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1.
Cancer Res ; 2021 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-34965936

RESUMO

Tumor dormancy is a stage in which residual cancer cells remain inactive, but regrowth of dormant cancer cells contributes to recurrence. The complex ecosystem in cancer that promotes cell survival and the factors that eventually overcome growth constraints and result in proliferation remain to be fully elucidated. Doing so may provide new insights and help identify novel strategies to prolong cancer dormancy and prevent disease recurrence. To dissect the molecular pathways and the microenvironments involved in regulation of dormancy, we utilized a novel immunocompetent transgenic model to study minimal residual disease and relapse. This model revealed a significant reorganization of cancer cell structures, stroma, and immune cells with cancer cells showing dormant cell signatures. Single-cell RNA sequencing uncovered remodeling of myeloid and lymphoid compartments. Additionally, the Jagged-1/Notch signaling pathway was shown to regulate many aspects of tumorigenesis, including stem cell development, epithelial-mesenchymal transition, and immune cell homeostasis during minimal residual disease. Treatment with an anti-Jagged-1 antibody inhibited the Jagged-1/Notch signaling pathway in tumor cells and the microenvironment, delaying tumor recurrence. These findings uncover a cascade of regulatory changes in the microenvironment during dormancy and identify a therapeutic strategy to undercut these changes.

2.
J Clin Invest ; 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34847079

RESUMO

Therapeutics targeting osteoclasts are commonly used treatments for bone metastasis; however, whether and how osteoclasts regulate pre-metastatic niche and bone tropism is largely unknown. In this study, we report that osteoclast precursors (OPs) can function as a pre-metastatic niche component that facilitates breast cancer (BCa) bone metastasis at early stages. At the molecular level, unbiased GPCR ligand/agonist screening in BCa cells suggested that R-spondin 2 (RSPO2) and RANKL, through interacting with their receptor LGR4, promoted osteoclastic pre-metastatic niche formation and enhanced BCa bone metastasis. This was achieved by RSPO2/RANKL-LGR4 signal modulating WNT inhibitor DKK1 through Gαq and ß-catenin signaling. DKK1 directly facilitated OP recruitment through suppressing its receptor low-density lipoprotein-related receptors 5 (LRP5) but not LRP6, upregulating Rnasek expression via inhibiting canonical WNT signaling. In clinical samples, RSPO2, LGR4 and DKK1 expression showed positive correlation with BCa bone metastasis. Furthermore, soluble LGR4 extracellular domain (ECD) protein, acting as a decoy receptor for RSPO2 and RANKL, significantly alleviated bone metastasis and osteolytic lesions in mouse bone metastasis model. These findings provide unique insights into the functional role of OPs as key components of pre-metastatic niche for BCa bone metastasis, indicate RSPO2/RANKL-LGR4 signaling as a promising target for inhibiting BCa bone metastasis.

4.
Nat Rev Cancer ; 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34611349

RESUMO

Many cancer types metastasize to bone. This propensity may be a product of genetic traits of the primary tumour in some cancers. Upon arrival, cancer cells establish interactions with various bone-resident cells during the process of colonization. These interactions, to a large degree, dictate cancer cell fates at multiple steps of the metastatic cascade, from single cells to overt metastases. The bone microenvironment may even influence cancer cells to subsequently spread to multiple other organs. Therefore, it is imperative to spatiotemporally delineate the evolving cancer-bone crosstalk during bone colonization. In this Review, we provide a summary of the bone microenvironment and its impact on bone metastasis. On the basis of the microscopic anatomy, we tentatively define a roadmap of the journey of cancer cells through bone relative to various microenvironment components, including the potential of bone to function as a launch pad for secondary metastasis. Finally, we examine common and distinct features of bone metastasis from various cancer types. Our goal is to stimulate future studies leading to the development of a broader scope of potent therapies.

