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This study explores the role of NTRK gene fusions in pediatric-type-high-grade gliomas, particularly how these fusions drive tumor formation and influence treatment responses. The researched used genetically engineered mouse models to investigate NTRK fusion-driven gliomas and found that all tested NTRK fusions were oncogenic in-vivo. The study also revealed that the type of NTRK fusion, its partner genes, and the presence of additional tumor suppressor losses impacted tumor behavior and aggressiveness. While treatment with TRK kinase inhibitors significantly extended survival, tumors eventually recurred due to resistance mutations. The research highlights the role of ERK activation in promoting resistance and suggests that combining TRK inhibitors with MEK inhibition may improve treatment outcomes.
In this paper, NTRK gene fusions (Neurotrophic Tyrosine Kinase Receptors) are being studied in relation to oncogenes and tumor initiating-events in the Kinase signaling pathway. NTRK fusions occur in up to 1% of all solid tumor types and are particularly significant in pediatric brain cancers, where NTRK fusions occur in tumors between 0.4%-40% depending on the exact type. In adults, NTRK fusions are less common and are not typically seen as the primary cause behind brain cancer development in later stages of life.
The second paragraph addresses the hypotheses and experimental questions asked such as are these gene fusions enough to cause tumors in animal models? Do different NTRK fusions have varying levels of oncogenic potential? And do the responses to tyrosine kinase inhibitors in lab cultures reflect what happens in living organisms? It also considers how developmental age may influence these outcomes. The main method of experimentation involves the use of genetically engineered mouse models (aka; "GEMMs") of human cancers in order to test preclinical drug efficacy and to study the molecular makeup of these tumors.
In paragraph three, eight different NTRK fusion-driven gliomas are identified in the GEMMs as tumor inducers. However, there were variations in their oncogenic potential, such as loss of tumor suppressor Cdkn2a, which greatly enhanced tumor formation/cell division. Later results using TKI's indicated increased survival rates for the mice, but tumors eventully recurred due to the presence of treatment resistant cells from spontaneous mutations. Essentially, the authors discovered that TKI's could extend survival of cancer afflicted mice, but did not completely eliminate the tumors.
Links related to the paper:
Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors
NTRK fusion-positive cancers and TRK inhibitor therapy - NTRK gene fusions involving either NTRK1, NTRK2 or NTRK3 (encoding the neurotrophin receptors TRKA, TRKB and TRKC, respectively) are oncogenic drivers of various adult and paediatric tumour types. The
Leveraging the replication-competent avian-like sarcoma virus/tumor virus receptor-A system for modeling human gliomas Gliomas are the most common primary intrinsic brain tumors occurring in adults. Of all malignant gliomas, glioblastoma (GBM) is considered the deadliest tumor type due to diffuse brain invasion.
Genetic driver mutations reveal distinct immune landscapes. - Glioblastoma is the most aggressive primary brain tumor. In addition to being genetically heterogeneous, GBMs are also immunologically heterogeneous, and there mutations unexplored
This article explores the role of the TRIM63 protein in the development of breast cancer, by activating the Wnt/β-catenin signaling pathway. Along with TRIM63, several other TRIM proteins have been identified as inducers to different cancers, by regulating various cell-signaling pathways. The TRIM63 gene itself (also known as MuRF1), has been noted in previous studies, to be a key factor in the emergence of muscle tissue diseases, when it is unregulated. Despite this research, there is no evidence to support that TRIM63 has a specific role in tumorigenesis.
This study is significant, because it aims to understand how expression levels of the TRIM63 protein may be related to the development of breast cancer, in response to disruptions to the Wnt/β-catenin signaling pathway, which is fairly unknown. The study found that the TRIM63 gene activated the Wnt/β-catenin signaling pathway, leading to cell proliferation and migration. In previous research, the researchers found that when TRIM63 activates the Wnt/β-catenin signaling pathway, active GSKSβ is upregulated (and phosphorylated), which subsequently causes expression levels of β-catenin to be inhibited. More specifically, β-catenin cannot be degraded as it normally should be.
By examining different breast cancer cell types (MCF-7 and MDA-MB-231), the researchers found that the protein expression levels of TRIM63 are critical during the development of breast cancer. Overexpression of TRIM63 in MCF-7 cells led to increased β-catenin levels, and caused MCF-7 cells to continue to proliferate. In MDA-MB-231 cells, 'knockdown' or stopping/reducing TRIM63 expression levels, inhibited proliferation.
Overall, the study shows that the presence of TRIM63 in breast cancer tissues activates the Wnt/β-catenin signaling pathway, by upregulating the expression of β-catenin and c-myc. The researchers used further studies as supporting evidence, to show that when TRIM63 is overexpressed, GSKβ phosphorylation and increased β-catenin levels are promoted.
Links related to the paper:
Wnt/β-catenin Signaling in Development and Disease
TRIM Family Proteins: Roles in Autophagy, Immunity, and Carcinogenesis
Emerging roles of tripartite motif family proteins (TRIMs) in breast cancer
MURF1/TRIM63, Master Regulator of Muscle Mass - goes into further detail about TRIM63 role in atrophy of of skeletal muscle mass and myocardium
The roles and targeting options of TRIM family proteins in tumor