RESUMO
Triple-negative breast cancer (TNBC) is an aggressive and highly metastatic type of tumor. TNBC is often enriched in tumor-infiltrating neutrophils (TINs), which support cancer growth in part by counteracting tumor-infiltrating lymphocytes (TILs). Prior studies identified the enhancer of zeste homolog 2 (EZH2) as a pro-tumor methyltransferase in primary and metastatic TNBCs. We hypothesized that EZH2 inhibition in TNBC cells per se would exert antitumor activity by altering the tumor immune microenvironment. To test this hypothesis, we used CRISPR to generate EZH2 gene knockout (KO) and overexpressing (OE) lines from parent (wild-type-WT) 4T1 cells, an established murine TNBC model, resulting in EZH2 protein KO and OE, respectively. In vitro, EZH2 KO and OE cells showed early, transient changes in replicative capacity and invasiveness, and marked changes in surface marker profile and cytokine/chemokine secretion compared to WT cells. In vivo, EZH2 KO cells showed significantly reduced primary tumor growth and a 10-fold decrease in lung metastasis compared to WT cells, while EZH2 OE cells were unchanged. Compared to WT tumors, TIN:TIL ratios were greatly reduced in EZH2 KO tumors but unchanged in EZH2 OE tumors. Thus, EZH2 is key to 4T1 aggressiveness as its tumor-intrinsic knockout alters their in vitro secretome and in vivo primary tumor growth, TIN/TIL poise, and metastasis.
Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste , Neoplasias Pulmonares , Linfócitos do Interstício Tumoral , Neoplasias de Mama Triplo Negativas , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Animais , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/imunologia , Camundongos , Feminino , Linhagem Celular Tumoral , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Microambiente Tumoral/imunologia , Proliferação de Células , Humanos , Camundongos Endogâmicos BALB C , Técnicas de Inativação de Genes , Modelos Animais de Doenças , Regulação Neoplásica da Expressão GênicaRESUMO
Few studies examine the relationship between sleep and executive function in diverse samples of young adults. Our research aims to fill this gap by analyzing how self-reported sleep quality is related to informant-rated executive function as a whole and its working memory component in a diverse sample of 29 healthy college students. Using the self-report measure, the Pittsburgh Sleep Quality Index (PSQI), we divided our sample into two groups based on cutoff criteria (score ≥5: poor sleep): good sleep quality (n = 11) and poor sleep quality (n = 18). Participants were on average 20.86 years old. Informants rated participants' executive functioning and working memory using the Frontal Systems Behavior Scale (FrSBe) and Behavior Rating Inventory of Executive Function (BRIEF). Individuals in the poor sleep quality group were reported as having significantly worse executive function and working memory scores. Young adult college students who report less than 7 hours of sleep per night have lower scores on informant measures of working memory and executive function. This study raises awareness about how self-reported sleep experiences are related to other's observation of cognitive abilities in everyday life in a diverse young adult sample.