[Show abstract][Hide abstract] ABSTRACT: Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer. Here we show that targeted therapy with BRAF, ALK or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed human and mouse melanoma and human lung adenocarcinoma cells. This therapy-induced secretome stimulates the outgrowth, dissemination and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression. The tumour-promoting secretome of melanoma cells treated with the kinase inhibitor vemurafenib is driven by downregulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of several signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and the PI(3)K/AKT/mTOR intracellular signalling pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant human melanoma, suggesting this combination therapy as a strategy against tumour relapse. Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy.
[Show abstract][Hide abstract] ABSTRACT: eLife digest
Tumors form when mistakes in the genes of a single cell allow it to multiply uncontrollably. Sometimes further mutations in genes allow the cancerous cells to escape from the tumor, enter the bloodstream and start a second cancer elsewhere in the body. However, many of the genetic changes behind this process, which is called metastasis, are poorly understood—especially those changes in genes that occur rarely, but can still help the cancer to spread.
Vanharanta, Marney et al. have looked at data on which genes are switched ‘on’ or ‘off’ in metastatic breast cancer cells. A gene called RBM47 was often switched off in these cells, and patients with a low level of RBM47 tended to have a poor clinical outcome.
To test the function of the gene, Vanharanta, Marney et al. switched on RBM47 in cancer cells that had spread from the breast to either the lungs or the brain, and then injected these cells into mice. Few of these cells were able to invade lung and brain tissues in the mice. However, switching off the RBM47 gene in breast cancer cells had the opposite effect; these cells invaded the lungs of mice more efficiently.
RBM47 encodes a protein that sticks to molecules of messenger RNA: molecules that transport the instructions encoded in DNA to the machinery that builds proteins. Vanharanta, Marney et al. found that the wild-type RBM47 protein increased the levels of 102 different messenger RNA molecules, but decreased the levels of another 92. Further experiments showed that RBM47 also slows the rate at which messenger RNA molecules are broken down inside cells: this results in the accumulation of proteins that slow down the growth of tumors. Without RBM47, tumor growth is unleashed. Further work is needed to test if increasing RBM47 activity could be used as a new treatment for some types of cancer.
[Show abstract][Hide abstract] ABSTRACT: How organ-specific metastatic traits arise in primary tumors remains unknown. Here, we show a role of the breast tumor stroma in selecting cancer cells that are primed for metastasis in bone. Cancer-associated fibroblasts (CAFs) in triple-negative (TN) breast tumors skew heterogeneous cancer cell populations toward a predominance of clones that thrive on the CAF-derived factors CXCL12 and IGF1. Limiting concentrations of these factors select for cancer cells with high Src activity, a known clinical predictor of bone relapse and an enhancer of PI3K-Akt pathway activation by CXCL12 and IGF1. Carcinoma clones selected in this manner are primed for metastasis in the CXCL12-rich microenvironment of the bone marrow. The evidence suggests that stromal signals resembling those of a distant organ select for cancer cells that are primed for metastasis in that organ, thus illuminating the evolution of metastatic traits in a primary tumor and its distant metastases.
[Show abstract][Hide abstract] ABSTRACT: Aberrant Wnt signaling can drive cancer development. In many cancer types, the genetic basis of Wnt pathway activation remains incompletely understood. Here, we report recurrent somatic mutations of the Drosophila melanogaster tumor suppressor-related gene FAT1 in glioblastoma (20.5%), colorectal cancer (7.7%), and head and neck cancer (6.7%). FAT1 encodes a cadherin-like protein, which we found is able to potently suppress cancer cell growth in vitro and in vivo by binding β-catenin and antagonizing its nuclear localization. Inactivation of FAT1 via mutation therefore promotes Wnt signaling and tumorigenesis and affects patient survival. Taken together, these data strongly point to FAT1 as a tumor suppressor gene driving loss of chromosome 4q35, a prevalent region of deletion in cancer. Loss of FAT1 function is a frequent event during oncogenesis. These findings address two outstanding issues in cancer biology: the basis of Wnt activation in non-colorectal tumors and the identity of a 4q35 tumor suppressor.