Synthetic Essentiality in Prostate Cancer
Through screening for mutually exclusive deletion patterns in the prostate cancer genome, Zhao and colleagues uncovered the chromatin helicase DNA-binding factor CHD1 as a putative synthetic-essential gene in PTEN-deficient cancers. That is, while CHD1 deletions occurred in some cancers, CHD1 was always retained in cancers deleted for PTEN. Consistent with a role as a putative synthetic-essential gene in PTEN-deficient cancers, CHD1 loss led to pronounced inhibition of both cell growth and tumorigenic potential. Mechanistically, PTEN loss stabilized CHD1, which in turn activated transcription of a protumorigenic TNF-NF-κB gene program. This study identifies a novel PTEN-CHD1 pathway in prostate cancer, provides an example of synthetic essentiality identifying an essential downstream effector in PTEN-deficient cells and presents a framework to discover targetable vulnerabilities in cancers harboring specific tumor-suppressor deficiencies.
Back to OTX2 in Group 3 Medulloblastoma
Boulay and colleagues performed chromatin immunoprecipitation sequencing on histone marks across primary poor prognosis Group 3 medulloblastomas. Active promoters occupied by H3K27ac and not H3K27me3 converged on OTX2 targets. Although OTX2 also occupied many inactive enhancers, active enhancers were enriched for concurrent NEUROD1 occupancy. Knockdown by shRNA and CRISPR/Cas9 decreased OTX2 levels and strongly reduced H3K27ac occupancy. Strikingly, overexpression of OTX2 in human mesenchymal stem cells (which do not express OTX2) revealed de novo activation in 66% of enhancers. Loci with significant changes in chromatin and gene expression revealed WEE1 and NEK2 to be promising targets, and MYC-amplified Group3 lines were sensitive to a NEK2 kinase inhibitor. This study reveals the power of analyzing the functional genome, including revisiting old targets and devising novel therapies.
KRAS Allelic Imbalance Modulates MEK Dependence
Using retroviral insertional mutagenesis in KRASG12D knockin mice, Burgess and colleagues characterized distinct acute myeloid leukemia clones for sensitivity to the MEK inhibitor, PD901. One outlier clone exhibited initial sensitivity to PD901, but eventually became refractory. The PD901-sensitive and -resistant subclones originated from the same parental retroviral insertion clone, resulting in duplication of KRASG12D. One KRASG12D-duplicated subclone subsequently lost KRASWT and comprised most of the tumor. Upon PD901 treatment, the subclone that also expressed KRASWT dominated growth. Restoration of KRASWT into the PD901-sensitive subclone similarly suppressed its growth. Analogous results were observed using human colorectal cancer but not non-small cell lung cancer or pancreatic cells. Intriguingly, over half of advanced RAS mutant human cancers exhibited allelic imbalance at the KRAS locus. Thus, KRAS is frequently mutated multiple times during progression, modifications that dictate the sensitivity of acute myeloid leukemia and colorectal cancer cells to MEK inhibitors.
Relevance of circCCDC66 in Colorectal Cancer
To understand how circular RNA (circRNA), a class of noncoding RNA, affect colorectal cancer, Hsiao and colleagues investigated a novel circRNA, circCCDC66, in this disease. Analyzing RNA-seq data from matched normal and tumor colon tissue samples for differentially expressed circRNAs, they observed that expression of circCCDC66 was elevated in polyps and colon cancer, and was associated with poor outcome. Using in vitro gain- and loss-of-function approaches, the authors showed that circCCDC66 regulated cell proliferation, migration, invasion, and anchorage-independent growth. They also provided insights into the mechanism of action of circCCDC66 and identified a subset of oncogenes regulated by circCCDC66. Using in vivo models, the authors demonstrated that knockdown of circCCDC66 inhibited tumor growth and invasion. In these contexts, the authors have identified a novel oncogenic function of circCCDC66 in colorectal cancer progression and metastasis.
YAP Recruits Macrophages to Drive Liver Cancers
Not all immune cells have tumor suppressor actions. Guo and colleagues activated the YAP pathway in hepatocytes in vivo using hydrodynamic tail vein injection. Incipient liver cancers secreted CCL2 to recruit tumor-associated macrophages (TAM) that were critical for evading immune surveillance and establishing macroscopic liver cancers. Furthermore, using traditional transgenic mice in combination with the hydrodynamic tail vein injection, they showed that secreted factors such as CCL2 may have additional roles in promoting liver cancer cell proliferation and evading senescence that were independent of recruitment of TAMs. Oncogenes such as AKT/EGFR, but not KRAS, could induce YAP activation that lead to the recruitment of TAMs. These non-cell autonomous functions of YAP in TAM recruitment for liver tumorigenesis suggest targeting YAP or TAMs as a new approach for prevention of liver cancer and potentially other cancers.
The Force behind CAF-Driven Metastasis
Labernadie and colleagues describe how cancer-associated fibroblasts (CAF) effectively pull cancer cells out to generate invasive strands traversing the tumor stroma. During cancer invasion, CAFs and carcinoma cells formed strong cell-cell adhesions between mesenchymal N-cadherin and epithelial E-cadherin receptors. These heterophilic adhesions were mechanically active. CAFs polarizing away from the carcinomas exerted force on the junction, triggering β-catenin recruitment and vinculin/α-catenin-dependent adhesion reinforcement. Impairing the E-cadherin/N-cadherin interaction abrogated cancer cell invasion. Importantly, CAF-mediated forces contributing to collective migration and invasion were applicable to squamous cell carcinoma and lung adenocarcinoma. Furthermore, E-cadherin/N-cadherin heterophilic adhesions were detected in patient samples. Thus, these virtually unexplored atypical cell-cell junctions play an unexpected role, enabling cancer cell adhesion, migration, and invasion, suggesting therapeutic targeting of this interaction as a strategy to block metastasis.
Labernadie A, Kato T, Bruqués A, Serra-Picamal X, Derzsi S, Arwert E, et al. A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion. Nat Cell Biol 2017;19:224–37.
Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.