacocinética , Albuminas/uso terapêutico , Animais , Animais Geneticamente Modificados , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/uso terapêutico , Colágeno/metabolismo , Relação Dose-Resposta a Droga , Camundongos , Osteonectina/genética , Paclitaxel/sangue , Paclitaxel/uso terapêutico , Polietilenoglicóis/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Gut ; 62(1): 112-20, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22466618

RESUMO

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDA) is characterised by stromal desmoplasia and vascular dysfunction, which critically impair drug delivery. This study examines the role of an abundant extracellular matrix component, the megadalton glycosaminoglycan hyaluronan (HA), as a novel therapeutic target in PDA. METHODS: Using a genetically engineered mouse model of PDA, the authors enzymatically depleted HA by a clinically formulated PEGylated human recombinant PH20 hyaluronidase (PEGPH20) and examined tumour perfusion, vascular permeability and drug delivery. The preclinical utility of PEGPH20 in combination with gemcitabine was assessed by short-term and survival studies. RESULTS: PEGPH20 rapidly and sustainably depleted HA, inducing the re-expansion of PDA blood vessels and increasing the intratumoral delivery of two chemotherapeutic agents, doxorubicin and gemcitabine. Moreover, PEGPH20 triggered fenestrations and interendothelial junctional gaps in PDA tumour endothelia and promoted a tumour-specific increase in macromolecular permeability. Finally, combination therapy with PEGPH20 and gemcitabine led to inhibition of PDA tumour growth and prolonged survival over gemcitabine monotherapy, suggesting immediate clinical utility. CONCLUSIONS: The authors demonstrate that HA impedes the intratumoral vasculature in PDA and propose that its enzymatic depletion be explored as a means to improve drug delivery and response in patients with pancreatic cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/fisiologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Ácido Hialurônico/fisiologia , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/irrigação sanguínea , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/fisiopatologia , Moléculas de Adesão Celular/administração & dosagem , Moléculas de Adesão Celular/farmacologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Doxorrubicina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Hialuronoglucosaminidase/administração & dosagem , Hialuronoglucosaminidase/farmacologia , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Camundongos , Camundongos Transgênicos , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/fisiopatologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Análise Serial de Tecidos , Resultado do Tratamento , Gencitabina
8.
bioRxiv ; 2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38405859

RESUMO

Molecular subtypes of Small Cell Lung Cancer (SCLC) have been described based on differential expression of transcription factors (TFs) ASCL1, NEUROD1, POU2F3 and immune-related genes. We previously reported an additional subtype based on expression of the neurogenic TF ATOH1 within our SCLC Circulating tumour cell-Derived eXplant (CDX) model biobank. Here we show that ATOH1 protein was detected in 7/81 preclinical models and 16/102 clinical samples of SCLC. In CDX models, ATOH1 directly regulated neurogenesis and differentiation programs consistent with roles in normal tissues. In ex vivo cultures of ATOH1-positive CDX, ATOH1 was required for cell survival. In vivo, ATOH1 depletion slowed tumour growth and suppressed liver metastasis. Our data validate ATOH1 as a bona fide oncogenic driver of SCLC with tumour cell survival and pro-metastatic functions. Further investigation to explore ATOH1 driven vulnerabilities for targeted treatment with predictive biomarkers is warranted.

9.
Gut ; 61(6): 877-84, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22157328

RESUMO

OBJECTIVE: The lysosomal protease cathepsin B is upregulated in human pancreatic ductal adenocarcinoma (PDA) and represents a potential therapeutic target. Loss of cathepsin B delays tumour progression in mouse models of islet, mammary and intestinal carcinoma and decreases invasion and metastasis. This study examines the role of cathepsin B in the initiation, progression and metastasis of PDA. METHODS: Cathepsin B germline knockout mice were crossed with animals expressing an endogenous Kras(G12D) allele in the pancreas, and mice were aged to evaluate the role of cathepsin B in pancreatic intraepithelial neoplasia (PanIN). A survival study was also performed with mice carrying an additional heterozygous conditional Trp53(R172H) allele. Cell lines derived from tumours were used to investigate the role of cathepsin B in vitro, and subcutaneous allografts investigated the cell autonomous and non-cell autonomous roles of cathepsin B in pancreatic cancer. RESULTS: Constitutive cathepsin B loss resulted in delayed progression of both PanIN and PDA and a significant survival advantage in mice. Cathepsin B-deficient PDA cells and PanIN showed decreased proliferation and mitogen-activated protein (MAP) kinase signalling. The reconstitution of deficient cells with cathepsin B reversed these findings, which correlated with decreased levels of the active forms of the related protease cathepsin L. Conversely, acute ablation of cathepsin L activated the MAP kinase cascade in PDA cells. CONCLUSIONS: These results confirm that cathepsin B plays an important cell autonomous role in the progression of PDA and suggest that the regulation of cathepsin L by cathepsin B may be a means of stimulating cell proliferation in neoplasia.


