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1.
Cell ; 160(1-2): 269-84, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25594183

RESUMO

The stem cells that maintain and repair the postnatal skeleton remain undefined. One model suggests that perisinusoidal mesenchymal stem cells (MSCs) give rise to osteoblasts, chondrocytes, marrow stromal cells, and adipocytes, although the existence of these cells has not been proven through fate-mapping experiments. We demonstrate here that expression of the bone morphogenetic protein (BMP) antagonist gremlin 1 defines a population of osteochondroreticular (OCR) stem cells in the bone marrow. OCR stem cells self-renew and generate osteoblasts, chondrocytes, and reticular marrow stromal cells, but not adipocytes. OCR stem cells are concentrated within the metaphysis of long bones not in the perisinusoidal space and are needed for bone development, bone remodeling, and fracture repair. Grem1 expression also identifies intestinal reticular stem cells (iRSCs) that are cells of origin for the periepithelial intestinal mesenchymal sheath. Grem1 expression identifies distinct connective tissue stem cells in both the bone (OCR stem cells) and the intestine (iRSCs).


Assuntos
Osso e Ossos/citologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Intestino Delgado/citologia , Células-Tronco Mesenquimais/citologia , Animais , Cartilagem/metabolismo , Intestino Delgado/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
2.
Genes Dev ; 35(1-2): 59-64, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33303641

RESUMO

Here, we showed that the acetylation-defective p53-4KR mice, lacking the ability of cell cycle arrest, senescence, apoptosis, and ferroptosis, were tumor prone but failed to develop early-onset tumors. By identifying a novel p53 acetylation site at lysine K136, we found that simultaneous mutations at all five acetylation sites (p53-5KR) diminished its remaining tumor suppression function. Moreover, the embryonic lethality caused by the deficiency of mdm2 was fully rescued in the background of p535KR/5KR , but not p534KR/4KR background. p53-4KR retained the ability to suppress mTOR function but this activity was abolished in p53-5KR cells. Notably, the early-onset tumor formation observed in p535KR/5KR and p53-null mice was suppressed upon the treatment of the mTOR inhibitor. These results suggest that p53-mediated mTOR regulation plays an important role in both embryonic development and tumor suppression, independent of cell cycle arrest, senescence, apoptosis, and ferroptosis.


Assuntos
Pontos de Checagem do Ciclo Celular/genética , Neoplasias/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Acetilação , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Embrião de Mamíferos , Lisina/genética , Lisina/metabolismo , Camundongos , Mutação/genética , Neoplasias/fisiopatologia , Proteínas Proto-Oncogênicas c-mdm2/deficiência , Proteínas Proto-Oncogênicas c-mdm2/genética , Sirolimo/farmacologia , Análise de Sobrevida
3.
Genes Dev ; 35(7-8): 528-541, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33737385

RESUMO

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers worldwide and evolves often to lung metastasis. P53R175H (homologous to Trp53R172H in mice) is a common hot spot mutation. How metastasis is regulated by p53R175H in ESCC remains to be investigated. To investigate p53R175H-mediated molecular mechanisms, we used a carcinogen-induced approach in Trp53R172H/- mice to model ESCC. In the primary Trp53R172H/- tumor cell lines, we depleted Trp53R172H (shTrp53) and observed a marked reduction in cell invasion in vitro and lung metastasis burden in a tail-vein injection model in comparing isogenic cells (shCtrl). Furthermore, we performed bulk RNA-seq to compare gene expression profiles of metastatic and primary shCtrl and shTrp53 cells. We identified the YAP-BIRC5 axis as a potential mediator of Trp53R172H -mediated metastasis. We demonstrate that expression of Survivin, an antiapoptotic protein encoded by BIRC5, increases in the presence of Trp53R172H Furthermore, depletion of Survivin specifically decreases Trp53R172H-driven lung metastasis. Mechanistically, Trp53R172H but not wild-type Trp53, binds with YAP in ESCC cells, suggesting their cooperation to induce Survivin expression. Furthermore, Survivin high expression level is associated with increased metastasis in several GI cancers. Taken together, this study unravels new insights into how mutant p53 mediates metastasis.


