Targeting the CINful genome: Strategies to overcome tumor heterogeneity

Cunningham, Chelsea E.; MacAuley, Mackenzie J; Yadav, Garima; Vizeacoumar, Frederick S.; Freywald, Andrew

doi:10.1016/j.pbiomolbio.2019.02.006

Cited by 17 publications

(16 citation statements)

References 131 publications

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“…cell-to-cell heterogeneity) or micronucleus formation may hold diagnostic, prognostic or therapeutic value within the clinic; however, future studies are required to specifically investigate the correlation between changes in nuclear areas or micronucleus formation with treatment response and disease outcome for all relevant cancer types. In addition, the genomic alterations resulting in reduced expression may represent genetic susceptibilities that can be leveraged for highly specific and targeted killing of cancer cells (reviewed in 10,[58][59][60] ). Synthetic lethality is one such approach that is now showing potential within the clinic and may hold tremendous therapeutic potential is targeting the reduced expression of cohesion genes in many cancer types 61,62 .…”

Section: Discussionmentioning

confidence: 99%

Reduced Expression of Genes Regulating Cohesion Induces Chromosome Instability that May Promote Cancer and Impact Patient Outcomes

Leylek

Jeusset

Lichtensztejn

et al. 2020

Sci Rep

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chromosome instability (cin), or continual changes in chromosome complements, is an enabling feature of cancer; however, the molecular determinants of cin remain largely unknown. emerging data now suggest that aberrant sister chromatid cohesion may induce cin and contribute to cancer. to explore this possibility, we employed clinical and fundamental approaches to systematically assess the impact reduced cohesion gene expression has on cin and cancer. ten genes encoding critical functions in cohesion were evaluated and remarkably, each exhibits copy number losses in 12 common cancer types, and reduced expression is associated with worse patient survival. to gain mechanistic insight, we combined siRnA-based silencing with single cell quantitative imaging microscopy to comprehensively assess the impact reduced expression has on cin in two karyotypically stable cell lines. We show that reduced expression induces cin phenotypes, namely increases in micronucleus formation and nuclear areas. Subsequent direct tests involving a subset of prioritized genes also revealed significant changes in chromosome numbers with corresponding increases in moderate and severe cohesion defects within mitotic chromosome spreads. Collectively, our clinical and fundamental findings implicate reduced sister chromatid cohesion, resulting from gene copy number losses, as a key pathogenic event in the development and progression of many cancer types.

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Section: Discussionmentioning

confidence: 99%

Reduced Expression of Genes Regulating Cohesion Induces Chromosome Instability that May Promote Cancer and Impact Patient Outcomes

Leylek

Jeusset

Lichtensztejn

et al. 2020

Sci Rep

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“…However, it is interesting to note that there are a small subset of cancers in which the presence of CIN corresponds with improved survival [63][64][65]. Collectively, an extensive body of evidence exists to suggest that low-to-intermediate levels of CIN may be a driving force in cancer, while reduced tumor cell viability may be associated with extreme levels of CIN, which is a common therapeutic strategy employed to selectively kill cancer cells (reviewed in [66,67]). Nevertheless, and despite these associations, the aberrant molecular determinants inducing CIN remain poorly understood.…”

Section: The Impact Of Cin On Cancer Development and Progressionmentioning

confidence: 99%

“…Collectively, the above data suggest that it is more likely the level of CIN (i.e., low versus high), rather than the tumor type itself, that discerns whether CIN is associated with better or worse clinical outcomes. This possibility is further underscored by the many therapeutic strategies (currently employed or under development) that now seek to induce extreme levels of CIN to enhance the killing of cancer cells [66,67,[138][139][140][141][142][143]. Accordingly, it is becoming increasingly important to determine the extent and level of CIN within tumors, whether primary or metastatic, as this critical information may hold tremendous diagnostic, prognostic, and therapeutic value.…”

Section: Cin and Cancer Prognosismentioning

confidence: 99%

Chromosome Instability; Implications in Cancer Development, Progression, and Clinical Outcomes

