RESUMO
Epithelial-to-mesenchymal transition (EMT), a biological phenomenon of cellular plasticity initially reported in embryonic development, has been increasingly recognized for its importance in cancer progression and metastasis. Despite tremendous progress being made in the past 2 decades in our understanding of the molecular mechanism and functional importance of EMT in cancer, there are several mysteries around EMT that remain unresolved. In this Unsolved Mystery, we focus on the variety of EMT types in metastasis, cooperative and collective EMT behaviors, spatiotemporal characterization of EMT, and strategies of therapeutically targeting EMT. We also highlight new technical advances that will facilitate the efforts to elucidate the unsolved mysteries of EMT in metastasis.
Assuntos
Neoplasias , Humanos , Neoplasias/patologia , Transição Epitelial-Mesenquimal , Desenvolvimento Embrionário , Metástase NeoplásicaRESUMO
Neuroblastoma is a pediatric cancer that can present as low- or high-risk tumors (LR-NBs and HR-NBs), the latter group showing poor prognosis due to metastasis and strong resistance to current therapy. Whether LR-NBs and HR-NBs differ in the way they exploit the transcriptional program underlying their neural crest, sympatho-adrenal origin remains unclear. Here, we identified the transcriptional signature distinguishing LR-NBs from HR-NBs, which consists mainly of genes that belong to the core sympatho-adrenal developmental program and are associated with favorable patient prognosis and with diminished disease progression. Gain- and loss-of-function experiments revealed that the top candidate gene of this signature, Neurexophilin-1 (NXPH1), has a dual impact on NB cell behavior in vivo: whereas NXPH1 and its receptor α-NRXN1 promote NB tumor growth by stimulating cell proliferation, they conversely inhibit organotropic colonization and metastasis. As suggested by RNA-seq analyses, these effects might result from the ability of NXPH1/α-NRXN signalling to restrain the conversion of NB cells from an adrenergic state to a mesenchymal one. Our findings thus uncover a transcriptional module of the sympatho-adrenal program that opposes neuroblastoma malignancy by impeding metastasis, and pinpoint NXPH1/α-NRXN signaling as a promising target to treat HR-NBs.
Assuntos
Neuroblastoma , Neuropeptídeos , Criança , Humanos , Crista Neural/patologia , Neuroblastoma/genética , Neuroblastoma/patologia , Neuropeptídeos/genética , GlicoproteínasAssuntos
Neoplasias da Mama , Melanoma , Neoplasias Cutâneas , Humanos , Feminino , Microambiente Tumoral , Melanoma Maligno CutâneoRESUMO
Resistance to cancer treatment remains a major clinical hurdle. Here, we demonstrate that the CoREST complex is a key determinant of endocrine resistance and ER+ breast cancer plasticity. In endocrine-sensitive cells, CoREST is recruited to regulatory regions co-bound to ERα and FOXA1 to regulate the estrogen pathway. In contrast, during temporal reprogramming towards a resistant state, CoREST is recruited to AP-1 sites. In reprogrammed cells, CoREST favors chromatin opening, cJUN binding to chromatin, and gene activation by controlling SWI/SNF recruitment independently of the demethylase activity of the CoREST subunit LSD1. Genetic and pharmacological CoREST inhibition reduces tumorigenesis and metastasis of endocrine-sensitive and endocrine-resistant xenograft models. Consistently, CoREST controls a gene signature involved in invasiveness in clinical breast tumors resistant to endocrine therapies. Our studies reveal CoREST functions that are co-opted to drive cellular plasticity and resistance to endocrine therapies and tumorigenesis, thus establishing CoREST as a potential therapeutic target for the treatment of advanced breast cancer.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas Correpressoras/genética , Proteínas Correpressoras/metabolismo , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Cromatina , CarcinogêneseRESUMO
About 50% of human epidermal growth factor receptor 2 (HER2)+ breast cancer patients do not benefit from HER2-targeted therapy and almost 20% of them relapse after treatment. Here, we conduct a detailed analysis of two independent cohorts of HER2+ breast cancer patients treated with trastuzumab to elucidate the mechanisms of resistance to anti-HER2 monoclonal antibodies. In addition, we develop a fully humanized immunocompetent model of HER2+ breast cancer recapitulating ex vivo the biological processes that associate with patients' response to treatment. Thanks to these two approaches, we uncover a population of TGF-beta-activated cancer-associated fibroblasts (CAF) specific from tumors resistant to therapy. The presence of this cellular subset related to previously described myofibroblastic (CAF-S1) and podoplanin+ CAF subtypes in breast cancer associates with low IL2 activity. Correspondingly, we find that stroma-targeted stimulation of IL2 pathway in unresponsive tumors restores trastuzumab anti-cancer efficiency. Overall, our study underscores the therapeutic potential of exploiting the tumor microenvironment to identify and overcome mechanisms of resistance to anti-cancer treatment.