Assuntos
Neoplasias Pulmonares/fisiopatologia , Survivina/genética , Survivina/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Pulmonares/genética , Camundongos , Mutação , Metástase Neoplásica , Transcriptoma , Proteína Supressora de Tumor p53/metabolismo
4.
Nature ; 610(7930): 190-198, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36131018

RESUMO

Although melanoma is notorious for its high degree of heterogeneity and plasticity1,2, the origin and magnitude of cell-state diversity remains poorly understood. Equally, it is unclear whether growth and metastatic dissemination are supported by overlapping or distinct melanoma subpopulations. Here, by combining mouse genetics, single-cell and spatial transcriptomics, lineage tracing and quantitative modelling, we provide evidence of a hierarchical model of tumour growth that mirrors the cellular and molecular logic underlying the cell-fate specification and differentiation of the embryonic neural crest. We show that tumorigenic competence is associated with a spatially localized perivascular niche, a phenotype acquired through an intercellular communication pathway established by endothelial cells. Consistent with a model in which only a fraction of cells are fated to fuel growth, temporal single-cell tracing of a population of melanoma cells with a mesenchymal-like state revealed that these cells do not contribute to primary tumour growth but, instead, constitute a pool of metastatic initiating cells that switch cell identity while disseminating to secondary organs. Our data provide a spatially and temporally resolved map of the diversity and trajectories of melanoma cell states and suggest that the ability to support growth and metastasis are limited to distinct pools of cells. The observation that these phenotypic competencies can be dynamically acquired after exposure to specific niche signals warrant the development of therapeutic strategies that interfere with the cancer cell reprogramming activity of such microenvironmental cues.


Assuntos
Proliferação de Células , Melanoma , Metástase Neoplásica , Animais , Comunicação Celular , Diferenciação Celular , Linhagem da Célula , Rastreamento de Células , Reprogramação Celular , Células Endoteliais , Melanoma/genética , Melanoma/patologia , Mesoderma/patologia , Camundongos , Metástase Neoplásica/patologia , Crista Neural/embriologia , Fenótipo , Análise de Célula Única , Transcriptoma , Microambiente Tumoral
5.
Cell ; 148(1-2): 349-61, 2012 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-22265420

RESUMO

Metastasis is the leading cause of cancer-associated death but has been difficult to study because it involves a series of rare, stochastic events. To capture these events, we developed a sensitive method to tag and track pancreatic epithelial cells in a mouse model of pancreatic cancer. Tagged cells invaded and entered the bloodstream unexpectedly early, before frank malignancy could be detected by rigorous histologic analysis; this behavior was widely associated with epithelial-to-mesenchymal transition (EMT). Circulating pancreatic cells maintained a mesenchymal phenotype, exhibited stem cell properties, and seeded the liver. EMT and invasiveness were most abundant at inflammatory foci, and induction of pancreatitis increased the number of circulating pancreatic cells. Conversely, treatment with the immunosuppressive agent dexamethasone abolished dissemination. These results provide insight into the earliest events of cellular invasion in situ and suggest that inflammation enhances cancer progression in part by facilitating EMT and entry into the circulation.


Assuntos
Carcinoma Ductal Pancreático/patologia , Transição Epitelial-Mesenquimal , Invasividade Neoplásica , Neoplasias Pancreáticas/patologia , Animais , Carcinoma Ductal Pancreático/imunologia , Modelos Animais de Doenças , Humanos , Camundongos , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/imunologia , Pancreatite/patologia
6.
Genes Dev ; 32(15-16): 1020-1034, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30068703

RESUMO

RNA-binding proteins (RBPs) are expressed broadly during both development and malignant transformation, yet their mechanistic roles in epithelial homeostasis or as drivers of tumor initiation and progression are incompletely understood. Here we describe a novel interplay between RBPs LIN28B and IMP1 in intestinal epithelial cells. Ribosome profiling and RNA sequencing identified IMP1 as a principle node for gene expression regulation downstream from LIN28B In vitro and in vivo data demonstrate that epithelial IMP1 loss increases expression of WNT target genes and enhances LIN28B-mediated intestinal tumorigenesis, which was reversed when we overexpressed IMP1 independently in vivo. Furthermore, IMP1 loss in wild-type or LIN28B-overexpressing mice enhances the regenerative response to irradiation. Together, our data provide new evidence for the opposing effects of the LIN28B-IMP1 axis on post-transcriptional regulation of canonical WNT signaling, with implications in intestinal homeostasis, regeneration and tumorigenesis.


