26 research outputs found
The Transcription Factor E4F1 Coordinates CHK1-Dependent Checkpoint and Mitochondrial Functions
Recent data support the notion that a group of key transcriptional regulators
involved in tumorigenesis, including MYC, p53, E2F1, and BMI1, share an
intriguing capacity to simultaneously regulate metabolism and cell cycle. Here,
we show that another factor, the multifunctional protein E4F1, directly
controls genes involved in mitochondria functions and cell-cycle checkpoints,
including Chek1, a major component of the DNA damage response. Coordination of
these cellular functions by E4F1 appears essential for the survival of
p53-deficient transformed cells. Acute inactivation of E4F1 in these cells
results in CHK1-dependent checkpoint deficiency and multiple mitochondrial
dysfunctions that lead to increased ROS production, energy stress, and
inhibition of de novo pyrimidine synthesis. This deadly cocktail leads to the
accumulation of uncompensated oxidative damage to proteins and extensive DNA
damage, ending in cell death. This supports the rationale of therapeutic
strategies simultaneously targeting mitochondria and CHK1 for selective killing
of p53-deficient cancer cells
E4F1 deficiency results in oxidative stress–mediated cell death of leukemic cells
Deletion of E4F1 inflicts mitochondrial damage and oxidative stress on murine and human myeloid leukemia cells but not healthy macrophages
Etude des mécanismes d'action du suppresseur de tumeur hSNF5/INI1 (rôle dans la différenciation et la migration cellulaires)
PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF
Cancer Cell Phenotype Plasticity as a Driver of Immune Escape in Melanoma
International audienceImmunotherapies blocking negative immune checkpoints are now approved for the treatment of a growing number of cancers. However, even in metastatic melanoma, where sustained responses are observed, a significant number of patients still do not respond or display resistance. Increasing evidence indicates that non-genetic cancer cell-intrinsic alterations play a key role in resistance to therapies and immune evasion. Cancer cell plasticity, mainly associated with the epithelial-to-mesenchymal transition in carcinoma, relies on transcriptional, epigenetic or translational reprogramming. In melanoma, an EMT-like dedifferentiation process is characterized by the acquisition of invasive or neural crest stem cell-like features. Herein, we discuss recent findings on the specific roles of phenotypic reprogramming of melanoma cells in driving immune evasion and resistance to immunotherapies. The mechanisms by which dedifferentiated melanoma cells escape T cell lysis, mediate T cell exclusion or remodel the immune microenvironment will be detailed. The expanded knowledge on tumor cell plasticity in melanoma should contribute to the development of novel therapeutic combination strategies to further improve outcomes in this deadly metastatic cancer
Treatment of -mutated advanced or metastatic melanoma: rationale, current trials and evidence to date
The disease course of BRAF (v-raf murine sarcoma viral oncogene homolog B1)-mutant melanoma has been drastically improved by the arrival of targeted therapies. NRAS (neuroblastoma RAS viral oncogene homolog)-mutated melanoma represents 15–25% of all metastatic melanoma patients. It currently does not have an approved targeted therapy. Metastatic patients receive immune-based therapies as first-line treatments, then cytotoxic chemotherapy like carboplatin/paclitaxel (C/P), dacarbazine (DTIC) or temozolomide (TMZ) as a second-line treatment. We will review current preclinical and clinical developments in NRAS -mutated melanoma, and analyze ongoing clinical trials that are evaluating the benefit of different targeted and immune-based therapies, either tested as single agents or in combination, in NRAS -mutant melanoma
EMT-Inducing Transcription Factors, Drivers of Melanoma Phenotype Switching, and Resistance to Treatment
Transcription factors, extensively described for their role in epithelial–mesenchymal transition (EMT-TFs) in epithelial cells, also display essential functions in the melanocyte lineage. Recent evidence has shown specific expression patterns and functions of these EMT-TFs in neural crest-derived melanoma compared to carcinoma. Herein, we present an update of the specific roles of EMT-TFs in melanocyte differentiation and melanoma progression. As major regulators of phenotype switching between differentiated/proliferative and neural crest stem cell-like/invasive states, these factors appear as major drivers of intra-tumor heterogeneity and resistance to treatment in melanoma, which opens new avenues in terms of therapeutic targeting
E4F1 connects the Bmi1-ARF-p53 pathway to epidermal stem cell-dependent skin homeostasis.
International audiencepas de résum
Plasticity of melanoma and EMT-TF reprogramming.
Plasticity of melanoma and EMT-TF reprogramming
RASGRF2 gene fusions identified in a variety of melanocytic lesions with distinct morphological features
International audienc