6 research outputs found
Recommended from our members
Genomic control of metastasis
Abstract: Metastasis remains the leading cause of cancer-associated mortality, and a detailed understanding of the metastatic process could suggest new therapeutic avenues. However, how metastatic phenotypes arise at the genomic level has remained a major open question in cancer biology. Comparative genetic studies of primary and metastatic cancers have revealed a complex picture of metastatic evolution with diverse temporal patterns and trajectories to dissemination. Whole-genome amplification is associated with metastatic cancer clones, but no metastasis-exclusive driver mutations have emerged. Instead, genetically activated oncogenic pathways that drive tumour initiation and early progression acquire metastatic traits by co-opting physiological programmes from stem cell, developmental and regenerative pathways. The functional consequences of oncogenic driver mutations therefore change via epigenetic mechanisms to promote metastasis. Increasing evidence is starting to uncover the molecular mechanisms that determine how specific oncogenic drivers interact with various physiological programmes, and what triggers their activation in support of metastasis. Detailed insight into the mechanisms that control metastasis is likely to reveal novel opportunities for intervention at different stages of metastatic progression
The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer
Large-scale human genetic data(1-3) have shown that cancer mutations display strong tissue-selectivity, but how this selectivity arises remains unclear. Here, using experimental models, functional genomics and analyses of patient samples, we demonstrate that the lineage transcription factor paired box 8 (PAX8) is required for oncogenic signalling by two common genetic alterations that cause clear cell renal cell carcinoma (ccRCC) in humans: the germline variant rs7948643 at 11q13.3 and somatic inactivation of the von Hippel-Lindau tumour suppressor (VHL)(4-6). VHL loss, which is observed in about 90% of ccRCCs, can lead to hypoxia-inducible factor 2 alpha (HIF2A) stabilization(6,7). We show that HIF2A is preferentially recruited to PAX8-bound transcriptional enhancers, including a pro-tumorigenic cyclin D1 (CCND1) enhancer that is controlled by PAX8 and HIF2A. The ccRCC-protective allele Cat rs7948643 inhibits PAX8 binding at this enhancer and downstream activation of CCND1 expression. Co-option of a PAX8-dependent physiological programme that supports the proliferation of normal renal epithelial cells is also required for MYC expression from the ccRCC metastasis-associated amplicons at 8q21.3-q24.3 (ref. (8)). These results demonstrate that transcriptional lineage factors are essential for oncogenic signalling and that they mediate tissue-specific cancer risk associated with somatic and inherited genetic variants.Peer reviewe
Recommended from our members
SMARCB1 Maintains Lineage Fidelity in Clear Cell Renal Cell Carcinoma
Lineage-specific transcription factors have emerged as a promising class of essential genes in cancer.
The best examples of leveraging this phenomenon in the clinic is targeting the androgen receptor and
the oestrogen receptor in prostate and breast cancer respectively. Despite the success of these
therapies, the mechanisms that maintain lineage fidelity in advanced cancer clones, and whether
lineage factor pathways could be exploited in other cancer types remain poorly understood. Using clear
cell renal cell carcinoma (ccRCC) as a model, I characterise mechanisms that underlie lineage factor
dependence in cancer. Using CRISPR/Cas9 loss-of-function screening coupled with in vitro and in vivo
validation I show that the loss of SMARCB1, a member of the SWI/SNF chromatin remodelling complex,
confers an advantage to ccRCC cells upon inhibition of the essential renal lineage factor PAX8. SMARCB1
knockout (KO) leads to large-scale loss of a kidney-specific enhancer program, conversion to a cellular
state resembling that of rhabdoid tumours, and the re-activation of proliferative pathways. Using a
second CRISPR/Cas9 screen, I show that these proliferative pathways are underpinned by the
acquisition of new transcriptional dependencies. These dependencies represent rare essential genes
across different lineage-specific and oncogenic pathways, a principle validated in a large-scale
CRISPR/Cas9 screening data set comprising hundreds of cancer cell lines. In summary, dependence on
tissue-specific lineage factors in cancer can be modulated via epigenetic remodelling
The SWI/SNF complex member SMARCB1 supports lineage fidelity in kidney cancer
Lineage switching can induce therapy resistance in cancer. Yet, how lineage fidelity is maintained and how it can be lost remain poorly understood. Here, we have used CRISPR-Cas9-based genetic screening to demonstrate that loss of SMARCB1, a member of the SWI/SNF chromatin remodeling complex, can confer an advantage to clear cell renal cell carcinoma (ccRCC) cells upon inhibition of the renal lineage factor PAX8. Lineage factor inhibition-resistant ccRCC cells formed tumors with morphological features, but not molecular markers, of neuroendocrine differentiation. SMARCB1 inactivation led to large-scale loss of kidney-specific epigenetic programs and restoration of proliferative capacity through the adoption of new dependencies on factors that represent rare essential genes across different cancers. We further developed an analytical approach to systematically characterize lineage fidelity using large-scale CRISPR-Cas9 data. An understanding of the rules that govern lineage switching could aid the development of more durable lineage factor-targeted and other cancer therapies.Peer reviewe
Recommended from our members
The SWI/SNF complex member SMARCB1 supports lineage fidelity in kidney cancer.
Lineage switching can induce therapy resistance in cancer. Yet, how lineage fidelity is maintained and how it can be lost remain poorly understood. Here, we have used CRISPR-Cas9-based genetic screening to demonstrate that loss of SMARCB1, a member of the SWI/SNF chromatin remodeling complex, can confer an advantage to clear cell renal cell carcinoma (ccRCC) cells upon inhibition of the renal lineage factor PAX8. Lineage factor inhibition-resistant ccRCC cells formed tumors with morphological features, but not molecular markers, of neuroendocrine differentiation. SMARCB1 inactivation led to large-scale loss of kidney-specific epigenetic programs and restoration of proliferative capacity through the adoption of new dependencies on factors that represent rare essential genes across different cancers. We further developed an analytical approach to systematically characterize lineage fidelity using large-scale CRISPR-Cas9 data. An understanding of the rules that govern lineage switching could aid the development of more durable lineage factor-targeted and other cancer therapies