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Neoplasias da Mama , Fibroblastos Associados a Câncer , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Humanos , Fatores Imunológicos , Imunoterapia , Interleucina-2 , Receptor ErbB-2 , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Microambiente TumoralRESUMO
Current therapy against colorectal cancer (CRC) is based on DNA-damaging agents that remain ineffective in a proportion of patients. Whether and how non-curative DNA damage-based treatment affects tumor cell behavior and patient outcome is primarily unstudied. Using CRC patient-derived organoids (PDO)s, we show that sublethal doses of chemotherapy (CT) does not select previously resistant tumor populations but induces a quiescent state specifically to TP53 wildtype (WT) cancer cells, which is linked to the acquisition of a YAP1-dependent fetal phenotype. Cells displaying this phenotype exhibit high tumor-initiating and metastatic activity. Nuclear YAP1 and fetal traits are present in a proportion of tumors at diagnosis and predict poor prognosis in patients carrying TP53 WT CRC tumors. We provide data indicating the higher efficacy of CT together with YAP1 inhibitors for eradication of therapy resistant TP53 WT cancer cells. Together these results identify fetal conversion as a useful biomarker for patient prognosis and therapy prescription.
Assuntos
Neoplasias Colorretais , Proteína Supressora de Tumor p53/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Proteína Supressora de Tumor p53/genéticaRESUMO
Ligand-dependent corepressor (LCOR) mediates normal and malignant breast stem cell differentiation. Cancer stem cells (CSCs) generate phenotypic heterogeneity and drive therapy resistance, yet their role in immunotherapy is poorly understood. Here we show that immune-checkpoint blockade (ICB) therapy selects for LCORlow CSCs with reduced antigen processing/presentation machinery (APM) driving immune escape and ICB resistance in triple-negative breast cancer (TNBC). We unveil an unexpected function of LCOR as a master transcriptional activator of APM genes binding to IFN-stimulated response elements (ISREs) in an IFN signaling-independent manner. Through genetic modification of LCOR expression, we demonstrate its central role in modulation of tumor immunogenicity and ICB responsiveness. In TNBC, LCOR associates with ICB clinical response. Importantly, extracellular vesicle (EV) Lcor-messenger RNA therapy in combination with anti-PD-L1 overcame resistance and eradicated breast cancer metastasis in preclinical models. Collectively, these data support LCOR as a promising target for enhancement of ICB efficacy in TNBC, by boosting of tumor APM independently of IFN.
Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia , Interferons/farmacologia , Melanoma , Proteínas Repressoras/uso terapêutico , Neoplasias Cutâneas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Melanoma Maligno CutâneoRESUMO
OVOL proteins (OVOL1 and OVOL2), vertebrate homologs of Drosophila OVO, are critical regulators of epithelial lineage determination and differentiation during embryonic development in tissues such as kidney, skin, mammary epithelia, and testis. OVOL can inhibit epithelial-mesenchymal transition and/or can promote mesenchymal-epithelial transition. Moreover, they can regulate the stemness of cancer cells, thus playing an important role during cancer cell metastasis. Due to their central role in differentiation and maintenance of epithelial lineage, OVOL overexpression has been shown to be capable of reprogramming fibroblasts to epithelial cells. Here, we review the roles of OVOL-mediated epithelial differentiation across multiple contexts, including embryonic development, cancer progression, and cellular reprogramming.
