RESUMEN
Tumor growth is influenced by a complex network of interactions between multiple cell types in the tumor microenvironment (TME). These constrained conditions trigger the endoplasmic reticulum (ER) stress response, which extensively reprograms mRNA translation. When uncontrolled over time, chronic ER stress impairs the antitumor effector function of CD8 T lymphocytes. How cells promote adaptation to chronic stress in the TME without the detrimental effects of the terminal unfolded protein response (UPR) is unknown. Here, we find that, in effector CD8 T lymphocytes, RNA-binding protein CPEB4 constitutes a new branch of the UPR that allows cells to adapt to sustained ER stress, yet remains decoupled from the terminal UPR. ER stress, induced during CD8 T-cell activation and effector function, triggers CPEB4 expression. CPEB4 then mediates chronic stress adaptation to maintain cellular fitness, allowing effector molecule production and cytotoxic activity. Accordingly, this branch of the UPR is required for the antitumor effector function of T lymphocytes, and its disruption in these cells exacerbates tumor growth.
Asunto(s)
Estrés del Retículo Endoplásmico , Neoplasias , Humanos , Estrés del Retículo Endoplásmico/genética , Respuesta de Proteína Desplegada , Neoplasias/metabolismo , Linfocitos T CD8-positivos/metabolismo , Adaptación Fisiológica , Microambiente Tumoral , Proteínas de Unión al ARN/metabolismoRESUMEN
The relative success of platinum (Pt)-based chemotherapy comes at the cost of severe adverse side effects and is associated with a high risk of pro-oncogenic activation in the tumor microenvironment. Here, we report the synthesis of C-POC, a novel Pt(IV) cell-penetrating peptide conjugate showing a reduced impact against nonmalignant cells. In vitro and in vivo evaluation using patient-derived tumor organoids and laser ablation inductively coupled plasma mass spectrometry indicates that C-POC maintains robust anticancer efficacy while displaying diminished accumulation in healthy organs and reduced adverse toxicity compared to the standard Pt-based therapy. Likewise, C-POC uptake is significantly lowered in the noncancerous cells populating the tumor microenvironment. This results in the downregulation of versican, a biomarker of metastatic spreading and chemoresistance that we found upregulated in patients treated with standard Pt-based therapy. Altogether, our findings underscore the importance of considering the off-target impact of anticancer treatment on normal cells to improve drug development and patient care.
Asunto(s)
Antineoplásicos , Platino (Metal) , Humanos , Platino (Metal)/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Péptidos/farmacología , Péptidos/uso terapéutico , Línea Celular TumoralRESUMEN
Around 30-40% of patients with colorectal cancer (CRC) undergoing curative resection of the primary tumour will develop metastases in the subsequent years1. Therapies to prevent disease relapse remain an unmet medical need. Here we uncover the identity and features of the residual tumour cells responsible for CRC relapse. An analysis of single-cell transcriptomes of samples from patients with CRC revealed that the majority of genes associated with a poor prognosis are expressed by a unique tumour cell population that we named high-relapse cells (HRCs). We established a human-like mouse model of microsatellite-stable CRC that undergoes metastatic relapse after surgical resection of the primary tumour. Residual HRCs occult in mouse livers after primary CRC surgery gave rise to multiple cell types over time, including LGR5+ stem-like tumour cells2-4, and caused overt metastatic disease. Using Emp1 (encoding epithelial membrane protein 1) as a marker gene for HRCs, we tracked and selectively eliminated this cell population. Genetic ablation of EMP1high cells prevented metastatic recurrence and mice remained disease-free after surgery. We also found that HRC-rich micrometastases were infiltrated with T cells, yet became progressively immune-excluded during outgrowth. Treatment with neoadjuvant immunotherapy eliminated residual metastatic cells and prevented mice from relapsing after surgery. Together, our findings reveal the cell-state dynamics of residual disease in CRC and anticipate that therapies targeting HRCs may help to avoid metastatic relapse.
Asunto(s)
Neoplasias Colorrectales , Metástasis de la Neoplasia , Proteínas de Neoplasias , Recurrencia Local de Neoplasia , Neoplasia Residual , Receptores de Superficie Celular , Animales , Humanos , Ratones , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Progresión de la Enfermedad , Proteínas de Neoplasias/deficiencia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/prevención & control , Recurrencia Local de Neoplasia/terapia , Neoplasia Residual/genética , Neoplasia Residual/patología , Receptores de Superficie Celular/deficiencia , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Metástasis de la Neoplasia/prevención & control , Metástasis de la Neoplasia/terapia , Modelos Animales de Enfermedad , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos Infiltrantes de Tumor/citología , Linfocitos Infiltrantes de Tumor/inmunología , Terapia Neoadyuvante , InmunoterapiaRESUMEN
Most patients with colorectal cancer die as a result of the disease spreading to other organs. However, no prevalent mutations have been associated with metastatic colorectal cancers. Instead, particular features of the tumour microenvironment, such as lack of T-cell infiltration, low type 1 T-helper cell (TH1) activity and reduced immune cytotoxicity or increased TGFß levels predict adverse outcomes in patients with colorectal cancer. Here we analyse the interplay between genetic alterations and the tumour microenvironment by crossing mice bearing conditional alleles of four main colorectal cancer mutations in intestinal stem cells. Quadruple-mutant mice developed metastatic intestinal tumours that display key hallmarks of human microsatellite-stable colorectal cancers, including low mutational burden, T-cell exclusion and TGFß-activated stroma. Inhibition of the PD-1-PD-L1 immune checkpoint provoked a limited response in this model system. By contrast, inhibition of TGFß unleashed a potent and enduring cytotoxic T-cell response against tumour cells that prevented metastasis. In mice with progressive liver metastatic disease, blockade of TGFß signalling rendered tumours susceptible to anti-PD-1-PD-L1 therapy. Our data show that increased TGFß in the tumour microenvironment represents a primary mechanism of immune evasion that promotes T-cell exclusion and blocks acquisition of the TH1-effector phenotype. Immunotherapies directed against TGFß signalling may therefore have broad applications in treating patients with advanced colorectal cancer.
