Highlights from Recent Cancer Literature
Journal: Cancer Research (2021)

Aneuploidy is a prominent characteristic of human triple-negative breast cancers carrying TP53 mutations. However, we know very little regarding when and how chromosomal rearrangements occur and are preserved during the growth of primary human tumors. Minussi and colleagues generated a single-cell, single-molecule DNA-sequencing method to investigate copy number evolution during primary breast tumor expansion. Using eight human triple-negative breast cancers and four cell lines, they analyzed 16,178 single cells for copy numbers and found that breast tumors and cell lines could be divided into 7 to 22 subclones that can be grouped into 3 to 5 major superclones. Analysis of chromosomal evolution indicated initial clonal p53 mutations, loss of heterozygosity, and genome doubling events were followed by a transient period of genomic instability and then ongoing copy number changes. Subcloning of single cells in culture demonstrated that tumor cells diversify their genomes and do not keep isogenic attributes.Expert Commentary: These results demonstrate that triple-negative breast cancers constantly develop chromosome anomalies and keep a supply of subclonal diversity during the expansion of primary tumors.Minussi DC, Nicholson MD, Ye H, Davis A, Wang K, Baker T, et al. Breast tumours maintain a reservoir of subclonal diversity during expansion. Nature 2021;592:302–8.Tumor-secreted factors are known to prime the metastatic niche, promoting survival and colonization of disseminated tumor cells. Using a model of metastatic breast cancer, Chiou and colleagues showed that tumor-conditioned media promotes bone growth in mice. While analysis of bones revealed that osteoclast and osteoblast activation pathways, which regulate bone turnover, were not altered in response to systemic delivery of tumor-derived factors, detailed morphometric analysis identified differences in bone structure. This was accompanied by changes in organic bone matrix composition at specific regions within bones that are prone to metastatic colonization.Expert Commentary: The use of multiple material analysis methodologies used in this study allowed microscale and nanoscale differences in the bone architecture and quality to be identified, providing insight into further ways that tumor cells can prime the bone environment.Chiou AE, Liu C, Moreno-Jiménez I, Tang T, Wagermaier W, Dean MN, et al. Breast cancer-secreted factors perturb murine bone growth in regions prone to metastasis. Sci Adv 2021;7:eabf2283. DOI: 10.1126/sciadv.abf2283.Surgery is well-established to control cancer. However, as the tumor and associated vessels are disrupted, cancer cells have the potential to escape into the circulation as circulating tumor cells (CTC). Moreover, surgery suppresses antitumor immunity, which may enhance colonization of distant organs by CTCs. Ren and colleagues reported that surgical stress-activated platelets enhanced formation of platelet-tumor cell aggregates, facilitating their entrapment by neutrophil extracellular traps (NET) and subsequent distant metastases. A murine hepatic ischemia/reperfusion injury model of localized surgical stress showed that ischemia/reperfusion promoted the capture of aggregated CTCs by NETs and eventual metastasis to the lungs, all abrogated when platelets were depleted. This prometastatic role of platelets was mediated by TLR4-dependent ERK5-GPIIb/IIIa integrin activation.Expert Commentary: This work delineates how platelets and neutrophils engage with CTCs to promote metastasis under surgical stress. Targeting platelet activation via TLR4/ERK5/integrin GPIIb/IIIa signaling shows potential for preventing NET-driven distant metastasis post-resection.Ren J, He J, Zhang H, Xia Y, Hu Z, Loughran P, et al. Platelet TLR4-ERK5 axis facilitates NET-mediated capturing of circulating tumor cells and distant metastasis after surgical stress. Cancer Res 2021;81:2373–85.Although patients with preleukemic conditions are at high risk to progress to acute myeloid leukemia (AML), little is known about the molecular mediators of the preleukemic-to-AML transition. Ueda and colleagues demonstrated that the MDMX/β-catenin pathway can promote transformation to AML. Although overexpression of MDMX (an MDM2 homolog and negative regulator of p53) was not sufficient to induce leukemogenesis, it increased the hematopoietic stem cell population and cooperated with multiple distinct oncogenic drivers to induce AML. MDMX was found to sequester CK1α, leading to increased β-catenin protein stability in a p53-independent manner. The combination of MDMX and β-catenin inhibitors significantly delayed transformation and improved survival.Expert Commentary: This study suggests that targeting the MDMX/β-catenin axis may be an effective therapy to prevent the preleukemic-to-AML transition.Ueda K, Kumari R, Schwenger E, Wheat JC, Bohorquez O, Narayanagari S-R, et al. MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism. Cancer Cell 2021;39:529–547.e7.The importance of gain-of-function activity of TP53 mutations in tumorigenesis is well recognized, however, the role of mutant TP53 in metastasis is poorly understood. Tang and colleagues demonstrated that the TP53R175H mutation could promote invasion and metastasis through the YAP-survivin pathway. TP53R175H expression was required for invasion and lung metastases of esophageal squamous cell carcinoma cells but not for proliferation or survival. TP53R175H but not wild-type TP53 was found to be able to bind to YAP and to promote expression of survivin (encoded by BIRC5). Expression of survivin was required for TP53R175H-driven lung metastases, and high survivin expression correlated with metastasis, TP53 mutation, and poor prognosis in gastrointestinal cancers.Expert Commentary: This study suggests that cancer harboring mutant TP53R175H is uniquely dependent on survivin and targeting survivin in these patients may be efficacious.Tang Q, Efe G, Chiarella AM, Leung J, Chen M, Yamazoe T, et al. Mutant p53 regulates Survivin to foster lung metastasis. Genes Dev 2021;35:528–41.While most gliomas arise sporadically, familial cases may associate with known genetic syndromes or arise among nonsyndromic families. Whole exome sequencing in a number of nonsyndromic families led to the discovery of germline mutations in POT1 (protection of telomeres 1) in affected individuals, linking POT1 mutations to risk of glioma. Jalali and colleagues showed that mutant POT1G95C promotes proliferation in glioma-initiating cells in vitro and leads to expansion of progenitor populations in the developing brain. Pot1a/b deficiency in a mouse model of glioma decreased survival in females compared to males. Pot1a/b-deficient tumors in female mice showed reduced expression of immune markers, while expression of cell-cycle signatures was increased. The observed sex-dependent trends were recapitulated in human gliomas with low POT1 expression.Expert Commentary: This work demonstrates that POT1 has sex-specific effects on tumorigenesis and expression signatures in glioma, establishing context-dependent functions for mutation or loss of POT1.Jalali A, Yu K, Beechar V, Bosquez Huerta N, Grichuk A, Mehra D, et al. POT1 regulates proliferation and confers sexual dimorphism in glioma. Cancer Res 2021;81:2703–13.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.