Assuntos
Neoplasias , Fatores de Transcrição , Diferenciação Celular/fisiologia , Proteínas de Ligação a DNA/metabolismo , Transição Epitelial-Mesenquimal , Feminino , Humanos , Masculino , Neoplasias/patologia , Gravidez , Pele/patologia , Fatores de Transcrição/metabolismoRESUMO
Fundamental biological processes of cell identity and cell fate determination are controlled by complex regulatory networks. These processes require molecular mechanisms that confer cellular phenotypic memory and state persistence. In this minireview, we will summarize mechanisms of cell memory based on regulatory hysteretic feedback loops and explore epigenetic mechanisms widely represented in nature, with special focus on epithelial-to-mesenchymal plasticity. We will also discuss the functional consequences of cell memory and epithelial-to-mesenchymal plasticity dynamics during development and cancer metastasis.
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Neoplasias , Plasticidade Celular , Epigênese Genética , Transição Epitelial-Mesenquimal , HumanosRESUMO
Interferons (IFNs) are pleiotropic cytokines critical for regulation of epithelial cell functions and for immune system regulation. In cancer, IFNs contribute to tumor-intrinsic and -extrinsic mechanisms that determine the quality of antitumor immunity and response to immunotherapy. In this Review, we focus on the different types of tumor IFN sensitivity that determine dynamic tumor-immune interactions and their coevolution during cancer progression and metastasis. We extend the discussion to new evidence supporting immunotherapy-mediated immunoediting and the dual opposing roles of IFNs that lead to immune checkpoint blockade response or resistance. Understanding the intricate dynamic responses to IFN will lead to novel immunotherapeutic strategies to circumvent protumorigenic effects of IFN while exploiting IFN-mediated antitumor immunity.
Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Interferons/imunologia , Neoplasias , Animais , Humanos , Metástase Neoplásica , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapiaRESUMO
Epithelial-mesenchymal transition (EMT), first described by Dr. Elizabeth (Betty) Hay in the 1980s during vertebrate embryonic development [1], has important implications in cancer aggressiveness [2]. [...].
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The cancer stem cell (CSC) concept stands for undifferentiated tumor cells with the ability to initiate heterogeneous tumors. It is also relevant in metastasis and can explain how metastatic tumors mirror the heterogeneity of primary tumors. Cellular plasticity, including the epithelial-to-mesenchymal transition (EMT), enables the generation of CSCs at different steps of the metastatic process including metastatic colonization. In this review, we update the concept of CSCs and provide evidence of the existence of metastatic stem cells (MetSCs). In addition, we highlight the nuanced understanding of EMT that has been gained recently and the association of mesenchymal-to-epithelial transition (MET) with the acquisition of CSCs properties during metastasis. We also comment on the computational approaches that have profoundly influenced our understanding of CSCs and EMT; and how these studies and new experimental technologies can yield a deeper understanding of the biological aspects of metastasis.
Assuntos
Transição Epitelial-Mesenquimal/genética , Neoplasias/metabolismo , Neoplasias/patologia , Células-Tronco Neoplásicas/metabolismo , Humanos , Metástase Neoplásica , Neoplasias/genética , Células-Tronco Neoplásicas/patologiaRESUMO
Genetic and phenotypic heterogeneity contribute to the generation of diverse tumor cell populations, thus enhancing cancer aggressiveness and therapy resistance. Compared to genetic heterogeneity, a consequence of mutational events, phenotypic heterogeneity arises from dynamic, reversible cell state transitions in response to varying intracellular/extracellular signals. Such phenotypic plasticity enables rapid adaptive responses to various stressful conditions and can have a strong impact on cancer progression. Herein, we have reviewed relevant literature on mechanisms associated with dynamic phenotypic changes and cellular plasticity, such as epithelial-mesenchymal transition (EMT) and cancer stemness, which have been reported to facilitate cancer metastasis. We also discuss how non-cell-autonomous mechanisms such as cell-cell communication can lead to an emergent population-level response in tumors. The molecular mechanisms underlying the complexity of tumor systems are crucial for comprehending cancer progression, and may provide new avenues for designing therapeutic strategies.
