Resistance to Targeted Therapy and RASSF1A Loss in Melanoma: What Are We Missing?

Melanoma is one of the most aggressive forms of skin cancer and is therapeutically challenging, considering its high mutation rate. Following the development of therapies to target BRAF, the most frequently found mutation in melanoma, promising therapeutic responses were observed. While mono- and combination therapies to target the MAPK cascade did induce a therapeutic response in BRAF-mutated melanomas, the development of resistance to MAPK-targeted therapies remains a challenge for a high proportion of patients. Resistance mechanisms are varied and can be categorised as intrinsic, acquired, and adaptive. RASSF1A is a tumour suppressor that plays an integral role in the maintenance of cellular homeostasis as a central signalling hub. RASSF1A tumour suppressor activity is commonly lost in melanoma, mainly by aberrant promoter hypermethylation. RASSF1A loss could be associated with several mechanisms of resistance to MAPK inhibition considering that most of the signalling pathways that RASSF1A controls are found to be altered targeted therapy resistant melanomas. Herein, we discuss resistance mechanisms in detail and the potential role for RASSF1A reactivation to re-sensitise BRAF mutant melanomas to therapy.

Differential chromatin accessibility landscape of gain-of-function mutant p53 tumours

Mutations in TP53 not only affect its tumour suppressor activity but also exerts oncogenic gain-of-function activity. While the genome-wide mutant p53 binding sites have been identified in cancer cell lines, the chromatin accessibility landscape driven by mutant p53 in primary tumours is unknown. Here, we leveraged the chromatin accessibility data of primary tumours from TCGA to identify differentially accessible regions in mutant p53 tumours compared to wild p53 tumours, especially in breast and colon cancers. We found 1587 lost and 984 gained accessible regions in breast, and 1143 lost and 640 gained regions in colon. However, less than half of those regions in both cancer types contain sequence motifs for wild-type or mutant p53 binding. Whereas, the remaining showed enrichment for master transcriptional regulators, such as FOX-Family TFs and NF-kB in lost and SMAD and KLF TFs in gained regions of breast. In colon, ATF3 and FOS/JUN TFs were enriched in lost, and CDX family TFs and HNF4A in gained regions. By integrating the gene expression data, we identified known and novel target genes regulated by the mutant p53. Together, these results suggest the tissue- and tumour-type specific role of mutant p53 in regulating chromatin structure and gene expression.

β-Catenin tumour-suppressor activity depends on its ability to promote Pro-N-Cadherin maturation

SUMMARYNeural stem cells (NSCs) form a pseudostratified, single-cell layered epithelium with a marked apico-basal polarity. In these cells, β-Catenin associates with classic cadherins in order to form the apical adherens junctions (AJs). We previously reported that oncogenic forms of β-Catenin (sβ-Catenin) maintain neural precursors as progenitors, while also enhancing their polarization and adhesiveness, thereby limiting their malignant potential. Here we show that β-Catenin can bind to phosphorylated Pro-N-Cadherin, promoting the excision of the propeptide and its maturation into N-Cadherin in the trans-Golgi network (TGN). Moreover, β-Catenin-assisted maturation of Pro-N-Cadherin is required for the formation of the AJs and for them to recruit other apical complex (AC) components like aPKC, and accordingly, to establish apico-basal polarity. Notably, we show that NSCs expressing unprocessed Pro-N-Cadherin invade the ventricle and they breach the basement membrane to invade the surrounding mesenchyme. Hence, we propose that the tumour-suppressor activity of sβ-Catenin depends on it promoting Pro-N-Cadherin processing.

Cancer and metabolism

This chapter covers the relationship between cancer and metabolism. It discusses the role of angiogenesis and metabolic reprogramming in influencing tumour growth. The transcription factors that orchestrate the metabolic switch are discussed. The chapter presents an overview of the contribution of tumour suppressors to increased glycolysis. The metabolic changes that support uncontrolled proliferation such as lactate and pH levels, hypoxia, and reactive oxygen species are discussed. The chapter also covers the contribution of metabolic genes with oncogenic or tumour suppressor activity to metabolic transformation, the upregulation of lipid biosynthesis in cancer, and glycogen synthesis in cancer. The chapter concludes with a description of the potential strategies for targeting metabolic transformation.

Cancer and metabolism

This chapter covers the relationship between cancer and metabolism. It discusses the role of angiogenesis and metabolic reprogramming in influencing tumour growth. The transcription factors that orchestrate the metabolic switch are discussed. The chapter presents an overview of the contribution of tumour suppressors to increased glycolysis. The metabolic changes that support uncontrolled proliferation such as lactate and pH levels, hypoxia, and reactive oxygen species are discussed. The chapter also covers the contribution of metabolic genes with oncogenic or tumour suppressor activity to metabolic transformation, the upregulation of lipid biosynthesis in cancer, and glycogen synthesis in cancer. The chapter concludes with a description of the potential strategies for targeting metabolic transformation.

Tribbles breaking bad: TRIB2 suppresses FOXO and acts as an oncogenic protein in melanoma

TRIB2 (tribbles homolog 2) encodes one of three members of the tribbles family in mammals. These members share a Trb (tribbles) domain, which is homologous to protein serine-threonine kinases, but lack the active site lysine. The tribbles proteins interact and modulate the activity of signal transduction pathways in a number of physiological and pathological processes. TRIB2 has been identified as an oncogene that inactivates the transcription factor CCAAT/enhancer-binding protein α (C/EBPα) and causes acute myelogenous leukaemia (AML). Recent research provided compelling evidence that TRIB2 can also act as oncogenic driver in solid tumours, such as lung and liver cancer. In particular, our recent work demonstrated that TRIB2 is dramatically overexpressed in malignant melanomas compared with normal skin and promotes the malignant phenotype of melanoma cells via the down-regulation of FOXO (forkhead box protein O) tumour suppressor activity in vitro and in vivo. TRIB2 was found to be expressed in normal skin, but its expression consistently increased in benign nevi, melanoma and was highest in samples from patients with malignant melanoma. The observation that TRIB2 strongly correlates with the progression of melanocyte-derived malignancies suggests TRIB2 as a meaningful biomarker to both diagnose and stage melanoma. In addition, interfering with TRIB2 activity might be a therapeutic strategy for the treatment of several different tumour types.