Assuntos
Carcinogênese , Regulação da Expressão Gênica , Mucosa Intestinal/metabolismo , Proteínas de Ligação a RNA/metabolismo , Regulon , Via de Sinalização Wnt , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Humanos , Mucosa Intestinal/fisiologia , Camundongos , Camundongos Transgênicos , Oncogenes , Biossíntese de Proteínas , Proteínas de Ligação a RNA/fisiologia , Regeneração , Células-Tronco/metabolismo
7.
Gastroenterology ; 165(3): 613-628.e20, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37257519

RESUMO

BACKGROUND & AIMS: Despite recent progress in identifying aberrant genetic and epigenetic alterations in esophageal squamous cell carcinoma (ESCC), the mechanism of ESCC initiation remains unknown. METHODS: Using CRISPR/Cas 9-based genetic ablation, we targeted 9 genes (TP53, CDKN2A, NOTCH1, NOTCH3, KMT2D, KMT2C, FAT1, FAT4, and AJUBA) in murine esophageal organoids. Transcriptomic phenotypes of organoids and chemokine released by organoids were analyzed by single-cell RNA sequencing. Tumorigenicity and immune evasion of organoids were monitored by allograft transplantation. Human ESCC single-cell RNA sequencing data sets were analyzed to classify patients and find subsets relevant to organoid models and immune evasion. RESULTS: We established 32 genetically engineered esophageal organoids and identified key genetic determinants that drive ESCC initiation. A single-cell transcriptomic analysis uncovered that Trp53, Cdkn2a, and Notch1 (PCN) triple-knockout induces neoplastic features of ESCC by generating cell lineage heterogeneity and high cell plasticity. PCN knockout also generates an immunosuppressive niche enriched with exhausted T cells and M2 macrophages via the CCL2-CCR2 axis. Mechanistically, CDKN2A inactivation transactivates CCL2 via nuclear factor-κB. Moreover, comparative single-cell transcriptomic analyses stratified patients with ESCC and identified a specific subtype recapitulating the PCN-type ESCC signatures, including the high expression of CCL2 and CD274/PD-L1. CONCLUSIONS: Our study unveils that loss of TP53, CDKN2A, and NOTCH1 induces esophageal neoplasia and immune evasion for ESCC initiation and proposes the CCL2 blockade as a viable option for targeting PCN-type ESCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Animais , Camundongos , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Evasão da Resposta Imune/genética , Mutação , Proteínas com Domínio LIM/genética
8.
Gastroenterology ; 164(7): 1119-1136.e12, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36740200

RESUMO

BACKGROUND & AIMS: Transformation of stem/progenitor cells has been associated with tumorigenesis in multiple tissues, but stem cells in the stomach have been hard to localize. We therefore aimed to use a combination of several markers to better target oncogenes to gastric stem cells and understand their behavior in the initial stages of gastric tumorigenesis. METHODS: Mouse models of gastric metaplasia and cancer by targeting stem/progenitor cells were generated and analyzed with techniques including reanalysis of single-cell RNA sequencing and immunostaining. Gastric cancer cell organoids were genetically manipulated with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) for functional studies. Cell division was determined by bromodeoxyuridine-chasing assay and the assessment of the orientation of the mitotic spindles. Gastric tissues from patients were examined by histopathology and immunostaining. RESULTS: Oncogenic insults lead to expansion of SOX9+ progenitor cells in the mouse stomach. Genetic lineage tracing and organoid culture studies show that SOX9+ gastric epithelial cells overlap with SOX2+ progenitors and include stem cells that can self-renew and differentiate to generate all gastric epithelial cells. Moreover, oncogenic targeting of SOX9+SOX2+ cells leads to invasive gastric cancer in our novel mouse model (Sox2-CreERT;Sox9-loxp(66)-rtTA-T2A-Flpo-IRES-loxp(71);Kras(Frt-STOP-Frt-G12D);P53R172H), which combines Cre-loxp and Flippase-Frt genetic recombination systems. Sox9 deletion impedes the expansion of gastric progenitor cells and blocks neoplasia after Kras activation. Although Sox9 is not required for maintaining tissue homeostasis where asymmetric division predominates, loss of Sox9 in the setting of Kras activation leads to reduced symmetric cell division and effectively attenuates the Kras-dependent expansion of stem/progenitor cells. Similarly, Sox9 deletion in gastric cancer organoids reduces symmetric cell division, organoid number, and organoid size. In patients with gastric cancer, high levels of SOX9 are associated with recurrence and poor prognosis. CONCLUSION: SOX9 marks gastric stem cells and modulates biased symmetric cell division, which appears to be required for the malignant transformation of gastric stem cells.