6.
Cancer Res ; 81(17): 4441-4454, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34099494

RESUMO

Leucine-rich repeat-containing G protein-coupled receptors 4, 5, and 6 (LGR4/5/6) play critical roles in development and cancer. The widely accepted mechanism is that these proteins, together with their R-spondin ligands, stabilize Wnt receptors, thus potentiating Wnt signaling. Here we show that LGR4 enhanced breast cancer cell metastasis even when Wnt signaling was deactivated pharmacologically or genetically. Furthermore, LGR4 mutants that cannot potentiate Wnt signaling nevertheless promoted breast cancer cell migration and invasion in vitro and breast cancer metastasis in vivo. Multiomic screening identified EGFR as a crucial mediator of LGR4 activity in cancer progression. Mechanistically, LGR4 interacted with EGFR and blocked EGFR ubiquitination and degradation, resulting in persistent EGFR activation. Together, these data uncover a Wnt-independent LGR4-EGFR signaling axis with broad implications for cancer progression and targeted therapy. SIGNIFICANCE: This work demonstrates a Wnt-independent mechanism by which LGR4 promotes cancer metastasis.See related commentary by Stevens and Williams, p. 4397.

7.
Sci Adv ; 7(26)2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34162538

RESUMO

Antibody-based therapies have proved to be of great value in cancer treatment. Despite the clinical success of these biopharmaceuticals, reaching targets in the bone microenvironment has proved to be difficult due to the relatively low vascularization of bone tissue and the presence of physical barriers. Here, we have used an innovative bone-targeting (BonTarg) technology to generate a first-in-class bone-targeting antibody. Our strategy involves the use of pClick antibody conjugation technology to chemically couple the bone-targeting moiety bisphosphonate to therapeutic antibodies. Bisphosphonate modification of these antibodies results in the delivery of higher conjugate concentrations to the bone metastatic niche, relative to other tissues. In xenograft mice models, this strategy provides enhanced inhibition of bone metastases and multiorgan secondary metastases that arise from bone lesions. Specific delivery of therapeutic antibodies to the bone, therefore, represents a promising strategy for the treatment of bone metastatic cancers and other bone diseases.

8.
Cell ; 184(9): 2471-2486.e20, 2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33878291

RESUMO

Metastasis has been considered as the terminal step of tumor progression. However, recent genomic studies suggest that many metastases are initiated by further spread of other metastases. Nevertheless, the corresponding pre-clinical models are lacking, and underlying mechanisms are elusive. Using several approaches, including parabiosis and an evolving barcode system, we demonstrated that the bone microenvironment facilitates breast and prostate cancer cells to further metastasize and establish multi-organ secondary metastases. We uncovered that this metastasis-promoting effect is driven by epigenetic reprogramming that confers stem cell-like properties on cancer cells disseminated from bone lesions. Furthermore, we discovered that enhanced EZH2 activity mediates the increased stemness and metastasis capacity. The same findings also apply to single cell-derived populations, indicating mechanisms distinct from clonal selection. Taken together, our work revealed an unappreciated role of the bone microenvironment in metastasis evolution and elucidated an epigenomic reprogramming process driving terminal-stage, multi-organ metastases.


Assuntos
Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Metástase Neoplásica , Neoplasias da Próstata/patologia , Microambiente Tumoral , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proliferação de Células , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Dev Cell ; 56(8): 1100-1117.e9, 2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33878299

RESUMO

Estrogen receptor-positive (ER+) breast cancer exhibits a strong bone tropism in metastasis. How the bone microenvironment (BME) impacts ER signaling and endocrine therapy remains poorly understood. Here, we discover that the osteogenic niche transiently and reversibly reduces ER expression and activities specifically in bone micrometastases (BMMs), leading to endocrine resistance. As BMMs progress, the ER reduction and endocrine resistance may partially recover in cancer cells away from the osteogenic niche, creating phenotypic heterogeneity in macrometastases. Using multiple approaches, including an evolving barcoding strategy, we demonstrated that this process is independent of clonal selection, and represents an EZH2-mediated epigenomic reprogramming. EZH2 drives ER+ BMMs toward a basal and stem-like state. EZH2 inhibition reverses endocrine resistance. These data exemplify how epigenomic adaptation to BME promotes phenotypic plasticity of metastatic seeds, fosters intra-metastatic heterogeneity, and alters therapeutic responses. Our study provides insights into the clinical enigma of ER+ metastatic recurrences despite endocrine therapies.


