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1.
Nat Commun ; 14(1): 1680, 2023 03 27.
Artículo en Inglés | MEDLINE | ID: mdl-36973261

RESUMEN

Profiling tumors at single-cell resolution provides an opportunity to understand complexities underpinning lymph-node metastases in head and neck squamous-cell carcinoma. Single-cell RNAseq (scRNAseq) analysis of cancer-cell trajectories identifies a subpopulation of pre-metastatic cells, driven by actionable pathways including AXL and AURK. Blocking these two proteins blunts tumor invasion in patient-derived cultures. Furthermore, scRNAseq analyses of tumor-infiltrating CD8 + T-lymphocytes show two distinct trajectories to T-cell dysfunction, corroborated by their clonal architecture based on single-cell T-cell receptor sequencing. By determining key modulators of these trajectories, followed by validation using external datasets and functional experiments, we uncover a role for SOX4 in mediating T-cell exhaustion. Finally, interactome analyses between pre-metastatic tumor cells and CD8 + T-lymphocytes uncover a putative role for the Midkine pathway in immune-modulation and this is confirmed by scRNAseq of tumors from humanized mice. Aside from specific findings, this study demonstrates the importance of tumor heterogeneity analyses in identifying key vulnerabilities during early metastasis.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Ratones , Animales , Carcinoma de Células Escamosas/patología , Evasión Inmune , Neoplasias de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Linfocitos T CD8-positivos , Linfocitos Infiltrantes de Tumor
4.
Commun Biol ; 3(1): 429, 2020 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-32764731

RESUMEN

The Eph family of receptor tyrosine kinases is crucial for assembly and maintenance of healthy tissues. Dysfunction in Eph signaling is causally associated with cancer progression. In breast cancer cells, dysregulated Eph signaling has been linked to alterations in receptor clustering abilities. Here, we implemented a single-cell assay and a scoring scheme to systematically probe the spatial organization of activated EphA receptors in multiple carcinoma cells. We show that cancer cells retain EphA clustering phenotype over several generations, and the degree of clustering reported for migration potential both at population and single-cell levels. Finally, using patient-derived cancer lines, we probed the evolution of EphA signalling in cell populations that underwent metastatic transformation and acquisition of drug resistance. Taken together, our scalable approach provides a reliable scoring scheme for EphA clustering that is consistent over multiple carcinomas and can assay heterogeneity of cancer cell populations in a cost- and time-effective manner.


Asunto(s)
Carcinoma/genética , Familia de Multigenes/genética , Receptores de la Familia Eph/genética , Análisis de la Célula Individual , Carcinoma/patología , Heterogeneidad Genética , Humanos , Fenotipo , Transducción de Señal/genética
5.
Nat Commun ; 9(1): 4931, 2018 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-30467425

RESUMEN

Chemo-resistance is one of the major causes of cancer-related deaths. Here we used single-cell transcriptomics to investigate divergent modes of chemo-resistance in tumor cells. We observed that higher degree of phenotypic intra-tumor heterogeneity (ITH) favors selection of pre-existing drug-resistant cells, whereas phenotypically homogeneous cells engage covert epigenetic mechanisms to trans-differentiate under drug-selection. This adaptation was driven by selection-induced gain of H3K27ac marks on bivalently poised resistance-associated chromatin, and therefore not expressed in the treatment-naïve setting. Mechanistic interrogation of this phenomenon revealed that drug-induced adaptation was acquired upon the loss of stem factor SOX2, and a concomitant gain of SOX9. Strikingly we observed an enrichment of SOX9 at drug-induced H3K27ac sites, suggesting that tumor evolution could be driven by stem cell-switch-mediated epigenetic plasticity. Importantly, JQ1 mediated inhibition of BRD4 could reverse drug-induced adaptation. These results provide mechanistic insights into the modes of therapy-induced cellular plasticity and underscore the use of epigenetic inhibitors in targeting tumor evolution.


Asunto(s)
Carcinoma de Células Escamosas/genética , Resistencia a Antineoplásicos/genética , Neoplasias de la Boca/genética , Células Madre Neoplásicas/metabolismo , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodos , Animales , Antineoplásicos/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/metabolismo , Línea Celular Tumoral , Cisplatino/farmacología , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Heterogeneidad Genética , Humanos , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
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