Assuntos
Proteínas Proto-Oncogênicas p21(ras) , Neoplasias Gástricas , Camundongos , Animais , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Neoplasias Gástricas/patologia , Proliferação de Células , Transformação Celular Neoplásica/patologia , Carcinogênese/patologia , Divisão Celular , Células-Tronco/metabolismo
9.
Am J Gastroenterol ; 2024 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-39166765

RESUMO

Esophageal squamous cell carcinoma (ESCC) remains the most common malignancy of the esophagus worldwide. Environmental and lifestyle exposures such as alcohol and tobacco have been well defined in the pathogenesis of ESCC, acting in concert with cell intrinsic epigenomic, genomic and transcriptomic changes. However, a variety of nonenvironmental etiologies including Fanconi anemia, lichen planus, chronic mucocutaneous candidiasis, esophageal epidermoid metaplasia, epidermolysis bullosa, tylosis, esophageal atresia, and achalasia receive minimal attention despite a high risk of ESCC in these diseases. The goal of this review was to promote clinical recognition and suggest a diagnostic framework for earlier detection of ESCC in patients with these rare diseases. In all the discussed conditions, a change in symptoms should trigger a prompt endoscopic evaluation, and endoscopic surveillance programs with advanced imaging techniques and chromoendoscopy should be considered. Moreover, we leverage the convergence of these diseases on ESCC to identify common mechanisms underlying malignant transformation including aberrant proliferation, mucosal barrier dysfunction, increased inflammation, and genome instability. In this study, we summarize the clinical presentation, pathologic findings, potential screening strategies, and common mechanisms of malignant transformation associated with these rare diseases that drive ESCC.

10.
Genes Dev ; 30(17): 1911-2, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27664234

RESUMO

Pancreatic stromal fibroblasts provide structural support. Activated fibroblasts are critical in the tumor microenvironment. In this issue of Genes & Development, Liu and colleagues (pp. 1943-1955) unravel the finding that depletion of Smoothened (Smo) in pancreatic stromal fibroblasts results in AKT activation and noncanonical GLI2 activation with subsequent TGFα secretion, activation of EGFR in pancreatic epithelial cells, and augmentation of acinar-ductal metaplasia. Additionally, Smo-mediated signaling has proproliferative effects on pancreatic tumor cells.


Assuntos
Pâncreas , Fator de Crescimento Transformador alfa , Fibroblastos , Proteínas Hedgehog/genética , Metaplasia , Neoplasias Pancreáticas/genética , Transdução de Sinais
12.
Genes Dev ; 30(2): 233-47, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26773005

