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1.
Cell ; 184(18): 4734-4752.e20, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34450029

RESUMO

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.


Assuntos
Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Proteínas Morfogenéticas Ósseas/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Compartimento Celular , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Estudos de Coortes , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA/genética , Células Endoteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade , Inflamação/patologia , Monócitos/patologia , Células Mieloides/patologia , Neutrófilos/patologia , Células Estromais/metabolismo , Linfócitos T/metabolismo , Transcrição Gênica
2.
Skeletal Radiol ; 50(1): 107-113, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32642791

RESUMO

OBJECTIVE: Use ultrashort echo time (UTE) magnetic resonance imaging to quantify bound water components of asymptomatic older Achilles tendons and investigate the relationship between UTE findings and imaging assessment of sub-clinical tendinopathy. MATERIALS AND METHODS: Thirteen young (age 25 ± 4.8) and thirteen older (age 67 ± 4.7) adults were tested. A UTE sequence was used to quantify the transverse relaxation times of bound ([Formula: see text]) and free ([Formula: see text]) water and the bound water fraction (Fs) in the Achilles tendon. Anatomical images were collected and graded by a musculoskeletal radiologist to identify signs of sub-clinical tendinopathy. Two-sample t tests were used to compare [Formula: see text], [Formula: see text], and Fs between age groups and between adults with and without sub-clinical tendinopathy. RESULTS: Older tendons exhibited a 60% longer [Formula: see text] (p = 0.004), similar [Formula: see text] (p = 0.86), and 5% smaller Fs (p = 0.048) than young tendons. Seven older adult tendons exhibited tendon thickening and increased signal intensity indicative of sub-clinical tendinopathy. This subset of tendons exhibited a 7% smaller bound water fraction (p = 0.02) and significantly longer [Formula: see text] (p < 0.001) than the normal tendons from young and older adults. CONCLUSION: Older adult tendons exhibited unique UTE signatures that are consistent with disruption of the collagen fiber network and changes in macromolecular content. UTE imaging metrics were sensitive to early indicators of tissue degeneration identified on anatomical images and hence could provide a quantitative biomarker by which to track changes in tissue health resulting from injury, disease, and treatment.


Assuntos
Tendão do Calcâneo , Tendinopatia , Tendão do Calcâneo/diagnóstico por imagem , Adulto , Idoso , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Tendinopatia/diagnóstico por imagem , Água , Adulto Jovem
3.
Sci Adv ; 9(39): eadd9668, 2023 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-37756410

RESUMO

Neuroendocrine tumors (NETs) are rare cancers that most often arise in the gastrointestinal tract and pancreas. The fundamental mechanisms driving gastroenteropancreatic (GEP)-NET growth remain incompletely elucidated; however, the heterogeneous clinical behavior of GEP-NETs suggests that both cellular lineage dynamics and tumor microenvironment influence tumor pathophysiology. Here, we investigated the single-cell transcriptomes of tumor and immune cells from patients with gastroenteropancreatic NETs. Malignant GEP-NET cells expressed genes and regulons associated with normal, gastrointestinal endocrine cell differentiation, and fate determination stages. Tumor and lymphoid compartments sparsely expressed immunosuppressive targets commonly investigated in clinical trials, such as the programmed cell death protein-1/programmed death ligand-1 axis. However, infiltrating myeloid cell types within both primary and metastatic GEP-NETs were enriched for genes encoding other immune checkpoints, including VSIR (VISTA), HAVCR2 (TIM3), LGALS9 (Gal-9), and SIGLEC10. Our findings highlight the transcriptomic heterogeneity that distinguishes the cellular landscapes of GEP-NET anatomic subtypes and reveal potential avenues for future precision medicine therapeutics.


Assuntos
Neoplasias Intestinais , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Neoplasias Gástricas , Humanos , Tumores Neuroendócrinos/genética , Neoplasias Intestinais/genética , Neoplasias Gástricas/genética , Neoplasias Pancreáticas/genética , Microambiente Tumoral/genética
4.
Nat Commun ; 14(1): 4317, 2023 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-37463915

RESUMO

Patients with pancreatic cancer commonly develop weight loss and muscle wasting. Whether adipose tissue and skeletal muscle losses begin before diagnosis and the potential utility of such losses for earlier cancer detection are not well understood. We quantify skeletal muscle and adipose tissue areas from computed tomography (CT) imaging obtained 2 months to 5 years before cancer diagnosis in 714 pancreatic cancer cases and 1748 matched controls. Adipose tissue loss is identified up to 6 months, and skeletal muscle wasting is identified up to 18 months before the clinical diagnosis of pancreatic cancer and is not present in the matched control population. Tissue losses are of similar magnitude in cases diagnosed with localized compared with metastatic disease and are not correlated with at-diagnosis circulating levels of CA19-9. Skeletal muscle wasting occurs in the 1-2 years before pancreatic cancer diagnosis and may signal an upcoming diagnosis of pancreatic cancer.


Assuntos
Composição Corporal , Neoplasias Pancreáticas , Humanos , Tecido Adiposo/metabolismo , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/metabolismo , Atrofia Muscular/patologia , Músculo Esquelético/metabolismo , Caquexia/diagnóstico , Caquexia/etiologia , Caquexia/metabolismo , Neoplasias Pancreáticas
5.
Cancer Discov ; 11(10): 2488-2505, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33926920

RESUMO

We conducted next-generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent FGFR2 fusions among patients with intrahepatic cholangiocarcinoma (IHCC), we identified FGFR2 extracellular domain in-frame deletions (EID) in 5 of 178 (2.8%) patients with IHCC, including two patients with FGFR2 p.H167_N173del. Expression of this FGFR2 EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with FGFR2 EIDs were treated with Debio 1347, an oral FGFR1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F FGFR2 kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal FGFR2 EIDs as an alternative mechanism of FGFR2 activation in IHCC that predicts sensitivity to FGFR inhibitors in the clinic. SIGNIFICANCE: FGFR2 EIDs are transforming genomic alterations that occur predominantly in patients with IHCC. These FGFR2 EIDs are sensitive to FGFR inhibition in vitro, and patients with these alterations benefited from treatment with FGFR inhibitors in the clinic.This article is highlighted in the In This Issue feature, p. 2355.


Assuntos
Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Adulto Jovem
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