Assuntos
Adaptação Fisiológica , Osso e Ossos/patologia , Neoplasias da Mama/patologia , Receptores de Estrogênio/metabolismo , Microambiente Tumoral , Animais , Neoplasias Ósseas/secundário , Neoplasias da Mama/metabolismo , Comunicação Celular , Evolução Clonal , Modelos Animais de Doenças , Regulação para Baixo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Junções Comunicantes/metabolismo , Genes Reporter , Proteínas de Fluorescência Verde/metabolismo , Humanos , Células MCF-7 , Camundongos , Micrometástase de Neoplasia , Osteogênese , Transdução de Sinais
10.
J Clin Invest ; 131(6)2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33720051

RESUMO

Many solid cancers metastasize to the bone and bone marrow (BM). This process may occur even before the diagnosis of primary tumors, as evidenced by the discovery of disseminated tumor cells (DTCs) in patients without occult malignancies. The cellular fates and metastatic progression of DTCs are determined by complicated interactions between cancer cells and BM niches. Not surprisingly, these niches also play important roles in normal biology, including homeostasis and turnover of skeletal and hematopoiesis systems. In this Review, we summarize recent findings on functions of BM niches in bone metastasis (BoMet), particularly during the early stage of colonization. In light of the rich knowledge of hematopoiesis and osteogenesis, we highlight how DTCs may progress into overt BoMet by taking advantage of niche cells and their activities in tissue turnover, especially those related to immunomodulation and bone repair.


Assuntos
Neoplasias Ósseas/secundário , Neoplasias da Medula Óssea/imunologia , Neoplasias da Medula Óssea/patologia , Neoplasias da Medula Óssea/secundário , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/patologia , Remodelação Óssea/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/patologia , Humanos , Privilégio Imunológico , Tolerância Imunológica , Masculino , Modelos Biológicos , Células Mieloides/imunologia , Metástase Neoplásica/imunologia , Metástase Neoplásica/patologia , Metástase Neoplásica/terapia , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Nicho de Células-Tronco/imunologia , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologia
11.
Cell ; 184(2): 384-403.e21, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33450205

RESUMO

Many oncogenic insults deregulate RNA splicing, often leading to hypersensitivity of tumors to spliceosome-targeted therapies (STTs). However, the mechanisms by which STTs selectively kill cancers remain largely unknown. Herein, we discover that mis-spliced RNA itself is a molecular trigger for tumor killing through viral mimicry. In MYC-driven triple-negative breast cancer, STTs cause widespread cytoplasmic accumulation of mis-spliced mRNAs, many of which form double-stranded structures. Double-stranded RNA (dsRNA)-binding proteins recognize these endogenous dsRNAs, triggering antiviral signaling and extrinsic apoptosis. In immune-competent models of breast cancer, STTs cause tumor cell-intrinsic antiviral signaling, downstream adaptive immune signaling, and tumor cell death. Furthermore, RNA mis-splicing in human breast cancers correlates with innate and adaptive immune signatures, especially in MYC-amplified tumors that are typically immune cold. These findings indicate that dsRNA-sensing pathways respond to global aberrations of RNA splicing in cancer and provoke the hypothesis that STTs may provide unexplored strategies to activate anti-tumor immune pathways.


Assuntos
Antivirais/farmacologia , Imunidade/efeitos dos fármacos , Spliceossomos/metabolismo , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Feminino , Amplificação de Genes/efeitos dos fármacos , Humanos , Íntrons/genética , Camundongos , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-myc/metabolismo , Splicing de RNA/efeitos dos fármacos , Splicing de RNA/genética , RNA de Cadeia Dupla/metabolismo , Transdução de Sinais/efeitos dos fármacos , Spliceossomos/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética
12.
Acta Neuropathol ; 141(2): 303-321, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33394124

RESUMO

The deadly complication of brain metastasis (BM) is largely confined to a relatively narrow cross-section of systemic malignancies, suggesting a fundamental role for biological mechanisms shared across commonly brain metastatic tumor types. To identify and characterize such mechanisms, we performed genomic, transcriptional, and proteomic profiling using whole-exome sequencing, mRNA-seq, and reverse-phase protein array analysis in a cohort of the lung, breast, and renal cell carcinomas consisting of BM and patient-matched primary or extracranial metastatic tissues. While no specific genomic alterations were associated with BM, correlations with impaired cellular immunity, upregulated oxidative phosphorylation (OXPHOS), and canonical oncogenic signaling pathways including phosphoinositide 3-kinase (PI3K) signaling, were apparent across multiple tumor histologies. Multiplexed immunofluorescence analysis confirmed significant T cell depletion in BM, indicative of a fundamentally altered immune microenvironment. Moreover, functional studies using in vitro and in vivo modeling demonstrated heightened oxidative metabolism in BM along with sensitivity to OXPHOS inhibition in murine BM models and brain metastatic derivatives relative to isogenic parentals. These findings demonstrate that pathophysiological rewiring of oncogenic signaling, cellular metabolism, and immune microenvironment broadly characterizes BM. Further clarification of this biology will likely reveal promising targets for therapeutic development against BM arising from a broad variety of systemic cancers.


