Molecular and Cellular Oncology最新文献

Glioblastoma (GBM) is one of the deadliest and aggressive forms of brain cancer. Environmental and intrinsic factors such as Western Diet and advanced age can function as powerful accelerants to the progression of GBM. Recently, we discovered that pre-clinical GBM models subject to an obesogenic and age-accelerating high fat diet (HFD) presented with hyperaggressive GBM phenotypes, including treatment-refractory cancer stem cell (CSC) enrichment. Mechanistically, HFD suppressed production of the gasotransmitter hydrogen sulfide (H₂S) and its downstream sulfhydration signaling in the brain. Likewise, we observed dramatic loss of sulfhydration in brains of GBM patients. Importantly, we showed the tumor suppressive effects of H₂S against GBM in cell culture and in vivo. Here, we discuss these recent findings and provide insight into how they can be leveraged to improve treatment modalities, prognosis, and quality of life for GBM patients.

AKT is the central phosphoinositide 3-kinase (PI3K) signaling effector, however, PIK3CA (p110α subunit of PI3Kα)-mutant estrogen receptor-positive (ER⁺) breast cancers exhibit minimal AKT activation and the downstream signaling is poorly characterized. We discovered that a subset of PIK3CA-mutant ER⁺ breast cancers exhibit increased inositol polyphosphate 4-phosphatase type II (INPP4B) expression, which promotes late endosome formation and glycogen synthase kinase 3 beta (GSK3β) trafficking, leading to enhanced Wingless-related integration site (WNT)/catenin beta 1 (β-catenin) activation.

Melanoma cells exploit mitophagy and hypoxia signaling to promote their growth. In a recent study, we found that loss of B-cell lymphoma 2 (BCL-2)/adenovirus E1B 19kDa protein-interacting protein 3 (BNIP3) curbed Hypoxia Inducible Factor 1 alpha (HIF-1α) levels and melanoma growth in vivo. Insufficient levels of BNIP3 boost iron-driven prolyl hydroxylase 2 (Phd2)-mediated degradation of HIF-1α by exacerbating nuclear receptor activator 4 (Ncoa4)-mediated ferritinophagy. Thus, BNIP3 promotes melanoma growth by controlling iron metabolism.

Through genetically engineered mouse models of melanoma, we identified Autophagy/beclin 1 regulator 1 (Ambra1) as novel tumor-suppressor in melanoma. In these settings, loss of Ambra1 associated with the hyperactivation of focal adhesion kinase 1 (Fak1) signaling, the inhibition of which resulted in reduced tumor growth and invasiveness. We therefore propose FAK1 inhibition for current melanoma therapy in AMBRA1-low tumors.

Abbreviations: AKT, serine/threonine kinase 1; AMBRA1, autophagy/beclin 1 regulator 1; BRAF, v-raf murine sarcoma viral oncogene homolog; BRAFi, BRAF inhibitor; CCLE, Cancer Cell Line Encyclopedia;g ESTDAB, European Searchable Tumor Line Database; FAK1, focal adhesion kinase 1; FAKi, FAK1 inhibitor; LMC, Leeds Melanoma Cohort; MEK, MAPK/ERK kinase; PP2A, protein phosphatase 2A; PTEN, phosphatase and tensin homolog; TCGA-SKCM, The Cancer Genome Atlas - Skin Cutaneous Melanoma; YAP, yes-associated protein 1.

TRK-fused gene (TFG) is a protein implicated in multiple neurodegenerative diseases and oncogenesis. We have recently shown that, under starvation conditions, TFG contributes to spatial control of autophagy by facilitating Unc-51 like autophagy activating kinase 1 (ULK1)-microtubule-associated protein 1 light chain 3 gamma (MAP1LC3C) interaction to modulate omegasome and autophagosome formation. Defective TFG-mediated autophagy could thus be postulated as a possible contributor to ontogenesis or progression of TFG-related diseases.

Our recent study revealed that non-neuroendocrine small cell lung cancer (SCLC) is sensitive to the induction of ferroptosis due to upregulation of ether lipid synthesis. While neuroendocrine SCLC is ferroptosis resistant, it acquires addiction to the thioredoxin pathway. Combined redox pathway targeting therefore achieves efficient anti-tumor activity in heterogenous SCLC.

The tumor microenvironment is a complex ecosystem of malignant and nonmalignant cells and extracellular proteins that work together to enhance tumor progression. We identified a mechanism in which adjacent nonmalignant epithelium enhances invasion of squamous cell carcinoma, thereby expanding the tumor microenvironment to include cancer-associated keratinocytes.

End resection excises several thousand bases from the 5'-ended strand during DNA double-strand break repair, creating 3'-end single-stranded DNA overhangs. This overhang requires strict protection from DNA2 or other nucleases digestion. A recent finding showed that the 3'-end overhangs are protected by the transient formation of RNA-DNA hybrids, and RNA polymerase III is an essential factor for homologous recombination.

Acute myeloid leukemia (AML) is heterogeneous with one common subtype recognized by the presence of recurrent mutation of nucleophosmin-1 (NPM1). Emerging evidence indicates that within NPM1 mutated AML there is variation in outcome which challenges how best to characterize and treat the individual patient. Our recent findings show that there are two distinct (primitive and committed) subtypes within NPM1 mutated AML patients. These subtypes exhibit specific molecular characteristics, disease differentiation states, patient survival, and differential drug responses.