Assuntos
Adenocarcinoma/fisiopatologia , Carcinoma Ductal Pancreático/fisiopatologia , Catepsina B/fisiologia , Neoplasias Pancreáticas/fisiopatologia , Adenocarcinoma/enzimologia , Alelos , Animais , Western Blotting , Carcinoma Ductal Pancreático/enzimologia , Catepsina B/genética , Catepsina L/fisiologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Heterozigoto , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transplante de Neoplasias , Neoplasias Pancreáticas/enzimologia
10.
J Thorac Oncol ; 18(10): 1362-1385, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37455012

RESUMO

INTRODUCTION: Vasculogenic mimicry (VM), the process of tumor cell transdifferentiation to endow endothelial-like characteristics supporting de novo vessel formation, is associated with poor prognosis in several tumor types, including SCLC. In genetically engineered mouse models (GEMMs) of SCLC, NOTCH, and MYC co-operate to drive a neuroendocrine (NE) to non-NE phenotypic switch, and co-operation between NE and non-NE cells is required for metastasis. Here, we define the phenotype of VM-competent cells and molecular mechanisms underpinning SCLC VM using circulating tumor cell-derived explant (CDX) models and GEMMs. METHODS: We analyzed perfusion within VM vessels and their association with NE and non-NE phenotypes using multiplex immunohistochemistry in CDX, GEMMs, and patient biopsies. We evaluated their three-dimensional structure and defined collagen-integrin interactions. RESULTS: We found that VM vessels are present in 23/25 CDX models, 2 GEMMs, and in 20 patient biopsies of SCLC. Perfused VM vessels support tumor growth and only NOTCH-active non-NE cells are VM-competent in vivo and ex vivo, expressing pseudohypoxia, blood vessel development, and extracellular matrix organization signatures. On Matrigel, VM-primed non-NE cells remodel extracellular matrix into hollow tubules in an integrin ß1-dependent process. CONCLUSIONS: We identified VM as an exemplar of functional heterogeneity and plasticity in SCLC and these findings take considerable steps toward understanding the molecular events that enable VM. These results support therapeutic co-targeting of both NE and non-NE cells to curtail SCLC progression and to improve the outcomes of patients with SCLC in the future.


Assuntos
Neoplasias Pulmonares , Animais , Camundongos , Humanos , Neoplasias Pulmonares/patologia , Neovascularização Patológica/genética , Transdiferenciação Celular , Linhagem Celular Tumoral
11.
Gut ; 60(6): 861-8, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20966025

RESUMO

Pancreatic ductal adenocarcinoma (PDA) is an almost uniformly lethal disease. One explanation for the devastating prognosis is the failure of many chemotherapies, including the current standard of care therapy gemcitabine. Although our knowledge of the molecular events underlying multistep carcinogenesis in PDA has steadily increased, translation into more effective therapeutic approaches has been inefficient over the last several decades. Evidence for this innate resistance to systemic therapies was recently provided in an accurate mouse model of PDA by the demonstration that chemotherapies are poorly delivered to PDA tissues because of a deficient vasculature. This vascular deficiency correlated with the presence of a dense stromal matrix that is a prominent histological hallmark of PDA tumours. Therapeutic targeting of stromal cells decreased the stroma from pancreatic tumours, resulting in increased intratumoral perfusion and therapeutic delivery of gemcitabine. Stromal cells contained within the PDA tumour microenvironment therefore represent an additional constituent to neoplastic cells that should be critically evaluated for optimal therapeutic development in preclinical models and early clinical trials.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Células Estromais/patologia , Animais , Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/patologia , Modelos Animais de Doenças , Engenharia Genética/métodos , Humanos , Camundongos , Camundongos Mutantes , Neoplasias Pancreáticas/patologia , Células Estromais/efeitos dos fármacos , Microambiente Tumoral/fisiologia
12.
Clin Cancer Res ; 28(10): 1999-2019, 2022 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-35091446

