Highlights from Recent Cancer Literature Free

Ceccarelli and colleagues examined gene expression, DNA copy number, DNA methylation, exome sequencing, and protein expression in 590 grade IV, 241 grade III, and 216 grade II diffuse gliomas in The Cancer Genome Atlas. Two flavors of glioma-CpG island methylator phenotype (G-CIMP) IDH1 mutant, 1p/19q-intact gliomas, differed in degree of hypermethylation. Strikingly, the G-CIMP-low tumors had the worst overall survival, whereas survival was similar between G-CIMP-high and 1p/19q-codeleted tumors. Furthermore, some primary lower grade gloma-recurrent GBM cases demonstrated partial demethylation at recurrence, suggesting G-CIMP-low might progress from G-CIMP-high. They also identified a small IDH1 wild-type cohort within grade II and III gliomas, with methylation profiles similar to pilocytic astrocytoma (PA, grade I). This group had alterations in traditional PA genes, rare typical GBM alterations including TERT promoter mutations, and prolonged survival, yet the histologic features were that of diffuse glioma.

Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, Morozova O, Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 2016;164:550–63.

Zhao and colleagues visualized the epithelial-to-mesenchymal transition (EMT) using an intravital two-photon laser scanning microscopy. Fsp1 (Atl1), a gate-keeper of EMT initiation, was used to monitor EMT in vivo. Utilizing the MMTV-PyMT, Rosa26-RFP-GFP, and Fsp1-Cre triple transgenic mouse model, the authors monitored conversion of RFP-positive epithelial cells to GFP-positive mesenchymal cells in mammary tumors. RFP positive transgenic cells were introduced into mammary fat pads of SCID mice. RFP-positive cells gradually converted to GFP-positive, spindle-shaped cells, preferentially near blood vessels. Cells undergoing EMT showed high levels of MET, and treating RFP-positive cells with a MET inhibitor, cabozantinib, suppressed RFP to GFP conversion in vitro and suppressed tumor growth in-vivo. Thus, the authors can visualize EMT at the single cell level in mice, providing insights into tumor dynamics and assessing therapeutic efficacy of treatment protocols.

Zhao Z, Zhu X, Cui K, Mancuso J, Federley R, Fischer K, et al. In vivo visualization and characterization of epithelial-mesenchymal transition in breast tumors. Cancer Res 2016:76:2094–104.

Liu and colleagues test whether chromosome 17p harbors tumor suppressors, besides TP53. They floxed a 4-megabase syntenic region of 17p13.1 in the mouse. Deletion of this chromosomal region was selected during lymphomagenesis, resulting in phenotypes distinct from mice in which TP53 was deleted in isolation. Using a Eμ-Myc driven hematopoietic stem cell system, manipulated in vitro and then implanted into recipient mice, they knocked down TP53 alone or in combination with a library of shRNA to ∼100 protein coding genes within the syntenic region of 17p13.1. This in vivo screen identified a number of potential tumor suppressors whose loss enhanced TP53-driven tumorigenesis. Thus, loss of genes on 17p13.1, in combination with loss of TP53, likely modifies the outcome and treatment options of patients harboring cancers deleted for chromosome 17p.

Liu Y, Chen C, Xu Z, Scuoppo C, Rillahan CD, Gao J. Deletions linked to TP53 loss drive cancer through p53-independent mechanisms. Nature 2016 Mar 16. doi: 10.1038/nature17157.

Girotti and colleagues developed a platform that exploits advances in sequencing technology and xenograft generation to monitor response to therapy, emergence of resistant clones, and explore new treatment options in melanoma. Systematic analysis of 364 samples from 214 patients with advanced melanoma showed that monitoring of circulating tumor DNA (ctDNA) was a biomarker of early disease progression, particularly in patients with delayed responses to immunotherapy. Patient-derived xenograft models were established for ∼70% of patients with a median latency of 49-days, providing an opportunity for ‘real-time’ assessment of alternative therapeutic strategies. The investigators established ctDNA-derived xenograft models from six patients with widespread late-stage disease. These resembled patient tumors and responses to therapies. This work highlights opportunities to develop integrative platforms to monitor patient responses and mechanisms of resistance.

Girotti MR, Gremel G, Lee R, Glavani E, Rothwell D, Viros A, et al. Application of sequencing, liquid biopsies, and patient-derived xenografts for personalized medicine in melanoma. Cancer Discov 2016;6:286–99.

Hata and colleagues showed that in PC9 non-small-cell lung cancer cells treated with the reversible EGFR inhibitor gefitinib, early resistance stemmed from rapidly expanding, resistant colonies and late-resistance from a small number of surviving, drug-tolerant cells. Early-resistant clones emerged from a pre-existing EGFR^T790M population, while late-emerging resistant clones evolved from drug-tolerant cells. These late-resistant clones invoked both EGFR^T790M-dependent and EGFR^T790M-independent mechanisms. Importantly, late-emerging clones had characteristic features of drug-tolerant cells, including reduced drug-induced apoptosis. A subset of lines from patients with EGFR^T790M-acquired resistance also demonstrated decreased response to the irreversible EGFR inhibitor WZ4002 and sensitivity to the dual BCL-XL and BCL-2 inhibitor ABT-263 (navitoclax). Thus, multiple mechanisms confer resistance to targeted therapies, and the route by which these alterations arise may be important for therapy.

Hata AN, Niederst MJ, Archibald HL, Gomez-Caraballo M, Siddiqui FM, Mulvey HE, et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med 2016;22:262–9.

Since TP53 is frequently mutated in high-grade ovarian cancers, Ren and colleagues assessed relevance in epithelial ovarian cancer (EOC). The mutant Trp53^R172H allele (homologous to human TP53^R175H) was introduced into Pten/Kras^G12D mouse model for EOC. Tumors in homozygous Trp53^R172H mice were undifferentiated and highly metastatic. Heterozygous WT/Trp53^R172H tumors invaded the ovarian stroma and accelerated intraperitoneal metastases. Further, primary tumor growth as well as metastases were enhanced in response to estradiol, due to high levels of estrogen receptor α in the tumors. Importantly, these mice also developed mucinous cystadenocarcinomas that recapitulated human mucinous ovarian tumors, which showed heterozygous TP53 mutations and KRAS mutations. Thus, the authors developed a novel mouse model of mucinous ovarian tumors and demonstrated mutant TP53 as a key regulator of progression, differentiation, and responsiveness to steroid hormones.

Ren YA, Mullany LK, Liu Z, Herron AJ, Wong KK, Richards JS. Mutant p53 promotes epithelial ovarian cancer by regulating tumor differentiation, metastasis, and responsiveness to steroid hormones. Cancer Res 2016;76:2206–18.

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.