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Genomic instability, and more specifically chromosomal instability (CIN), arises from a number of processes that are defective in cancer, such as aberrant mitotic cell division, replication stress, defective DNA damage repair, and ineffective telomere maintenance. CIN is an emerging hallmark of cancer that contributes to tumor heterogeneity through increased rates of genetic alterations. As genetic heterogeneity within a single tumor and between tumors is a key challenge leading to treatment failures, this brings to question, whether therapeutic approaches should aim at the genetic diversity or a specific mutation present within these tumors. Answering this question will determine the future of personalized targeted therapies. Here we discuss, how the genetic diversity associated with CIN in tumor cells can be used as a therapeutic advantage and targeted by exploiting the genetic concepts of synthetic lethality and synthetic dosage lethality. Given that a number of CIN-related pathways work together to fix the DNA damage within our genome and ensure proper segregation of chromosomes, we specifically focus on the genetic interactions amongst these pathways and their potential therapeutic applicability in cancer. We also discuss, how tumor genetic heterogeneity can be targeted in emerging immunotherapeutic approaches.

Chromosomal rearrangements involving the mixed-lineage leukemia (MLL1) gene are common in a unique group of acute leukemias, with more than 100 fusion partners in this malignancy alone. However, do these fusions occur or have a role in solid tumors? We performed extensive network analyses of MLL1-fusion partners in patient datasets, revealing that multiple MLL1-fusion partners exhibited significant interactions with the androgen-receptor signaling pathway. Further exploration of tumor sequence data from TCGA predicts the presence of MLL1 fusions with truncated SET domain in prostate tumors. To investigate the physiological relevance of MLL1 fusions in solid tumors, we engineered a truncated version of MLL1 by fusing it with one of its known fusion partners, ZC3H13, to use as a model system. Functional characterization with cell-based assays revealed that MLL1-ZC3H13 fusion induced chromosomal instability, affected mitotic progression, and enhanced tumorsphere formation. The MLL1-ZC3H13 chimera consistently increased the expression of a cancer stem cell marker (CD44); in addition, we detected potential collateral lethality between DOT1L and MLL1 fusions. Our work reveals that MLL1 fusions are likely prevalent in solid tumors and exhibit a potential pro-tumorigenic role.

Can transcriptomic alterations drive the evolution of tumors? We asked if changes in gene expression found in all patients arise earlier in tumor development and can be relevant to tumor progression. Our analyses of non-mutated genes from the non-amplified regions of the genome of 158 triple-negative breast cancer (TNBC) cases identified 219 exclusively expression-altered (EEA) genes that may play important role in TNBC. Phylogenetic analyses of these genes predict a “punctuated burst” of multiple gene upregulation events occurring at early stages of tumor development, followed by minimal subsequent changes later in tumor progression. Remarkably, this punctuated burst of expressional changes is instigated by hypoxia-related molecular events, predominantly in two groups of genes that control chromosomal instability (CIN) and those that remodel tumor microenvironment (TME). We conclude that alterations in the transcriptome are not stochastic and that early-stage hypoxia induces CIN and TME remodeling to permit further tumor evolution., Tumorigenesis: Hypoxia affects CIN and TME genes simultaneously Altered gene expression is universal in tumors, but does it impact tumor development and progression? A collaborative team lead by Franco Vizeacoumar and Jei Han from Canada’s University of Saskatchewan and University of Alberta respectively, analyzed expression of non-mutated and non-amplified genes in Triple-Negative Breast Cancer (TNBC) patients. This exclusively expression-altered genes, included those that regulate chromosomal instability (CIN) and remodeling of tumor microenvironment (TME). Further analyses predict hypoxia induced a “punctuated burst” of changes in expression patterns of genes involved in CIN and TME, driving early stages of tumor development. This work provides a novel strategy to co-inhibit CIN and TME genes to disrupt tumor development.

