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1.
Nat Commun ; 12(1): 1366, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33649320

RESUMEN

Cancer stem cells drive disease progression and relapse in many types of cancer. Despite this, a thorough characterization of these cells remains elusive and with it the ability to eradicate cancer at its source. In acute myeloid leukemia (AML), leukemic stem cells (LSCs) underlie mortality but are difficult to isolate due to their low abundance and high similarity to healthy hematopoietic stem cells (HSCs). Here, we demonstrate that LSCs, HSCs, and pre-leukemic stem cells can be identified and molecularly profiled by combining single-cell transcriptomics with lineage tracing using both nuclear and mitochondrial somatic variants. While mutational status discriminates between healthy and cancerous cells, gene expression distinguishes stem cells and progenitor cell populations. Our approach enables the identification of LSC-specific gene expression programs and the characterization of differentiation blocks induced by leukemic mutations. Taken together, we demonstrate the power of single-cell multi-omic approaches in characterizing cancer stem cells.


Asunto(s)
Células Clonales/patología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Análisis de la Célula Individual , Transcriptoma/genética , Biomarcadores de Tumor/genética , Médula Ósea/patología , Diferenciación Celular , Regulación Leucémica de la Expresión Génica , Genoma , Células Madre Hematopoyéticas/patología , Humanos , Células K562 , Mitocondrias/genética , Mutación/genética
2.
Blood ; 136(13): 1507-1519, 2020 09 24.
Artículo en Inglés | MEDLINE | ID: mdl-32556243

RESUMEN

Acute myeloid leukemia is characterized by the accumulation of clonal myeloid blast cells unable to differentiate into mature leukocytes. Chemotherapy induces remission in the majority of patients, but relapse rates are high and lead to poor clinical outcomes. Because this is primarily caused by chemotherapy-resistant leukemic stem cells (LSCs), it is essential to eradicate LSCs to improve patient survival. LSCs have predominantly been studied at the transcript level, thus information about posttranscriptionally regulated genes and associated networks is lacking. Here, we extend our previous report on LSC proteomes to healthy age-matched hematopoietic stem and progenitor cells (HSPCs) and correlate the proteomes to the corresponding transcriptomes. By comparing LSCs to leukemic blasts and healthy HSPCs, we validate candidate LSC markers and highlight novel and potentially targetable proteins that are absent or only lowly expressed in HSPCs. In addition, our data provide strong evidence that LSCs harbor a characteristic energy metabolism, adhesion molecule composition, as well as RNA-processing properties. Furthermore, correlating proteome and transcript data of the same individual samples highlights the strength of proteome analyses, which are particularly potent in detecting alterations in metabolic pathways. In summary, our study provides a comprehensive proteomic and transcriptomic characterization of functionally validated LSCs, blasts, and healthy HSPCs, representing a valuable resource helping to design LSC-directed therapies.


Asunto(s)
Leucemia Mieloide Aguda/metabolismo , Células Madre Neoplásicas/metabolismo , Animales , Metabolismo Energético , Regulación Leucémica de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/genética , Ratones , Proteoma/genética , Proteoma/metabolismo , Proteómica , Transcriptoma
3.
Gastroenterology ; 159(2): 665-681.e13, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32330476

RESUMEN

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is frequently accompanied by excruciating pain, which has been associated with attraction of cancer cells and their invasion of intrapancreatic sensory nerves. Neutralization of the chemokine CCL2 reduced cancer-associated pain in a clinical trial, but there have been no systematic analyses of the highly diverse chemokine families and their receptors in PDAC. METHODS: We performed an open, unbiased RNA-interference screen of mammalian chemokines in co-cultures of mouse PDAC cells (K8484) and mouse peripheral sensory neurons, and confirmed findings in studies of DT8082 PDAC cells. We studied the effects of chemokines on migration of PDAC cell lines. Orthotopic tumors were grown from K8484 cells in mice, and mice were given injections of neutralizing antibodies against chemokines, antagonists, or control antibodies. We analyzed abdominal mechanical hypersensitivity and collected tumors and analyzed them by histology and immunohistochemistry to assess neural remodeling. We collected PDAC samples and information on pain levels from 74 patients undergoing resection and measured levels of CXCR3 and CCR7 by immunohistochemistry and immunoblotting. RESULTS: Knockdown of 9 chemokines in DRG neurons significantly reduced migration of PDAC cells towards sensory neurons. Sensory neuron-derived CCL21 and CXCL10 promoted migration of PDAC cells via their receptors CCR7 and CXCR3, respectively, which were expressed by cells in orthotopic tumors and PDAC specimens from patients. Neutralization of CCL21 or CXCL10, or their receptors, in mice with orthotopic tumors significantly reduced nociceptive hypersensitivity and nerve fiber hypertrophy and improved behavioral parameters without affecting tumor infiltration by T cells or neutrophils. Increased levels of CXCR3 and CCR7 in human PDAC specimens were associated with increased frequency of cancer-associated pain, determined from patient questionnaires. CONCLUSIONS: In an unbiased screen of chemokines, we identified CCL21 and CXCL10 as proteins that promote migration of pancreatic cancer cells toward sensory neurons. Inhibition of these chemokines or their receptors reduce hypersensitivity in mice with orthotopic tumors, and patients with PDACs with high levels of the chemokine receptors of CXCR3 and CCR7 had increased frequency of cancer-associated pain.


Asunto(s)
Dolor en Cáncer/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Movimiento Celular , Quimiocina CCL21/metabolismo , Quimiocina CXCL10/metabolismo , Ganglios Espinales/metabolismo , Neoplasias Pancreáticas/metabolismo , Células Receptoras Sensoriales/metabolismo , Analgésicos/farmacología , Animales , Anticuerpos Neutralizantes/farmacología , Dolor en Cáncer/genética , Dolor en Cáncer/patología , Dolor en Cáncer/prevención & control , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Quimiocina CCL21/antagonistas & inhibidores , Quimiocina CCL21/genética , Quimiocina CXCL10/antagonistas & inhibidores , Quimiocina CXCL10/genética , Técnicas de Cocultivo , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/patología , Humanos , Ratones Endogámicos C57BL , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Receptores CCR7/metabolismo , Receptores CXCR3/metabolismo , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/patología , Transducción de Señal
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