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The original version of this Article contained an error in the spelling of the author Daniel D. Liu, which was incorrectly given as Daniel Liu. This has now been corrected in both the PDF and HTML versions of the Article.
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Triple-negative breast cancer (TNBC) patients have the worst prognosis and distant metastasis-free survival among all major subtypes of breast cancer. The poor clinical outlook is further exacerbated by a lack of effective targeted therapies for TNBC. Here we show that ectopic expression and therapeutic delivery of the secreted protein Tubulointerstitial nephritis antigen-like 1 (Tinagl1) suppresses TNBC progression and metastasis through direct binding to integrin α5ß1, αvß1, and epidermal growth factor receptor (EGFR), and subsequent simultaneous inhibition of focal adhesion kinase (FAK) and EGFR signaling pathways. Moreover, Tinagl1 protein level is associated with good prognosis and reversely correlates with FAK and EGFR activation status in TNBC. Our results suggest Tinagl1 as a candidate therapeutic agent for TNBC by dual inhibition of integrin/FAK and EGFR signaling pathways.
Assuntos
Proteínas da Matriz Extracelular/genética , Integrina alfa5beta1/metabolismo , Lipocalinas/genética , Neoplasias Pulmonares/terapia , Receptores de Vitronectina/metabolismo , Neoplasias de Mama Triplo Negativas/terapia , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Receptores ErbB/metabolismo , Proteínas da Matriz Extracelular/administração & dosagem , Proteínas da Matriz Extracelular/metabolismo , Feminino , Quinase 1 de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Lipocalinas/administração & dosagem , Lipocalinas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Prognóstico , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
Epithelial-mesenchymal transition (EMT) have been extensively characterized in development and cancer, and its dynamics have been modeled as a non-linear process. However, less is known about how such dynamics may affect its biological impact. Here, we use mathematical modeling and experimental analysis of the TGF-ß-induced EMT to reveal a non-linear hysteretic response of E-cadherin repression tightly controlled by the strength of the miR-200s/ZEBs negative feedback loop. Hysteretic EMT conveys memory state, ensures rapid and robust cellular response and enables EMT to persist long after withdrawal of stimuli. Importantly, while both hysteretic and non-hysteretic EMT confer similar morphological changes and invasive potential of cancer cells, only hysteretic EMT enhances lung metastatic colonization efficiency. Cells that undergo hysteretic EMT differentially express subsets of stem cell and extracellular matrix related genes with significant clinical prognosis value. These findings illustrate distinct biological impact of EMT depending on the dynamics of the transition.
Assuntos
Transição Epitelial-Mesenquimal , Metástase Neoplásica/patologia , Animais , Caderinas/metabolismo , Linhagem Celular Tumoral , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Retroalimentação Fisiológica , Feminino , Camundongos Endogâmicos BALB C , MicroRNAs/genética , MicroRNAs/metabolismo , Modelos Biológicos , Metástase Neoplásica/genética , Fator de Crescimento Transformador beta/farmacologia , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismoRESUMO
Metastasis is an inefficient process, especially during colonization at a distant organ. This bottleneck underlies the importance of the metastatic niche for seeding and outgrowth of metastases. Here, we classify the common functions of different metastatic niches: anchorage, survival support, protection from external insults, licensing proliferation and outgrowth. We highlight the emerging role of the metastatic niche in maintaining cancer stemness and promoting immune evasion, and discuss therapeutic opportunities against the metastatic niche.
