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1.
Nat Cancer ; 5(3): 433-447, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38286827

RESUMO

Liver metastasis (LM) confers poor survival and therapy resistance across cancer types, but the mechanisms of liver-metastatic organotropism remain unknown. Here, through in vivo CRISPR-Cas9 screens, we found that Pip4k2c loss conferred LM but had no impact on lung metastasis or primary tumor growth. Pip4k2c-deficient cells were hypersensitized to insulin-mediated PI3K/AKT signaling and exploited the insulin-rich liver milieu for organ-specific metastasis. We observed concordant changes in PIP4K2C expression and distinct metabolic changes in 3,511 patient melanomas, including primary tumors, LMs and lung metastases. We found that systemic PI3K inhibition exacerbated LM burden in mice injected with Pip4k2c-deficient cancer cells through host-mediated increase in hepatic insulin levels; however, this circuit could be broken by concurrent administration of an SGLT2 inhibitor or feeding of a ketogenic diet. Thus, this work demonstrates a rare example of metastatic organotropism through co-optation of physiological metabolic cues and proposes therapeutic avenues to counteract these mechanisms.


Assuntos
Neoplasias Hepáticas , Proteínas Proto-Oncogênicas c-akt , Humanos , Camundongos , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases , Transdução de Sinais , Insulina , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo
2.
Cell Syst ; 11(3): 272-285.e9, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32898474

RESUMO

Accurately profiling systemic immune responses to cancer initiation and progression is necessary for understanding tumor surveillance and, ultimately, improving therapy. Here, we describe the SYLARAS software tool (systemic lymphoid architecture response assessment) and a dataset collected with SYLARAS that describes the frequencies of immune cells in primary and secondary lymphoid organs and in the tumor microenvironment of mice engrafted with a standard syngeneic glioblastoma (GBM) model. The data resource involves profiles of 5 lymphoid tissues in 48 mice and shows that GBM causes wide-spread changes in the local and systemic immune architecture. We use SYLARAS to identify a subset of CD45R/B220+ CD8+ T cells that is depleted from circulation but accumulates in the tumor mass and confirm this finding using multiplexed immunofluorescence microscopy. SYLARAS is freely available for download at (https://github.com/gjbaker/sylaras). A record of this paper's transparent peer review process is included in the Supplemental Information.


Assuntos
Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/imunologia , Glioblastoma/epidemiologia , Glioblastoma/imunologia , Animais , Humanos , Camundongos
3.
Proc Natl Acad Sci U S A ; 111(37): 13427-32, 2014 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-25197064

RESUMO

Aneuploidy is a hallmark of human solid cancers that arises from errors in mitosis and results in gain and loss of oncogenes and tumor suppressors. Aneuploidy poses a growth disadvantage for cells grown in vitro, suggesting that cancer cells adapt to this burden. To understand better the consequences of aneuploidy in a rapidly proliferating adult tissue, we engineered a mouse in which chromosome instability was selectively induced in T cells. A flanked by Lox mutation was introduced into the monopolar spindle 1 (Mps1) spindle-assembly checkpoint gene so that Cre-mediated recombination would create a truncated protein (Mps1(DK)) that retained the kinase domain but lacked the kinetochore-binding domain and thereby weakened the checkpoint. In a sensitized p53(+/-) background we observed that Mps1(DK/DK) mice suffered from rapid-onset acute lymphoblastic lymphoma. The tumors were highly aneuploid and exhibited a metabolic burden similar to that previously characterized in aneuploid yeast and cultured cells. The tumors nonetheless grew rapidly and were lethal within 3-4 mo after birth.


Assuntos
Aneuploidia , Instabilidade Cromossômica/genética , Mutação/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Proteínas Serina-Treonina Quinases/genética , Estresse Fisiológico/genética , Proteína Supressora de Tumor p53/genética , Animais , Aberrações Cromossômicas , Células Clonais , Dosagem de Genes , Regulação Leucêmica da Expressão Gênica , Heterozigoto , Humanos , Cariotipagem , Pontos de Checagem da Fase M do Ciclo Celular/genética , Camundongos , Proteínas Serina-Treonina Quinases/química , Estrutura Terciária de Proteína , Transcrição Gênica
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