Assuntos
Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Impressões Digitais de DNA/métodos , Genômica/métodos , Animais , Sequência de Bases , Neoplasias Encefálicas/imunologia , Sobrevivência Celular , Feminino , Imunofluorescência , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos SCID , Transplante de Neoplasias , Análise Serial de Proteínas , Proteômica , Superóxido Dismutase/metabolismo , Análise de Sobrevida , Sequenciamento Completo do Exoma
13.
Cancer Res ; 81(1): 50-63, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33115805

RESUMO

Metabolic dysregulation is a known hallmark of cancer progression, yet the oncogenic signals that promote metabolic adaptations to drive metastatic cancer remain unclear. Here, we show that transcriptional repression of mitochondrial deacetylase sirtuin 3 (SIRT3) by androgen receptor (AR) and its coregulator steroid receptor coactivator-2 (SRC-2) enhances mitochondrial aconitase (ACO2) activity to favor aggressive prostate cancer. ACO2 promoted mitochondrial citrate synthesis to facilitate de novo lipogenesis, and genetic ablation of ACO2 reduced total lipid content and severely repressed in vivo prostate cancer progression. A single acetylation mark lysine258 on ACO2 functioned as a regulatory motif, and the acetylation-deficient Lys258Arg mutant was enzymatically inactive and failed to rescue growth of ACO2-deficient cells. Acetylation of ACO2 was reversibly regulated by SIRT3, which was predominantly repressed in many tumors including prostate cancer. Mechanistically, SRC-2-bound AR formed a repressive complex by recruiting histone deacetylase 2 to the SIRT3 promoter, and depletion of SRC-2 enhanced SIRT3 expression and simultaneously reduced acetylated ACO2. In human prostate tumors, ACO2 activity was significantly elevated, and increased expression of SRC-2 with concomitant reduction of SIRT3 was found to be a genetic hallmark enriched in prostate cancer metastatic lesions. In a mouse model of spontaneous bone metastasis, suppression of SRC-2 reactivated SIRT3 expression and was sufficient to abolish prostate cancer colonization in the bone microenvironment, implying this nuclear-mitochondrial regulatory axis is a determining factor for metastatic competence. SIGNIFICANCE: This study highlights the importance of mitochondrial aconitase activity in the development of advanced metastatic prostate cancer and suggests that blocking SRC-2 to enhance SIRT3 expression may be therapeutically valuable. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/1/50/F1.large.jpg.


Assuntos
Aconitato Hidratase/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/secundário , Regulação Neoplásica da Expressão Gênica , Mitocôndrias/enzimologia , Neoplasias da Próstata/patologia , Sirtuína 3/metabolismo , Aconitato Hidratase/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Proliferação de Células , Humanos , Masculino , Camundongos , Camundongos Nus , Coativador 3 de Receptor Nuclear/genética , Coativador 3 de Receptor Nuclear/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Sirtuína 3/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Oncogene ; 40(5): 997-1011, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33323970