RESUMO

The two major isoforms of the paired-related homeodomain transcription factor 1 (Prrx1), Prrx1a and Prrx1b, are involved in pancreatic development, pancreatitis, and carcinogenesis, although the biological role that these isoforms serve in the systemic dissemination of pancreatic ductal adenocarcinoma (PDAC) has not been investigated. An epithelial-mesenchymal transition (EMT) is believed to be important for primary tumor progression and dissemination, whereas a mesenchymal-epithelial transition (MET) appears crucial for metastatic colonization. Here, we describe novel roles for both isoforms in the metastatic cascade using complementary in vitro and in vivo models. Prrx1b promotes invasion, tumor dedifferentiation, and EMT. In contrast, Prrx1a stimulates metastatic outgrowth in the liver, tumor differentiation, and MET. We further demonstrate that the switch from Prrx1b to Prrx1a governs EMT plasticity in both mouse models of PDAC and human PDAC. Last, we identify hepatocyte growth factor ( HGF) as a novel transcriptional target of Prrx1b. Targeted therapy of HGF in combination with gemcitabine in a preclinical model of PDAC reduces primary tumor volume and eliminates metastatic disease. Overall, we provide new insights into the isoform-specific roles of Prrx1a and Prrx1b in primary PDAC formation, dissemination, and metastatic colonization, allowing for novel therapeutic strategies targeting EMT plasticity.


Assuntos
Carcinoma Ductal Pancreático/fisiopatologia , Proteínas de Homeodomínio/metabolismo , Invasividade Neoplásica/fisiopatologia , Neoplasias Pancreáticas/fisiopatologia , Animais , Carcinogênese/genética , Carcinoma Ductal Pancreático/genética , Células Cultivadas , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento de Hepatócito/genética , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Metástase Neoplásica/genética , Neoplasias Pancreáticas/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Células Tumorais Cultivadas
13.
Oncologist ; 28(5): 425-432, 2023 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-36807743

RESUMO

BACKGROUND: In preclinical pancreatic ductal adenocarcinoma (PDAC) models, inhibition of hepatocyte growth factor (HGF) signaling using ficlatuzumab, a recombinant humanized anti-HGF antibody, and gemcitabine reduced tumor burden. METHODS: Patients with previously untreated metastatic PDAC enrolled in a phase Ib dose escalation study with 3 + 3 design of 2 dose cohorts of ficlatuzumab 10 and 20 mg/kg administered intravenously every other week with gemcitabine 1000 mg/m2 and albumin-bound paclitaxel 125 mg/m2 given 3 weeks on and 1 week off. This was followed by an expansion phase at the maximally tolerated dose of the combination. RESULTS: Twenty-six patients (sex, 12 male:14 female; median age, 68 years [range, 49-83 years]) were enrolled, 22 patients were evaluable. No dose-limiting toxicities were identified (N = 7 pts) and ficlatuzumab at 20 mg/kg was chosen as the maximum tolerated dose. Among the 21 patients treated at the MTD, best response by RECISTv1.1: 6 (29%) partial response, 12 (57%) stable disease, 1 (5%) progressive disease, and 2 (9%) not evaluable. Median progression-free survival and overall survival times were 11.0 months (95% CI, 7.6-11.4 months) and 16.2 months (95% CI, 9.1 months to not reached), respectively. Toxicities attributed to ficlatuzumab included hypoalbuminemia (grade 3, 16%; any grade, 52%) and edema (grade 3, 8%; any grade, 48%). Immunohistochemistry for c-Met pathway activation demonstrated higher tumor cell p-Met levels in patients who experienced response to therapy. CONCLUSION: In this phase Ib trial, ficlatuzumab, gemcitabine, and albumin-bound paclitaxel were associated with durable treatment responses and increased rates of hypoalbuminemia and edema.


Assuntos
Hipoalbuminemia , Neoplasias Pancreáticas , Humanos , Masculino , Feminino , Idoso , Gencitabina , Paclitaxel Ligado a Albumina , Hipoalbuminemia/induzido quimicamente , Paclitaxel/efeitos adversos , Neoplasias Pancreáticas/patologia , Albuminas/efeitos adversos , Edema/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Pancreáticas
14.
N Engl J Med ; 383(11): 1028-1039, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32905675

