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1.
Cancers (Basel) ; 15(22)2023 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-38001575

RESUMO

The metastasis of tumor cells into vital organs is a major cause of death from diverse types of malignancies [...].

2.
Nat Commun ; 14(1): 4313, 2023 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-37463901

RESUMO

Metastatic breast-cancer is a major cause of death in women worldwide, yet the relationship between oncogenic drivers that promote metastatic versus primary cancer is still contentious. To elucidate this relationship in treatment-naive animals, we hereby describe mammary-specific transposon-mutagenesis screens in female mice together with loss-of-function Rb, which is frequently inactivated in breast-cancer. We report gene-centric common insertion-sites (gCIS) that are enriched in primary-tumors, in metastases or shared by both compartments. Shared-gCIS comprise a major MET-RAS network, whereas metastasis-gCIS form three additional hubs: Rho-signaling, Ubiquitination and RNA-processing. Pathway analysis of four clinical cohorts with paired primary-tumors and metastases reveals similar organization in human breast-cancer with subtype-specific shared-drivers (e.g. RB1-loss, TP53-loss, high MET, RAS, ER), primary-enriched (EGFR, TGFß and STAT3) and metastasis-enriched (RHO, PI3K) oncogenic signaling. Inhibitors of RB1-deficiency or MET plus RHO-signaling cooperate to block cell migration and drive tumor cell-death. Thus, targeting shared- and metastasis- but not primary-enriched derivers offers a rational avenue to prevent metastatic breast-cancer.


Assuntos
Neoplasias da Mama , Feminino , Humanos , Animais , Camundongos , Neoplasias da Mama/patologia , Transdução de Sinais , Metástase Neoplásica
3.
Nat Commun ; 11(1): 1825, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286280

RESUMO

Pineoblastoma is a rare pediatric cancer induced by germline mutations in the tumor suppressors RB1 or DICER1. Presence of leptomeningeal metastases is indicative of poor prognosis. Here we report that inactivation of Rb plus p53 via a WAP-Cre transgene, commonly used to target the mammary gland during pregnancy, induces metastatic pineoblastoma resembling the human disease with 100% penetrance. A stabilizing mutation rather than deletion of p53 accelerates metastatic dissemination. Deletion of Dicer1 plus p53 via WAP-Cre also predisposes to pineoblastoma, albeit with lower penetrance. In silico analysis predicts tricyclic antidepressants such as nortriptyline as potential therapeutics for both pineoblastoma models. Nortriptyline disrupts the lysosome, leading to accumulation of non-functional autophagosome, cathepsin B release and pineoblastoma cell death. Nortriptyline further synergizes with the antineoplastic drug gemcitabine to effectively suppress pineoblastoma in our preclinical models, offering new modality for this lethal childhood malignancy.


Assuntos
Mutação em Linhagem Germinativa/genética , Lisossomos/metabolismo , Pinealoma/tratamento farmacológico , Pinealoma/genética , Animais , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Autofagossomos/ultraestrutura , Autofagia/efeitos dos fármacos , Análise por Conglomerados , Modelos Animais de Doenças , Deleção de Genes , Humanos , Integrases/metabolismo , Estimativa de Kaplan-Meier , Lisossomos/efeitos dos fármacos , Camundongos , Metástase Neoplásica , Nortriptilina/farmacologia , Nortriptilina/uso terapêutico , Pinealoma/patologia , Pinealoma/ultraestrutura , Proteína do Retinoblastoma/metabolismo , Proteína Supressora de Tumor p53/metabolismo
4.
Mol Cell Oncol ; 5(4): e1481814, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30250928

RESUMO

The dual phosphatase CDC25 has recently been identified as a target for diverse triple-negative breast cancers including RB1/PTEN/P53-deficient tumors. Moreover, CDC25 inhibitors effectively synergize with PI3K inhibitors to suppress tumor growth. We discuss these findings and the challenges that lie ahead in bringing CDC25 inhibitors to the clinic.