RESUMO

Estrogen receptor alpha gene (ESR1) mutations occur frequently in ER-positive metastatic breast cancer, and confer clinical resistance to aromatase inhibitors. Expression of the ESR1 Y537S mutation induced an epithelial-mesenchymal transition (EMT) with cells exhibiting enhanced migration and invasion potential in vitro. When small subpopulations of Y537S ESR1 mutant cells were injected along with WT parental cells, tumor growth was enhanced with mutant cells becoming the predominant population in distant metastases. Y537S mutant primary xenograft tumors were resistant to the antiestrogen tamoxifen (Tam) as well as to estradiol (E2) withdrawal. Y537S ESR1 mutant primary tumors metastasized efficiently in the absence of E2; however, Tam treatment significantly inhibited metastasis to distant sites. We identified a nine-gene expression signature, which predicted clinical outcomes of ER-positive breast cancer patients, as well as breast cancer metastasis to the lung. Androgen receptor (AR) protein levels were increased in mutant models, and the AR agonist dihydrotestosterone significantly inhibited estrogen-regulated gene expression, EMT, and distant metastasis in vivo, suggesting that AR may play a role in distant metastatic progression of ESR1 mutant tumors.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Receptor alfa de Estrogênio/genética , Receptores Androgênicos/genética , Tamoxifeno/farmacologia , Animais , Inibidores da Aromatase/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Di-Hidrotestosterona/farmacologia , Estradiol/metabolismo , Estrogênios/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Mutação/genética , Metástase Neoplásica , Receptores Androgênicos/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Front Immunol ; 11: 553967, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33343560

RESUMO

Tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) have been extensively studied. Their pleotropic roles were observed in multiple steps of tumor progression and metastasis, and sometimes appeared to be inconsistent across different studies. In this review, we collectively discussed many lines of evidence supporting the mutual influence between cancer cells and TAMs/TANs. We focused on how direct interactions among these cells dictate co-evolution involving not only clonal competition of cancer cells, but also landscape shift of the entire tumor microenvironment (TME). This co-evolution may take distinct paths and contribute to the heterogeneity of cancer cells and immune cells across different tumors. A more in-depth understanding of the cancer-TAM/TAN co-evolution will shed light on the development of TME that mediates metastasis and therapeutic resistance.


Assuntos
Macrófagos/imunologia , Neoplasias/imunologia , Neutrófilos/imunologia , Microambiente Tumoral/imunologia , Humanos , Macrófagos/patologia , Neoplasias/patologia , Neutrófilos/patologia
16.
Cells ; 10(1)2020 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-33374595

RESUMO

The word myeloid is derived from the Greek word muelós which means "marrow". Therefore, myeloid cells are described as cells that arise in the bone marrow. They can be distinguished from lymphoid cells based on their different differentiation trajectories-Lymphoid cells (B and T cells) are usually born in the bone marrow, but they need to migrate to lymphoid organs to mature and differentiate usually in response to antigens produced due to infections and diseases like cancer. On the other hand, myeloid cells do not follow this differentiation trajectory. They arise from the bone marrow, and do not need an encounter with antigens to gain their functionality. Thus, while lymphoid cells are a part of the adaptive immune system, myeloid cells are a part of the innate immune system. Hematopoiesis gives rise to two progenitor cells-the common myeloid progenitor (CMP) and the common lymphoid progenitor (CLP). The CMP can give rise to megakaryocytes, erythrocytes, mast cells and myeloblasts. Myeloblasts in turn lead to the formation of basophils, neutrophils, eosinophils and monocytes that can further differentiate into macrophages. This review will focus on macrophages as well as the phenotypes they acquire with the tumor immune microenvironment (TIME) in triple-negative breast cancer (TNBC). It will address how cancer cells in the tumor microenvironment (TME) recruit macrophages and may switch to recruiting neutrophils upon depletion of these tumor-associated macrophages (TAMs). Finally, it will also shed light on past and current treatment options that specifically target these cells and how those affect patient outcomes in TNBC.


Assuntos
Carcinoma/patologia , Macrófagos/imunologia , Células Supressoras Mieloides/imunologia , Linfócitos T/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/imunologia , Animais , Diferenciação Celular , Feminino , Humanos , Macrófagos/citologia , Camundongos , Células Supressoras Mieloides/patologia , Linfócitos T/citologia
17.
NPJ Breast Cancer ; 6: 42, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32964116

RESUMO

Migration and invasion are key properties of metastatic cancer cells. These properties can be acquired through intrinsic reprogramming processes such as epithelial-mesenchymal transition. In this study, we discovered an alternative "migration-by-tethering" mechanism through which cancer cells gain the momentum to migrate by adhering to mesenchymal stem cells or osteoblasts. This tethering is mediated by both heterotypic adherens junctions and gap junctions, and leads to a unique cellular protrusion supported by cofilin-coated actin filaments. Inhibition of gap junctions or depletion of cofilin reduces migration-by-tethering. We observed evidence of these protrusions in bone segments harboring experimental and spontaneous bone metastasis in animal models. These data exemplify how cancer cells may acquire migratory ability without intrinsic reprogramming. Furthermore, given the important roles of osteogenic cells in early-stage bone colonization, our observations raise the possibility that migration-by-tethering may drive the relocation of disseminated tumor cells between different niches in the bone microenvironment.