RESUMO

BACKGROUND: The efficacy and safety of combination therapy with eflornithine and sulindac, as compared with either drug alone, in delaying disease progression in patients with familial adenomatous polyposis are unknown. METHODS: We evaluated the efficacy and safety of the combination of eflornithine and sulindac, as compared with either drug alone, in adults with familial adenomatous polyposis. The patients were stratified on the basis of anatomical site with the highest polyp burden and surgical status; the strata were precolectomy (shortest projected time to disease progression), rectal or ileal pouch polyposis after colectomy (longest projected time), and duodenal polyposis (intermediate projected time). The patients were then randomly assigned in a 1:1:1 ratio to receive 750 mg of eflornithine, 150 mg of sulindac, or both once daily for up to 48 months. The primary end point, assessed in a time-to-event analysis, was disease progression, defined as a composite of major surgery, endoscopic excision of advanced adenomas, diagnosis of high-grade dysplasia in the rectum or pouch, or progression of duodenal disease. RESULTS: A total of 171 patients underwent randomization. Disease progression occurred in 18 of 56 patients (32%) in the eflornithine-sulindac group, 22 of 58 (38%) in the sulindac group, and 23 of 57 (40%) in the eflornithine group, with a hazard ratio of 0.71 (95% confidence interval [CI], 0.39 to 1.32) for eflornithine-sulindac as compared with sulindac (P = 0.29) and 0.66 (95% CI, 0.36 to 1.24) for eflornithine-sulindac as compared with eflornithine. Among 37 precolectomy patients, the corresponding values in the treatment groups were 2 of 12 patients (17%), 6 of 13 (46%), and 5 of 12 (42%) (hazard ratios, 0.30 [95% CI, 0.07 to 1.32] and 0.20 [95% CI, 0.03 to 1.32]); among 34 patients with rectal or ileal pouch polyposis, the values were 4 of 11 patients (36%), 2 of 11 (18%), and 5 of 12 (42%) (hazard ratios, 2.03 [95% CI, 0.43 to 9.62] and 0.84 [95% CI, 0.24 to 2.90]); and among 100 patients with duodenal polyposis, the values were 12 of 33 patients (36%), 14 of 34 (41%), and 13 of 33 (39%) (hazard ratios, 0.73 [95% CI, 0.34 to 1.52] and 0.76 [95% CI, 0.35 to 1.64]). Adverse and serious adverse events were similar across the treatment groups. CONCLUSIONS: In this trial involving patients with familial adenomatous polyposis, the incidence of disease progression was not significantly lower with the combination of eflornithine and sulindac than with either drug alone. (Funded by Cancer Prevention Pharmaceuticals; ClinicalTrials.gov number, NCT01483144; EudraCT number, 2012-000427-41.).


Assuntos
Polipose Adenomatosa do Colo/tratamento farmacológico , Progressão da Doença , Eflornitina/uso terapêutico , Sulindaco/uso terapêutico , Adulto , Quimioterapia Combinada , Eflornitina/efeitos adversos , Feminino , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Sulindaco/efeitos adversos , Resultado do Tratamento
15.
Gastroenterology ; 162(3): 890-906, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34883119

RESUMO

BACKGROUND & AIMS: Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CAFs associated with poor prognosis. METHODS: To elucidate CAF origins, we used a colitis-associated CRC mouse model in 5 different fate-mapping mouse lines with 5-bromodeoxyuridine dosing. RNA sequencing of fluorescence-activated cell sorting-purified CRC CAFs was performed to identify a potential therapeutic target in CAFs. To examine the prognostic significance of the stromal target, CRC patient RNA sequencing data and tissue microarray were used. CRC organoids were injected into the colons of knockout mice to assess the mechanism by which the stromal gene contributes to colorectal tumorigenesis. RESULTS: Our lineage-tracing studies revealed that in CRC, many ACTA2+ CAFs emerge through proliferation from intestinal pericryptal leptin receptor (Lepr)+ cells. These Lepr-lineage CAFs, in turn, express melanoma cell adhesion molecule (MCAM), a CRC stroma-specific marker that we identified with the use of RNA sequencing. High MCAM expression induced by transforming growth factor ß was inversely associated with patient survival in human CRC. In mice, stromal Mcam knockout attenuated orthotopically injected colorectal tumoroid growth and improved survival through decreased tumor-associated macrophage recruitment. Mechanistically, fibroblast MCAM interacted with interleukin-1 receptor 1 to augment nuclear factor κB-IL34/CCL8 signaling that promotes macrophage chemotaxis. CONCLUSIONS: In colorectal carcinogenesis, pericryptal Lepr-lineage cells proliferate to generate MCAM+ CAFs that shape the tumor-promoting immune microenvironment. Preventing the expansion/differentiation of Lepr-lineage CAFs or inhibiting MCAM activity could be effective therapeutic approaches for CRC.