RESUMO

Poorly differentiated neuroendocrine carcinomas (PD-NEC) are rare cancers garnering interest as they become more commonly encountered in the clinic. This is due to improved diagnostic methods and the increasingly observed phenomenon of "NE lineage plasticity," whereby nonneuroendocrine (non-NE) epithelial cancers transition to aggressive NE phenotypes after targeted treatment. Effective treatment options for patients with PD-NEC are challenging for several reasons. This includes a lack of targetable, recurrent molecular drivers, a paucity of patient-relevant preclinical models to study biology and test novel therapeutics, and the absence of validated biomarkers to guide clinical management. Although advances have been made pertaining to molecular subtyping of small cell lung cancer (SCLC), a PD-NEC of lung origin, extrapulmonary (EP)-PD-NECs remain understudied. This review will address emerging SCLC-like, same-organ non-NE cancer-like and tumor-type-agnostic biological vulnerabilities of EP-PD-NECs, with the potential for therapeutic exploitation. The hypotheses surrounding the origin of these cancers and how "NE lineage plasticity" can be leveraged for therapeutic purposes are discussed. SCLC is herein proposed as a paradigm for supporting progress toward precision medicine in EP-PD-NECs. The aim of this review is to provide a thorough portrait of the current knowledge of EP-PD-NEC biology, with a view to informing new avenues for research and future therapeutic opportunities in these cancers of unmet need.


Assuntos
Carcinoma Neuroendócrino , Neoplasias Pulmonares , Tumores Neuroendócrinos , Carcinoma de Pequenas Células do Pulmão , Biomarcadores Tumorais/uso terapêutico , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Humanos , Recém-Nascido , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Carcinoma de Pequenas Células do Pulmão/patologia
13.
Nat Cancer ; 3(10): 1260-1270, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35941262

RESUMO

Small cell lung cancer (SCLC) is characterized by morphologic, epigenetic and transcriptomic heterogeneity. Subtypes based upon predominant transcription factor expression have been defined that, in mouse models and cell lines, exhibit potential differential therapeutic vulnerabilities, with epigenetically distinct SCLC subtypes also described. The clinical relevance of these subtypes is unclear, due in part to challenges in obtaining tumor biopsies for reliable profiling. Here we describe a robust workflow for genome-wide DNA methylation profiling applied to both patient-derived models and to patients' circulating cell-free DNA (cfDNA). Tumor-specific methylation patterns were readily detected in cfDNA samples from patients with SCLC and were correlated with survival outcomes. cfDNA methylation also discriminated between the transcription factor SCLC subtypes, a precedent for a liquid biopsy cfDNA-methylation approach to molecularly subtype SCLC. Our data reveal the potential clinical utility of cfDNA methylation profiling as a universally applicable liquid biopsy approach for the sensitive detection, monitoring and molecular subtyping of patients with SCLC.


Assuntos
Ácidos Nucleicos Livres , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Animais , Camundongos , Ácidos Nucleicos Livres/genética , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Epigenoma/genética , Metilação de DNA/genética , Neoplasias Pulmonares/diagnóstico , Fatores de Transcrição/genética
14.
Nat Cell Biol ; 5(11): 987-93, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14562058

RESUMO

During early embryogenesis in Drosophila melanogaster, extensive vesicle transport occurs to build cell boundaries for 6,000 nuclei. Here we show that this important process depends on a functional complex formed between the tumour suppressor and adaptor protein Discs-Large (Dlg) and the integral membrane protein Strabismus (Stbm)/Van Gogh (Vang). In support of this idea, embryos with mutations in either dlg or stbm displayed severe defects in plasma membrane formation. Conversely, overexpression of Dlg and Stbm synergistically induced excessive plasma membrane formation. In addition, ectopic co-expression of Stbm (which associated with post-Golgi vesicles) and the mammalian Dlg homologue SAP97/hDlg promoted translocation of SAP97 from the cytoplasm to both post-Golgi vesicles and the plasma membrane. This effect was dependent on the interaction between Stbm and SAP97. These findings suggest that the Dlg-Stbm complex recruits membrane-associated proteins and lipids from internal membranes to sites of new plasma membrane formation.