Asunto(s)
Neoplasias del Colon/genética , Neoplasias del Colon/patología , Evasión Inmune , Inmunoterapia , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/inmunología , Factor de Crecimiento Transformador beta/inmunología , Alelos , Animales , Diferenciación Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/inmunología , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Femenino , Humanos , Evasión Inmune/efectos de los fármacos , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Intestinos/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/secundario , Masculino , Ratones , Mutación , Metástasis de la Neoplasia/tratamiento farmacológico , Metástasis de la Neoplasia/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Células Madre/patología , Linfocitos T Citotóxicos/citología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
Recent molecular classifications of colorectal cancer (CRC) based on global gene expression profiles have defined subtypes displaying resistance to therapy and poor prognosis. Upon evaluation of these classification systems, we discovered that their predictive power arises from genes expressed by stromal cells rather than epithelial tumor cells. Bioinformatic and immunohistochemical analyses identify stromal markers that associate robustly with disease relapse across the various classifications. Functional studies indicate that cancer-associated fibroblasts (CAFs) increase the frequency of tumor-initiating cells, an effect that is dramatically enhanced by transforming growth factor (TGF)-ß signaling. Likewise, we find that all poor-prognosis CRC subtypes share a gene program induced by TGF-ß in tumor stromal cells. Using patient-derived tumor organoids and xenografts, we show that the use of TGF-ß signaling inhibitors to block the cross-talk between cancer cells and the microenvironment halts disease progression.
Asunto(s)
Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Fibroblastos/metabolismo , Células Madre Neoplásicas/metabolismo , Animales , Análisis por Conglomerados , Neoplasias Colorrectales/clasificación , Neoplasias Colorrectales/patología , Fibroblastos/patología , Regulación Neoplásica de la Expresión Génica , Células HT29 , Humanos , Ratones , Ratones Desnudos , Análisis por Micromatrices , Invasividad Neoplásica , Metástasis de la Neoplasia , Células Madre Neoplásicas/patología , Pronóstico , Células del Estroma/metabolismo , Células del Estroma/patología , TranscriptomaRESUMEN
We sought to understand the mechanisms behind the potent effect of stromal TGF-beta program on the capacity of colorectal cancer (CRC) cells to initiate metastasis. We discovered that mice subcutaneous tumors and metastases generated in the context of a TGF-beta activated microenvironment displayed prominent accumulation of p-STAT3 in CRC cells compared with those derived from control cells. STAT3 signaling depended on GP130 as shown by strong reduction of epithelial p STAT3 levels upon GP130 shRNA-mediated knockdown in CRC cells.
RESUMEN
A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-ß pathway, yet, paradoxically, they are characterized by elevated TGF-ß production. Here, we unveil a prometastatic program induced by TGF-ß in the microenvironment that associates with a high risk of CRC relapse upon treatment. The activity of TGF-ß on stromal cells increases the efficiency of organ colonization by CRC cells, whereas mice treated with a pharmacological inhibitor of TGFBR1 are resilient to metastasis formation. Secretion of IL11 by TGF-ß-stimulated cancer-associated fibroblasts (CAFs) triggers GP130/STAT3 signaling in tumor cells. This crosstalk confers a survival advantage to metastatic cells. The dependency on the TGF-ß stromal program for metastasis initiation could be exploited to improve the diagnosis and treatment of CRC.
Asunto(s)
Neoplasias Colorrectales/patología , Factor de Crecimiento Transformador beta/fisiología , Animales , Neoplasias Colorrectales/tratamiento farmacológico , Receptor gp130 de Citocinas/genética , Receptor gp130 de Citocinas/metabolismo , Receptor gp130 de Citocinas/fisiología , Células HT29 , Humanos , Interleucina-11/genética , Interleucina-11/metabolismo , Interleucina-11/fisiología , Ratones , Metástasis de la Neoplasia/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Recurrencia , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/fisiología , Transducción de Señal , Células del Estroma/metabolismo , Células del Estroma/patología , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Células Tumorales Cultivadas , Microambiente TumoralRESUMEN
The genes encoding tyrosine kinase receptors EphB2 and EphB3 are beta-catenin and Tcf4 target genes in colorectal cancer (CRC) and in normal intestinal cells. In the intestinal epithelium, EphB signaling controls the positioning of cell types along the crypt-villus axis. In CRC, EphB activity suppresses tumor progression beyond the earliest stages. Here we show that EphB receptors compartmentalize the expansion of CRC cells through a mechanism dependent on E-cadherin-mediated adhesion. We demonstrate that EphB-mediated compartmentalization restricts the spreading of EphB-expressing tumor cells into ephrin-B1-positive territories in vitro and in vivo. Our results indicate that CRC cells must silence EphB expression to avoid repulsive interactions imposed by normal ephrin-B1-expressing intestinal cells at the onset of tumorigenesis.