Assuntos
Fibroblastos Associados a Câncer/patologia , Fibroblastos Associados a Câncer/fisiologia , Carcinogênese/patologia , Linhagem da Célula , Neoplasias Colorretais/patologia , Células-Tronco Mesenquimais/fisiologia , Actinas/genética , Actinas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antígeno CD146/genética , Antígeno CD146/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Diferenciação Celular , Proliferação de Células , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Mucosa Intestinal/patologia , Antígeno Ki-67/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Organoides/patologia , Organoides/fisiologia , Prognóstico , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Análise de Sequência de RNA , Taxa de Sobrevida , Microambiente Tumoral
16.
EMBO Rep ; 22(2): e48351, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33403789

RESUMO

Esophageal squamous cell carcinoma (ESCC) is the most common subtype of esophageal cancer worldwide. The most commonly mutated gene in ESCC is TP53. Using a combinatorial genetic and carcinogenic approach, we generate a novel mouse model of ESCC expressing either mutant or null p53 and show that mutant p53 exhibits enhanced tumorigenic properties and displays a distinct genomic profile. Through RNA-seq analysis, we identify several endocytic recycling genes, including Rab Coupling Protein (Rab11-FIP1), which are significantly downregulated in mutant p53 tumor cells. In 3-dimensional (3D) organoid models, genetic knockdown of Rab11-FIP1 results in increased organoid size. Loss of Rab11-FIP1 increases tumor cell invasion in part through mutant p53 but also in an independent manner. Furthermore, loss of Rab11-FIP1 in human ESCC cell lines decreases E-cadherin expression and increases mesenchymal lineage-specific markers, suggesting induction of epithelial-mesenchymal transition (EMT). Rab11-FIP1 regulates EMT through direct inhibition of Zeb1, a key EMT transcriptional factor. Our novel findings reveal that Rab11-FIP1 regulates organoid formation, tumor cell invasion, and EMT.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Transição Epitelial-Mesenquimal/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica
17.
EMBO Rep ; 22(9): e51872, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34324787

RESUMO

Epithelial plasticity, or epithelial-to-mesenchymal transition (EMT), is a well-recognized form of cellular plasticity, which endows tumor cells with invasive properties and alters their sensitivity to various agents, thus representing a major challenge to cancer therapy. It is increasingly accepted that carcinoma cells exist along a continuum of hybrid epithelial-mesenchymal (E-M) states and that cells exhibiting such partial EMT (P-EMT) states have greater metastatic competence than those characterized by either extreme (E or M). We described recently a P-EMT program operating in vivo by which carcinoma cells lose their epithelial state through post-translational programs. Here, we investigate the underlying mechanisms and report that prolonged calcium signaling induces a P-EMT characterized by the internalization of membrane-associated E-cadherin (ECAD) and other epithelial proteins as well as an increase in cellular migration and invasion. Signaling through Gαq-associated G-protein-coupled receptors (GPCRs) recapitulates these effects, which operate through the downstream activation of calmodulin-Camk2b signaling. These results implicate calcium signaling as a trigger for the acquisition of hybrid/partial epithelial-mesenchymal states in carcinoma cells.


Assuntos
Sinalização do Cálcio , Transição Epitelial-Mesenquimal , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Plasticidade Celular
19.
Gastroenterology ; 161(2): 453-462.e15, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33839100

