A metabolic function of FGFR3-TACC3 gene fusions in cancer

Abstract

Chromosomal translocations that generate in-frame oncogenic gene fusions are powerful examples of success of targeted cancer therapies1–3. We discovered FGFR3-TACC3 (F3-T3) gene fusions in 3% of human glioblastoma4. Subsequent studies reported similar frequencies of F3-T3 in many other cancers, thus qualifying F3-T3 as one of the most recurrent fusions across all tumor types5,6. F3-T3 fusions are potent oncogenes that confer sensitivity to FGFR inhibitors but the downstream oncogenic signaling remains largely unknown2,4–6. Here, we report that tumors harboring F3-T3 cluster within transcriptional subgroups characterized by activation of mitochondrial functions. F3-T3 activates oxidative phosphorylation and mitochondrial biogenesis and induces sensitivity to inhibitors of oxidative metabolism. We show that phosphorylation of PIN4 is the signaling intermediate for the activation of mitochondrial metabolism. The F3-T3-PIN4 axis triggers peroxisome biogenesis and new protein synthesis. The anabolic response converges on PGC1α through intracellular ROS, enabling mitochondrial respiration and tumor growth. Our analyses uncover the oncogenic circuit engaged by F3-T3, expose reliance on mitochondrial respiration as unexpected therapeutic opportunity for F3-T3-positive tumors and provide a clue to the genetic alterations that initiate the chain of metabolic responses driving mitochondrial metabolism in cancer.

A MAP of tumor-host interactions in glioma at single cell resolution

“…The basic workflow of scTHI is presented in Figure 1. First, we perform a cell-specific identification using the gene set enrichment Mann-Whitney-Wilcoxon Gene Set Test (mww-GST) (Frattini et al, 2018) based on a collection of 295 gene immune and stromal signatures. We adopt mww-GST since it has been proven to perform better than other enrichment analysis in situations of weak and noisy signals, and therefore can be used in the single cell scenarios with the presence of low detection efficiency and drop-out phenomena.…”

“…To evaluate the enrichment of each immune cell type in glioma samples we used Normalized Enrichment Score (NES) of the Mann Whitney Wilcoxon Gene Set test (mww-GST) that we previously described in (Frattini et al, 2018). Briefly, NES is an estimate of the probability that the expression of a gene in the gene set is greater than the expression of a gene outside this set: where m is the number of genes in a gene set, n is the number of those outside the gene set, U = mn + m ( m + 1) − T , and T is the sum of the ranks of the genes in the gene set.…”

CRTC1-MAML2 Establishes a PGC1α-IGF1 Circuit that Confers Vulnerability to PPARγ Inhibition

“…PGC-1a has been shown to exert oncogenic (Frattini et al, 2018) or tumor suppressive (Torrano et al, 2016) activity depending on cell type and context-dependent metabolic cues (Mastropasqua et al, 2018;Sancho et al, 2015;Xing et al, 2017). Notably, the PGC-1a family of transcriptional coactivators is composed of an expanding list of transcript isoforms generated by multiple promoters and alternative pre-mRNA splicing, and these resulting protein variants are known to display unique functional properties (Martínez-Redondo et al, 2016;Martínez-Redondo et al, 2015).…”

Metabolic Mechanisms and a Rational Combinational Application of Carboxyamidotriazole in Fighting Pancreatic Cancer Progression after Chemotherapy

“…We hypothesize that if CAI is applied to the cancer cell types or subpopulations that are more dependent on mitochondrial respiration, or combined with other metabolism-disturbing drugs (Ben Sahra et al, 2010;Cheong et al, 2011;LeBleu et al, 2014;Caino et al, 2015;Ansó et al, 2017;Frattini et al, 2018), it may exert much higher anticancer efficacy. In several studies, pancreatic cancer stem cells (CSCs) have been considered to be highly dependent on OXPHOS (Viale et al, 2014;Sancho et al, 2015).…”