Metabolic alterations play an important role in cancer and yet, few metabolic cancer driver genes are known. Here we perform a combined genomic and metabolic modeling analysis searching for metabolic drivers of colorectal cancer. Our analysis predicts FUT9, which catalyzes the biosynthesis of Ley glycolipids, as a driver of advanced‐stage colon cancer. Experimental testing reveals FUT9's complex dual role; while its knockdown enhances proliferation and migration in monolayers, it suppresses colon cancer cells expansion in tumorspheres and inhibits tumor development in a mouse xenograft models. These results suggest that FUT9's inhibition may attenuate tumor‐initiating cells (TICs) that are known to dominate tumorspheres and early tumor growth, but promote bulk tumor cells. In agreement, we find that FUT9 silencing decreases the expression of the colorectal cancer TIC marker CD44 and the level of the OCT4 transcription factor, which is known to support cancer stemness. Beyond its current application, this work presents a novel genomic and metabolic modeling computational approach that can facilitate the systematic discovery of metabolic driver genes in other types of cancer.

// Chelsea E. Cunningham 1, * , Shuangshuang Li 1, * , Frederick S. Vizeacoumar 1, * , Kalpana Kalyanasundaram Bhanumathy 1 , Joo Sang Lee 2 , Sreejit Parameswaran 1 , Levi Furber 1 , Omar Abuhussein 3 , James M. Paul 1 , Megan McDonald 1 , Shaina D. Templeton 1 , Hersh Shukla 1 , Amr M. El Zawily 1 , Frederick Boyd 1 , Nezeka Alli 1 , Darrell D. Mousseau 4 , Ron Geyer 1 , Keith Bonham 5 , Deborah H. Anderson 5 , Jiong Yan 1 , Li-Yuan Yu-Lee 6 , Beth A. Weaver 7 , Maruti Uppalapati 1 , Eytan Ruppin 2 , Anna Sablina 8 , Andrew Freywald 1 , Franco J. Vizeacoumar 1, 3, 5 1 Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada 2 Center for Bioinformatics and Computational Biology, Department of Computer Science, University of Maryland, Maryland, MD 20742, USA 3 College of Pharmacy, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 2Z4, Canada 4 Cell Signaling Laboratory, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada 5 Cancer Research, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, S7N 5E5, Canada 6 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA 7 Department of Cell and Regenerative Biology and Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705-2275, USA 8 VIB Center for the Biology of Disease, VIB, 3000 Leuven, Belgium * These authors contributed equally to this work Correspondence to: Franco J. Vizeacoumar, email: franco.vizeacoumar@usask.ca Keywords: synthetic dosage lethality, PLK1, PP2A, chromosomal instability, mitotic checkpoint Received: March 30, 2016 Accepted: August 10, 2016 Published: August 19, 2016 ABSTRACT Chromosomal Instability (CIN) is regarded as a unifying feature of heterogeneous tumor populations, driving intratumoral heterogeneity. Polo-Like Kinase 1 (PLK1), a serine-threonine kinase that is often overexpressed across multiple tumor types, is one of the key regulators of CIN and is considered as a potential therapeutic target. However, targeting PLK1 has remained a challenge due to the off-target effects caused by the inhibition of other members of the polo-like family. Here we use synthetic dosage lethality (SDL), where the overexpression of PLK1 is lethal only when another, normally non-lethal, mutation or deletion is present. Rather than directly inhibiting PLK1, we found that inhibition of PP2A causes selective lethality to PLK1-overexpressing breast, pancreatic, ovarian, glioblastoma, and prostate cancer cells. As PP2A is widely regarded as a tumor suppressor, we resorted to gene expression datasets from cancer patients to functionally dissect its therapeutic relevance. We identified two major classes of PP2A subunits that negatively correlated with each other. Interestingly, most mitotic regulators, including PLK1, exhibited SDL interactions with only one class of PP2A subunits (PPP2R1A, PPP2R2D, PPP2R3B, PPP2R5B and PPP2R5D). Validation studies and other functional cell-based assays showed that inhibition of PPP2R5D affects both levels of phospho-Rb as well as sister chromatid cohesion in PLK1-overexpressing cells. Finally, analysis of clinical data revealed that patients with high expression of mitotic regulators and low expression of Class I subunits of PP2A improved survival. Overall, these observations point to a context-dependent role of PP2A that warrants further exploration for therapeutic benefits.