Assuntos
Movimento Celular , Neoplasias/patologia , Células-Tronco Neoplásicas/patologia , Nicho de Células-Tronco , Microambiente Tumoral , Animais , Antineoplásicos/uso terapêutico , Comunicação Celular , Movimento Celular/efeitos dos fármacos , Plasticidade Celular , Proliferação de Células , Sobrevivência Celular , Transição Epitelial-Mesenquimal , Humanos , Metástase Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/metabolismo , Fenótipo , Transdução de Sinais , Nicho de Células-Tronco/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacosRESUMO
The stem cell niche is a specialized environment that dictates stem cell function during development and homeostasis. We show that Dll1, a Notch pathway ligand, is enriched in mammary gland stem cells (MaSCs) and mediates critical interactions with stromal macrophages in the surrounding niche in mouse models. Conditional deletion of Dll1 reduced the number of MaSCs and impaired ductal morphogenesis in the mammary gland. Moreover, MaSC-expressed Dll1 activates Notch signaling in stromal macrophages, increasing their expression of Wnt family ligands such as Wnt3, Wnt10A, and Wnt16, thereby initiating a feedback loop that promotes the function of Dll1-expressing MaSCs. Together, these findings reveal functionally important cross-talk between MaSCs and their macrophageal niche through Dll1-mediated Notch signaling.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Macrófagos/fisiologia , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Receptores Notch/metabolismo , Nicho de Células-Tronco/fisiologia , Células-Tronco/fisiologia , Animais , Proteínas de Ligação ao Cálcio , Contagem de Células , Feminino , Técnicas de Inativação de Genes , Peptídeos e Proteínas de Sinalização Intercelular/genética , Ligantes , Macrófagos/citologia , Glândulas Mamárias Animais/metabolismo , Camundongos , Camundongos Knockout , Morfogênese , Transdução de Sinais , Células-Tronco/citologia , Células Estromais/citologia , Células Estromais/fisiologia , Proteínas Wnt/metabolismoRESUMO
Cancer arises from subpopulations of transformed cells with high tumor initiation and repopulation ability, known as cancer stem cells (CSCs), which share many similarities with their normal counterparts. In the mammary gland, several studies have shown common molecular regulators between adult mammary stem cells (MaSCs) and breast cancer stem cells (bCSCs). Cell plasticity and self-renewal are essential abilities for MaSCs to maintain tissue homeostasis and regenerate the gland after pregnancy. Intriguingly, these properties are similarly executed in breast cancer stem cells to drive tumor initiation, tumor heterogeneity and recurrence after chemotherapy. In addition, both stem cell phenotypes are strongly influenced by external signals from the microenvironment, immune cells and supportive specific niches. This review focuses on the intrinsic and extrinsic connections of MaSC and bCSCs with clinical implications for breast cancer progression and their possible therapeutic applications.
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Tumour-initiating cells, or cancer stem cells (CSCs), possess stem-cell-like properties observed in normal adult tissue stem cells. Normal and cancerous stem cells may therefore share regulatory mechanisms for maintaining self-renewing capacity and resisting differentiation elicited by cell-intrinsic or microenvironmental cues. Here, we show that miR-199a promotes stem cell properties in mammary stem cells and breast CSCs by directly repressing nuclear receptor corepressor LCOR, which primes interferon (IFN) responses. Elevated miR-199a expression in stem-cell-enriched populations protects normal and malignant stem-like cells from differentiation and senescence induced by IFNs that are produced by epithelial and immune cells in the mammary gland. Importantly, the miR-199a-LCOR-IFN axis is activated in poorly differentiated ER- breast tumours, functionally promotes tumour initiation and metastasis, and is associated with poor clinical outcome. Our study therefore reveals a common mechanism shared by normal and malignant stem cells to protect them from suppressive immune cytokine signalling.