RESUMO
The last few years have seen an increasing number of discoveries which collectively demonstrate that histone and DNA modifying enzyme modulate different stages of metastasis. Moreover, epigenomic alterations can now be measured at multiple scales of analysis and are detectable in human tumors or liquid biopsies. Malignant cell clones with a proclivity for relapse in certain organs may arise in the primary tumor as a consequence of epigenomic alterations which cause a loss in lineage integrity. These alterations may occur due to genetic aberrations acquired during tumor progression or concomitant to therapeutic response. Moreover, evolution of the stroma can also alter the epigenome of cancer cells. In this review, we highlight current knowledge with a particular emphasis on leveraging chromatin and DNA modifying mechanisms as biomarkers of disseminated disease and as therapeutic targets to treat metastatic cancers.
Assuntos
Epigenômica , Neoplasias , Humanos , Histonas/genética , Histonas/metabolismo , Neoplasias/genética , Neoplasias/terapia , Metilação de DNA , DNA , Epigênese GenéticaRESUMO
The brain is a major sanctuary site for metastatic cancer cells that evade systemic therapies. Through pre-clinical pharmacological, biological, and molecular studies, we characterize the functional link between drug resistance and central nervous system (CNS) relapse in Epidermal Growth Factor Receptor- (EGFR-) mutant non-small cell lung cancer, which can progress in the brain when treated with the CNS-penetrant EGFR inhibitor osimertinib. Despite widespread osimertinib distribution in vivo, the brain microvascular tumor microenvironment (TME) is associated with the persistence of malignant cell sub-populations, which are poised to proliferate in the brain as osimertinib-resistant lesions over time. Cellular and molecular features of this poised state are regulated through a Ras homolog family member A (RhoA) and Serum Responsive Factor (SRF) gene expression program. RhoA potentiates the outgrowth of disseminated tumor cells on osimertinib treatment, preferentially in response to extracellular laminin and in the brain. Thus, we identify pre-existing and adaptive features of metastatic and drug-resistant cancer cells, which are enhanced by RhoA/SRF signaling and the brain TME during the evolution of osimertinib-resistant disease.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteína rhoA de Ligação ao GTP/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Receptores ErbB/genética , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Encéfalo/patologia , Mutação , Resistencia a Medicamentos Antineoplásicos/genética , Microambiente TumoralRESUMO
At the restriction point (R), mammalian cells irreversibly commit to divide. R has been viewed as a point in G1 that is passed when growth factor signaling initiates a positive feedback loop of Cdk activity. However, recent studies have cast doubt on this model by claiming R occurs prior to positive feedback activation in G1 or even before completion of the previous cell cycle. Here we reconcile these results and show that whereas many commonly used cell lines do not exhibit a G1 R, primary fibroblasts have a G1 R that is defined by a precise Cdk activity threshold and the activation of cell-cycle-dependent transcription. A simple threshold model, based solely on Cdk activity, predicted with more than 95% accuracy whether individual cells had passed R. That a single measurement accurately predicted cell fate shows that the state of complex regulatory networks can be assessed using a few critical protein activities.