5.
Neoplasia ; 15(7): 712-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23814483

RESUMO

Desmoid tumor (also called aggressive fibromatosis) is a lesion of mesenchymal origin that can occur as a sporadic tumor or a manifestation of the preneoplastic syndrome, familial adenomatous polyposis caused by a mutation in adenomatous polyposis coli (APC). This tumor type is characterized by the stabilization of ß-catenin and activation of Tcf-mediated transcription. Cell transplantation data suggest that desmoid tumors are derived from mesenchymal progenitor cells (MSCs). As such, modulating cell signaling pathways that regulate MSC differentiation or proliferation, such as hedgehog (Hh) signaling, could alter the tumor phenotype. Here, we found that Hh signaling is activated in human and murine desmoid tumors. Inhibiting Hh signaling in human cell cultures decreased cell proliferation and ß-catenin protein levels. Apc(+)/Apc(1638N) mice, which develop desmoid tumors, develop smaller and fewer tumors when Hh signaling was inhibited either genetically (by crossing Apc(+)/Apc(1638N) mice with mice lacking one copy of a Hh-activated transcription factor, Gli2 (+/-) mice) or using a pharmacologic inhibitor. Both in mice and in human tumor cell cultures, ß-catenin and Hh-mediated signaling positively regulate each other's activity. These data show that targeting a pathway that regulates MSC differentiation influences desmoid tumor behavior, providing functional evidence supporting the notion that these tumors are derived from mesenchymal progenitors. It also suggests Hh blockade as a therapeutic approach for this tumor type.


Assuntos
Fibromatose Agressiva/metabolismo , Proteínas Hedgehog/metabolismo , Células-Tronco Mesenquimais/metabolismo , Transdução de Sinais , Animais , Proliferação de Células , Fibromatose Agressiva/genética , Fibromatose Agressiva/patologia , Genes APC , Proteínas Hedgehog/antagonistas & inibidores , Xenoenxertos , Humanos , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , Camundongos Transgênicos , Transdução de Sinais/efeitos dos fármacos , Triparanol/farmacologia , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Proteína Gli2 com Dedos de Zinco , beta Catenina/metabolismo
6.
Cancer Res ; 72(4): 1013-22, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22232736

RESUMO

Like many solid tumors, sarcomas are heterogeneous and include a small fraction of the so-called side population (SP) cells with stem-like tumor-initiating potential. Here, we report that SP cells from a soft tissue tumor of enigmatic origin termed undifferentiated pleomorphic sarcoma (also known as malignant fibrous histiocytoma or MFH sarcoma) display activation of both the Hedgehog and Notch pathways. Blockade to these pathways in murine xenograft models, this human cancer decreased the proportion of SP cells present and suppressed tumor self-renewal, as illustrated by the striking inability of xenograft tumors subjected to pathway blockade to be serially transplanted to new hosts. In contrast, conventional chemotherapies increased the proportion of SP cells present in tumor xenografts and did not affect their ability to be serially transplanted. SP cells from these tumors displayed an unexpectedly high proliferation rate which was selectively inhibited by Hedgehog and Notch blockade compared with conventional chemotherapies. Together, our findings deepen the concept that Hedgehog and Notch signaling are fundamental drivers of tumor self-renewal, acting in a small population of tumor-initiating cells present in tumors. Furthermore, our results suggest not only novel treatment strategies for deadly recurrent unresectable forms of this soft tumor subtype, but also potential insights into its etiology which has been historically controversial.


Assuntos
Proteínas Hedgehog/metabolismo , Histiocitoma Fibroso Maligno/metabolismo , Histiocitoma Fibroso Maligno/patologia , Receptores Notch/metabolismo , Animais , Proliferação de Células , Transformação Celular Neoplásica , Perfilação da Expressão Gênica , Proteínas Hedgehog/antagonistas & inibidores , Humanos , Camundongos , Camundongos SCID , Transplante de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Receptores Notch/antagonistas & inibidores , Transdução de Sinais/fisiologia , Triparanol/farmacologia
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