18.
Nat Cell Biol ; 22(10): 1162-1169, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32958856

RESUMO

Stem cells need to be protected from genotoxic and proteotoxic stress to maintain a healthy pool throughout life1-3. Little is known about the proteostasis mechanism that safeguards stem cells. Here we report endoplasmic reticulum-associated degradation (ERAD) as a protein quality checkpoint that controls the haematopoietic stem cell (HSC)-niche interaction and determines the fate of HSCs. The SEL1L-HRD1 complex, the most conserved branch of ERAD4, is highly expressed in HSCs. Deletion of Sel1l led to niche displacement of HSCs and a complete loss of HSC identity, and allowed highly efficient donor-HSC engraftment without irradiation. Mechanistic studies identified MPL, the master regulator of HSC identity5, as a bona fide ERAD substrate that became aggregated in the endoplasmic reticulum following ERAD deficiency. Restoration of MPL signalling with an agonist partially rescued the number and reconstitution capacity of Sel1l-deficient HSCs. Our study defines ERAD as an essential proteostasis mechanism to safeguard a healthy stem cell pool by regulating the stem cell-niche interaction.


Assuntos
Degradação Associada com o Retículo Endoplasmático , Retículo Endoplasmático/metabolismo , Células-Tronco Hematopoéticas/citologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Receptores de Trombopoetina/metabolismo , Nicho de Células-Tronco , Ubiquitina-Proteína Ligases/metabolismo , Animais , Feminino , Células-Tronco Hematopoéticas/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Trombopoetina/genética , Ubiquitina-Proteína Ligases/genética
19.
Nat Immunol ; 21(11): 1444-1455, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32958928

RESUMO

Acquisition of a lipid-laden phenotype by immune cells has been defined in infectious diseases and atherosclerosis but remains largely uncharacterized in cancer. Here, in breast cancer models, we found that neutrophils are induced to accumulate neutral lipids upon interaction with resident mesenchymal cells in the premetastatic lung. Lung mesenchymal cells elicit this process through repressing the adipose triglyceride lipase (ATGL) activity in neutrophils in prostaglandin E2-dependent and -independent manners. In vivo, neutrophil-specific deletion of genes encoding ATGL or ATGL inhibitory factors altered neutrophil lipid profiles and breast tumor lung metastasis in mice. Mechanistically, lipids stored in lung neutrophils are transported to metastatic tumor cells through a macropinocytosis-lysosome pathway, endowing tumor cells with augmented survival and proliferative capacities. Pharmacological inhibition of macropinocytosis significantly reduced metastatic colonization by breast tumor cells in vivo. Collectively, our work reveals that neutrophils serve as an energy reservoir to fuel breast cancer lung metastasis.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Metabolismo dos Lipídeos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Células-Tronco Mesenquimais/metabolismo , Neutrófilos/metabolismo , Animais , Biomarcadores , Proliferação de Células , Progressão da Doença , Endocitose , Feminino , Imunofluorescência , Humanos , Camundongos , Metástase Neoplásica , Neutrófilos/ultraestrutura
20.
Front Oncol ; 10: 1100, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32850317

RESUMO

Metastases-the spreading of cancer cells from primary tumors to distant organs, including bone-is often incurable and is the major cause of morbidity in cancer patients. Understanding how cancer cells acquire the ability to colonize to bone and become overt metastases is critical to identify new therapeutic targets and develop new therapies against bone metastases. Recent reports indicate that the endoplasmic reticulum (ER) stress and, as its consequence, the unfolded protein response (UPR) is activated during metastatic dissemination. However, their roles in this process remain largely unknown. In this review, we discuss the recent progress on evaluating the tumorigenic, immunoregulatory and metastatic effects of ER stress and the UPR on bone metastases. We explore new opportunities to translate this knowledge into potential therapeutic strategies for patients with bone metastases.

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