Vishwakarma

McManus

2020

Cancers

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Chromosome instability (CIN) refers to an ongoing rate of chromosomal changes and is a driver of genetic, cell-to-cell heterogeneity. It is an aberrant phenotype that is intimately associated with cancer development and progression. The presence, extent, and level of CIN has tremendous implications for the clinical management and outcomes of those living with cancer. Despite its relevance in cancer, there is still extensive misuse of the term CIN, and this has adversely impacted our ability to identify and characterize the molecular determinants of CIN. Though several decades of genetic research have provided insight into CIN, the molecular determinants remain largely unknown, which severely limits its clinical potential. In this review, we provide a definition of CIN, describe the two main types, and discuss how it differs from aneuploidy. We subsequently detail its impact on cancer development and progression, and describe how it influences metastatic potential with reference to cancer prognosis and outcomes. Finally, we end with a discussion of how CIN induces genetic heterogeneity to influence the use and efficacy of several precision medicine strategies, including patient and risk stratification, as well as its impact on the acquisition of drug resistance and disease recurrence.

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“…Most studies attribute this to very complex regulatory mechanisms dedicated to ensuring genomic stability, where too big or too small shift in either direction might produce undesirable effects. On the tumorigenic side, elevated CIN leads to an increased array of mutations and phenotypes in the heterogenous tumor cell population, some of which will likely confer a growth advantage or drug resistance in the altered tumor microenvironment [ 210 ]. However within the tumor suppressive response, extremely high levels of CIN are just not compatible with cell viability, as eventually, the accumulation of DNA defects will render cancer cells unable to complete mitosis or carry out other vital cell processes, causing their elimination [ 210 ].…”

Section: Targeting Cancer Cells Through Plk1mentioning

confidence: 99%

“…On the tumorigenic side, elevated CIN leads to an increased array of mutations and phenotypes in the heterogenous tumor cell population, some of which will likely confer a growth advantage or drug resistance in the altered tumor microenvironment [ 210 ]. However within the tumor suppressive response, extremely high levels of CIN are just not compatible with cell viability, as eventually, the accumulation of DNA defects will render cancer cells unable to complete mitosis or carry out other vital cell processes, causing their elimination [ 210 ]. Consistent with these ideas, it has been shown that CIN levels dictate whether it acts in a tumor suppressive or pro-oncogenic manner [ 209 , 211 ], and the worst prognoses are associated with low to intermediate CIN rather than its higher levels [ 212 ].…”

Section: Targeting Cancer Cells Through Plk1mentioning

confidence: 99%

The CINs of Polo-Like Kinase 1 in Cancer

Cunningham

MacAuley

Vizeacoumar

et al. 2020

Cancers

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Polo-like kinase 1 (PLK1) is overexpressed near ubiquitously across all cancer types and dysregulation of this enzyme is closely tied to increased chromosomal instability and tumor heterogeneity. PLK1 is a mitotic kinase with a critical role in maintaining chromosomal integrity through its function in processes ranging from the mitotic checkpoint, centrosome biogenesis, bipolar spindle formation, chromosome segregation, DNA replication licensing, DNA damage repair, and cytokinesis. The relation between dysregulated PLK1 and chromosomal instability (CIN) makes it an attractive target for cancer therapy. However, clinical trials with PLK1 inhibitors as cancer drugs have generally displayed poor responses or adverse side-effects. This is in part because targeting CIN regulators, including PLK1, can elevate CIN to lethal levels in normal cells, affecting normal physiology. Nevertheless, aiming at related genetic interactions, such as synthetic dosage lethal (SDL) interactions of PLK1 instead of PLK1 itself, can help to avoid the detrimental side effects associated with increased levels of CIN. Since PLK1 overexpression contributes to tumor heterogeneity, targeting SDL interactions may also provide an effective strategy to suppressing this malignant phenotype in a personalized fashion.

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Targeting the CINful genome: Strategies to overcome tumor heterogeneity

Cited by 17 publications

References 131 publications

Reduced Expression of Genes Regulating Cohesion Induces Chromosome Instability that May Promote Cancer and Impact Patient Outcomes

Reduced Expression of Genes Regulating Cohesion Induces Chromosome Instability that May Promote Cancer and Impact Patient Outcomes

Chromosome Instability; Implications in Cancer Development, Progression, and Clinical Outcomes

The CINs of Polo-Like Kinase 1 in Cancer

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