Highlights from Recent Cancer Literature

Transcriptional regulation is interconnected with 3D genome organization enabling chromatin partitioning into topological associating domains (TAD). TADs, in turn, influence gene expression by dictating chromatin accessibility within such domains. Activating mutations in the histone lysine methyltransferase EZH2 in lymphoma result in increased H3K27me3 and subsequent transcriptional repression, although their impact on chromatin architecture has yet to be elucidated. By comparing EZH2 WT with mutant (Y646X) lymphoma cell lines and patient samples, Donaldson-Collier and colleagues demonstrate that altered EZH2-mediated H3K27me3 changes were associated with selective inactivation of TADs comprising genes encoding tumor suppressors, including SESN1, FOXO3, and ARMC2. Perturbation of intra-TAD interactions led to synergistic silencing of such genes to support lymphomagenesis, an effect abrogated by pharmacological inhibition of EZH2. These findings reveal EZH2^Y646X as an oncogenic modulator of TAD architecture and underlying transcriptional activity.

Expert Commentary: This study adds to the growing body of evidence that alterations in chromatin architecture can lead to the aberrant expression of genes that specify disease states including cancer.

Donaldson-Collier MC, Sungalee S, Zufferey M, Tavernari D, Katanayeva N, Battistello E, et al. EZH2 oncogenic mutations drive epigenetic, transcriptional, and structural changes within chromatin domains. Nat Genet 2019;51:517–28.

Poor clinical efficacy of chemotherapy has been linked to the presence of both macrophages and neutrophils in tumors. A recent study shows that targeted elimination of macrophages synergizes with platinum-based chemotherapy in a mouse model of breast cancer. Treatment with anti-CSF1R to deplete intratumoral macrophages was associated with stimulation of a type I IFN response, which was necessary for enhancing the efficacy of platinum-based chemotherapy. Increased expression of IFN-stimulated genes in tumor biopsies from patients treated with anti-CSF1R supports further investigation into IFN signaling in chemotherapy action. However, targeting of intratumoral neutrophils was also required to engage a full antitumor T-cell response and tumor regression.

Expert Commentary: This study highlights the importance of unravelling the complex interplay between different immune cell populations when considering approaches to stimulate antitumor immunity in the clinical setting.

Salvagno C, Ciampricotti M, Tuit S, Hau CS, van Weverwijk A, Coffelt SB, et al. Therapeutic targeting of macrophages enhances chemotherapy efficacy by unleashing type I interferon response. Nat Cell Biol 2019;21:511–21.

Burkitt lymphoma is the most common B-cell lymphoma in children, but also occurs in adults. Endemic Burkitt lymphoma predominates in the malaria belt in Africa, frequently involves jaw and facial bones, and is closely linked to Epstein-Barr virus (EBV) infection. Immunodeficiency-associated Burkitt lymphoma typically presents as nodal disease, with 25–40% correlation to EBV. Sporadic Burkitt lymphoma, the most common form outside the malaria belt, presents as abdominal disease or in lymph nodes with 10-20% EBV association. López and colleagues performed whole genome and transcriptome sequencing of 39 sporadic Burkitt lymphomas. They demonstrated interaction of structural, mutational, and transcriptional changes, which contributed to MYC oncogene dysregulation together with the hallmark Ig-MYC translocation. By mapping IgH translocation breakpoints, they found that the precursor of a subset of Burkitt lymphoma was a B cell poised to express IgHA.

Expert Commentary: This study identifies novel mutations including Ig-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing, which could potentially be targeted.

López C, Kleinheinz K, Aukema SM, Rohde M, Bernhart SH, Hübschmann D, et al. Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma. Nat Commun 2019;10:1459. doi: 10.1038/s41467-019-08578-3.

Many tumors consist of genetically diverse subclones, believed to reflect cancer evolution.

Körber and colleagues studied how intratumoral genetic heterogeneity shapes tumor growth and therapy response in rapidly regrowing glioblastoma with wild-type isocitrate dehydrogenase (IDH). The authors inferred the evolutionary trajectories of pairs of primary and relapsed tumors based on deep whole-genome-sequencing data and found large genetic diversity in primary and recurrent aggressive IDH-wild-type glioblastomas. All these diverse tumors mapped to a common path of early tumorigenesis, where characteristic driver mutations were acquired by losses or gains of chromosomes including chromosome 7 gain, 9p loss, or 10 loss. Mutation rates suggested that these tumor-initiating events predated diagnosis by several years. TERT promoter mutations often occurred later as a prerequisite for rapid growth. Importantly, relapsed tumors typically regrew from oligoclonal origins, suggesting sparse selective pressure by therapeutic measures.

Expert Commentary: This study suggests that further genetic diversification contributes little to tumor regrowth after therapy.

Körber V, Yang J, Barah P, Wu Y, Stichel D, Gu Z, et al. Evolutionary trajectories of IDH^WT glioblastomas reveal a common path of early tumorigenesis instigated years ahead of initial diagnosis. Cancer Cell 2019;35:692–704.e12.

The failure of neoadjuvant therapy (NACT) in triple-negative breast cancer (TNBC) is a significant clinical problem. Echeverria and colleagues utilized treatment-naïve xenografts from patients with TNBC and serial biopsies from patients undergoing NACT to elucidate mechanisms of NACT resistance. They found that residual tumors after NACT regained chemosensitivity upon regrowth. Residual tumors underwent reversible histologic, transcriptomic, and proteomic changes that were not seen at baseline nor after regrowth. Neither clonal selection nor gain or loss of genetic alterations were observed, suggesting that resistance occurred through reversible nongenetic mechanisms. Residual tumors demonstrated increased dependence on oxidative phosphorylation, as inhibition of oxidative phosphorylation delayed recurrence after NACT.

Expert Commentary: This study suggests that failure of NACT in TNBC is due to a nonclonal and reversible drug-tolerant state that can be targeted though oxidation phosphorylation inhibition.

Echeverria GV, Ge Z, Seth S, Zhang X, Jeter-Jones S, Zhou X, et al. Resistance to neoadjuvant chemotherapy in triple-negative breast cancer mediated by a reversible drug-tolerant state. Sci Transl Med 2019;11. doi: 10.1126/scitranslmed.aav0936.

Unbiased strategies that effectively identify and prioritize targets in tumors may improve the success rates of cancer therapies. Behan and colleagues performed a genome-wide CRISPR-Cas9-based functional screen across 324 human cancer cell lines, derived from 30 distinct types of cancer. Using cancer cell fitness as an endpoint, they designed a statistical framework to prioritize context-specific fitness genes from the core-conserved fitness genes most likely to exhibit generalized toxicity when targeted with drugs in vivo. They further ranked these candidates based on their expression levels in primary tumors, the association between their dependence score and a specific genetic biomarker, and the druggability of this class of therapeutic targets. Using this approach, they prioritized the Werner syndrome ATP-dependent helicase (WRN) as a synthetic lethal target in colon and ovarian cancers with microsatellite instability. They validated this finding by mining data from published siRNA screens and by experimentally monitoring the viability of colon cancer cell lines with or without the inducible loss of WRN in vitro and in vivo.

Expert Commentary: The principles used in this study could be extrapolated to identify novel, and diverse, therapeutic targets for different cancers.

Behan FM, Iorio F, Picco G, Gonçalves E, Beaver CM, Migliardi G, et al. Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature 2019;568:511–6.

Note: Breaking Insights 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.