RESUMO

BACKGROUND AND AIMS: Lynch syndrome is associated with pathogenic variants in 4 mismatch repair (MMR) genes that increase lifetime risk of colorectal cancer. Guidelines recommend intensive colorectal cancer surveillance with colonoscopy every 1-2 years starting at age 25 years for all carriers of Lynch syndrome-associated variants, regardless of gene product. We constructed a simulation model to analyze the effects of different ages of colonoscopy initiation and surveillance intervals for each MMR gene (MLH1, MSH2, MSH6, and PMS2) on colorectal cancer incidence and mortality, quality-adjusted life-years, and cost. METHODS: Using published literature, we developed a Markov simulation model of Lynch syndrome progression for patients with each MMR variant. The model simulated clinical trials of Lynch syndrome carriers, varying age of colonoscopy initiation (5-year increments from 25-40 years), and surveillance intervals (1-5 years). We assessed the optimal strategy for each gene, defined as the strategy with the highest quality-adjusted life-years and incremental cost-effectiveness ratio below a $100,000 willingness-to-pay threshold. RESULTS: Optimal surveillance for patients with pathogenic variants in the MLH1 and MSH2 genes was colonoscopy starting at age 25 years, with 1- to 2-year surveillance intervals. Initiating colonoscopy at age 35 and 40 years, with 3-year intervals, was cost-effective for patients with pathogenic variants in MSH6 or PMS2, respectively. CONCLUSIONS: We developed a simulation model to select optimal surveillance starting ages and intervals for patients with Lynch syndrome based on MMR variant. The model supports recommendations for intensive surveillance of patients with Lynch syndrome-associated variants in MLH1 or MSH2. However, for patients with Lynch syndrome-associated variants of MSH6 or PMS2, later initiation of surveillance at 35 and 40 years, respectively, and at 3-year intervals, can be considered.


Assuntos
Biomarcadores Tumorais/genética , Colonoscopia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Técnicas de Apoio para a Decisão , Detecção Precoce de Câncer , Variação Genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Tomada de Decisão Clínica , Colonoscopia/economia , Neoplasias Colorretais Hereditárias sem Polipose/mortalidade , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Simulação por Computador , Análise Custo-Benefício , Proteínas de Ligação a DNA/genética , Detecção Precoce de Câncer/economia , Feminino , Predisposição Genética para Doença , Custos de Cuidados de Saúde , Nível de Saúde , Humanos , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Qualidade de Vida , Anos de Vida Ajustados por Qualidade de Vida , Medição de Risco , Fatores de Risco , Fatores de Tempo
20.
Gastroenterology ; 160(1): 346-361.e24, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33007300

RESUMO

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibroblast-rich desmoplastic stroma. Cancer-associated fibroblasts (CAFs) have been shown to display a high degree of interconvertible states including quiescent, inflammatory, and myofibroblastic phenotypes; however, the mechanisms by which this plasticity is achieved are poorly understood. Here, we aim to elucidate the role of CAF plasticity and its impact on PDAC biology. METHODS: To investigate the role of mesenchymal plasticity in PDAC progression, we generated a PDAC mouse model in which CAF plasticity is modulated by genetic depletion of the transcription factor Prrx1. Primary pancreatic fibroblasts from this mouse model were further characterized by functional in vitro assays. To characterize the impact of CAFs on tumor differentiation and response to chemotherapy, various coculture experiments were performed. In vivo, tumors were characterized by morphology, extracellular matrix composition, and tumor dissemination and metastasis. RESULTS: Our in vivo findings showed that Prrx1-deficient CAFs remain constitutively activated. Importantly, this CAF phenotype determines tumor differentiation and disrupts systemic tumor dissemination. Mechanistically, coculture experiments of tumor organoids and CAFs showed that CAFs shape the epithelial-to-mesenchymal phenotype and confer gemcitabine resistance of PDAC cells induced by CAF-derived hepatocyte growth factor. Furthermore, gene expression analysis showed that patients with pancreatic cancer with high stromal expression of Prrx1 display the squamous, most aggressive, subtype of PDAC. CONCLUSIONS: Here, we define that the Prrx1 transcription factor is critical for tuning CAF activation, allowing a dynamic switch between a dormant and an activated state. This work shows that Prrx1-mediated CAF plasticity has significant impact on PDAC biology and therapeutic resistance.


Assuntos
Fibroblastos Associados a Câncer/fisiologia , Carcinoma Ductal Pancreático/etiologia , Carcinoma Ductal Pancreático/patologia , Proteínas de Homeodomínio/fisiologia , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/patologia , Animais , Plasticidade Celular/fisiologia , Modelos Animais de Doenças , Camundongos
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