Assuntos
Membrana Celular , Proteínas de Drosophila/fisiologia , Proteínas de Membrana/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Animais , Células COS , Drosophila melanogaster/embriologia , Drosophila melanogaster/fisiologia , Desenvolvimento Embrionário , Imuno-Histoquímica , Mutação , Técnicas do Sistema de Duplo-Híbrido
15.
Cancer Cell ; 39(3): 297-299, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33577787

RESUMO

In this issue of Cancer Cell, Gay et al. describe a molecular classification of small cell lung cancers and extend prior studies that highlight the potential for personalized treatments. Notably, they identify a new "inflamed" subtype that may emerge following acquired chemoresistance but which may become more susceptible to immunotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Medicina de Precisão , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética
16.
Open Biol ; 11(1): 200247, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33435818

RESUMO

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. Although advances are being made towards earlier detection and the development of impactful targeted therapies and immunotherapies, the 5-year survival of patients with advanced disease is still below 20%. Effective cancer research relies on pre-clinical model systems that accurately reflect the evolutionary course of disease progression and mimic patient responses to therapy. Here, we review pre-clinical models, including genetically engineered mouse models and patient-derived materials, such as cell lines, primary cell cultures, explant cultures and xenografts, that are currently being used to interrogate NSCLC evolution from pre-invasive disease through locally invasive cancer to the metastatic colonization of distant organ sites.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Modelos Biológicos , Animais , Carcinogênese , Modelos Animais de Doenças , Humanos , Metástase Neoplásica , Recidiva Local de Neoplasia , Microambiente Tumoral
17.
Nat Commun ; 12(1): 6652, 2021 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-34789728

RESUMO

Small cell lung cancer (SCLC) has a 5-year survival rate of <7%. Rapid emergence of acquired resistance to standard platinum-etoposide chemotherapy is common and improved therapies are required for this recalcitrant tumour. We exploit six paired pre-treatment and post-chemotherapy circulating tumour cell patient-derived explant (CDX) models from donors with extensive stage SCLC to investigate changes at disease progression after chemotherapy. Soluble guanylate cyclase (sGC) is recurrently upregulated in post-chemotherapy progression CDX models, which correlates with acquired chemoresistance. Expression and activation of sGC is regulated by Notch and nitric oxide (NO) signalling with downstream activation of protein kinase G. Genetic targeting of sGC or pharmacological inhibition of NO synthase re-sensitizes a chemoresistant CDX progression model in vivo, revealing this pathway as a mediator of chemoresistance and potential vulnerability of relapsed SCLC.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Etoposídeo/uso terapêutico , Neoplasias Pulmonares/metabolismo , Carcinoma de Pequenas Células do Pulmão/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Animais , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores Enzimáticos/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Células Neoplásicas Circulantes/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Receptores Notch/metabolismo , Transdução de Sinais/genética , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Guanilil Ciclase Solúvel/genética
18.
J Thorac Oncol ; 15(12): 1836-1843, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32721553

RESUMO

INTRODUCTION: Recent consensus defines four SCLC subtypes on the basis of transcription factor expression: ASCL1, NEUROD1, POU2F3, and YAP1. The rare YAP1 subtype is associated with "neuroendocrine (NE)-low" cells among SCLC cell lines and patient samples. We evaluated YAP1 in 39 patients with phenotypically diverse circulating tumor cell-derived explant (CDX) models and revisited YAP1 in terms of prevalence, cell phenotype, and intertumor and intratumor heterogeneity. METHODS: YAP1 transcript and protein expression were assessed by RNA sequencing and immunohistochemistry or multiplexed immunofluorescence of NE and non-NE CDX subpopulations. Physically separated NE and non-NE CDX ex vivo culture lysates were Western blotted for YAP1, NE marker SYP, and AXL. RESULTS: RNA sequencing normalized for the four subtype transcription factors identified YAP1 expression in 14 of 39 CDX. A total of 10 CDX expressed YAP1 protein, and eight had strong YAP1 expression confined to rare non-NE cell clusters. This was confirmed in ex vivo CDX cultures in which adherent non-NE cells lacking SYP expression expressed YAP1. However, in two CDX, weaker cellular YAP1 expression was observed, widely dispersed in SYP-positive NE cells. CONCLUSIONS: YAP1 was predominantly expressed in non-NE cell clusters in SCLC CDX, but two of 39 CDX expressed YAP1 in NE cells. CDX22P, with relatively high YAP1 expression, is an ASCL1 NE subtype with a low NE score and an outlier within this subtype in our CDX biobank. These descriptive data reveal subtly different YAP1 expression profiles, paving the way for functional studies to compare YAP1 signaling in non-NE and low NE cell contexts for potentially personalized therapeutic approaches.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Bancos de Espécimes Biológicos , Neoplasias Pulmonares , Células Neoplásicas Circulantes , Fatores de Transcrição , Proteínas Adaptadoras de Transdução de Sinal/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Fatores de Transcrição/genética , Proteínas de Sinalização YAP
19.
Lung Cancer ; 150: 216-220, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33221678

RESUMO

INTRODUCTION: Small cell lung cancer (SCLC) has a dismal prognosis. Circulating tumour cells (CTCs) can be used to generate CTC derived explants (CDX) for the study of SCLC biology and the development of novel therapeutics. We investigated whether there are demographic or clinical predictors of the success of CDX generation, and whether CDX models are representative of the SCLC patient population. METHODS: This was a single centre, retrospective analysis of SCLC patients who had participated in the CHEMORES Study. Paired blood samples were donated for CTC enumeration and CDX generation attempt at pre-treatment baseline, disease progression and intervening timepoints. Clinical and demographic data was collected from electronic records, and analysed for differences between patients whose samples did and did not generate a CDX. RESULTS: 231 paired blood samples were taken from 147 patients. 45 CDX were generated from 34 patients. CTC number was significantly higher in blood samples which successfully generated a CDX than those which didn't, at both baseline (p=<0.0001) and progression (p = 0.0001). The group with successful blood samples had a poorer performance status (p = 0.0067), and a higher proportion of patients with chemorefractory disease (p = 0.0077). Both progression free survival (PFS) (p = 0.0132) and overall survival (p=< 0.0001) were significantly shorter for patients with successful samples. CONCLUSIONS: Patients whose samples generate CDX models may have a higher disease burden and more aggressive disease. Thus, insights gained by study of SCLC CDX may have a significant impact, particularly in the SCLC subpopulation with the greatest clinical need.


Assuntos
Neoplasias Pulmonares , Células Neoplásicas Circulantes , Carcinoma de Pequenas Células do Pulmão , Biomarcadores Tumorais , Humanos , Prognóstico , Estudos Retrospectivos
20.
Nat Cancer ; 1(4): 437-451, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-35121965

RESUMO

Although small cell lung cancer (SCLC) is treated as a homogeneous disease, biopsies and preclinical models reveal heterogeneity in transcriptomes and morphology. SCLC subtypes were recently defined by neuroendocrine transcription factor (NETF) expression. Circulating-tumor-cell-derived explant models (CDX) recapitulate donor patients' tumor morphology, diagnostic NE marker expression and chemotherapy responses. We describe a biobank of 38 CDX models, including six CDX pairs generated pretreatment and at disease progression revealing complex intra- and intertumoral heterogeneity. Transcriptomic analysis confirmed three of four previously described subtypes based on ASCL1, NEUROD1 and POU2F3 expression and identified a previously unreported subtype based on another NETF, ATOH1. We document evolution during disease progression exemplified by altered MYC and NOTCH gene expression, increased 'variant' cell morphology, and metastasis without strong evidence of epithelial to mesenchymal transition. This CDX biobank provides a research resource to facilitate SCLC personalized medicine.


Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Bancos de Espécimes Biológicos , Progressão da Doença , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Carcinoma de Pequenas Células do Pulmão/genética
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