Clinical application of a systems model of apoptosis execution for the prediction of colorectal cancer therapy responses and personalisation of therapy

Hector, Suzanne; Rehm, Markus; Schmid, Jasmin; Kehoe, Joan; McCawley, Niamh; Dicker, Patrick; Murray, Frank E.; McNamara, Deborah A.; Kay, Elaine W.; Concannon, Caoimhín G.; Huber, Heinrich J.; Prehn, Jochen H.M.

doi:10.1136/gutjnl-2011-300433

Cited by 49 publications

(69 citation statements)

References 44 publications

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“…Integrating information on protein-protein interplay and pathway topology into data sets on protein expression may therefore allow multivariate statistical models to accurately and case-specifically predict cell death responsiveness. The perspectives offered by systems biological and systems medical approaches, 9 and the first successful proofof-principle systems medical studies in the field of cancer and apoptosis 10,11 support this notion.…”

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confidence: 67%

Systems analysis of apoptosis protein expression allows the case-specific prediction of cell death responsiveness of melanoma cells

et al. 2013

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Many cancer entities and their associated cell line models are highly heterogeneous in their responsiveness to apoptosis inducers and, despite a detailed understanding of the underlying signaling networks, cell death susceptibility currently cannot be predicted reliably from protein expression profiles. Here, we demonstrate that an integration of quantitative apoptosis protein expression data with pathway knowledge can predict the cell death responsiveness of melanoma cell lines. By a total of 612 measurements, we determined the absolute expression (nM) of 17 core apoptosis regulators in a panel of 11 melanoma cell lines, and enriched these data with systems-level information on apoptosis pathway topology. By applying multivariate statistical analysis and multi-dimensional pattern recognition algorithms, the responsiveness of individual cell lines to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or dacarbazine (DTIC) could be predicted with very high accuracy (91 and 82% correct predictions), and the most effective treatment option for individual cell lines could be pre-determined in silico. In contrast, cell death responsiveness was poorly predicted when not taking knowledge on protein-protein interactions into account (55 and 36% correct predictions). We also generated mathematical predictions on whether anti-apoptotic Bcl-2 family members or x-linked inhibitor of apoptosis protein (XIAP) can be targeted to enhance TRAIL responsiveness in individual cell lines. Subsequent experiments, making use of pharmacological Bcl-2/Bcl-xL inhibition or siRNA-based XIAP depletion, confirmed the accuracy of these predictions. We therefore demonstrate that cell death responsiveness to TRAIL or DTIC can be predicted reliably in a large number of melanoma cell lines when investigating expression patterns of apoptosis regulators in the context of their network-level interplay. The capacity to predict responsiveness at the cellular level may contribute to personalizing anti-cancer treatments in the future.

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confidence: 67%

Systems analysis of apoptosis protein expression allows the case-specific prediction of cell death responsiveness of melanoma cells

et al. 2013

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“…Indeed, with such quantitative signal transduction models, we were previously able to predict patient specific susceptibility to chemotherapy [31,44,54,84,85]. It is therefore expected that these models in combination with biomolecular studies that investigate molecular mediators of apoptosis can further help to identify patient more vulnerable to DOX-induced cardiac apoptosis and DCM.…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Kankeu

Clarke²,

Passante

et al. 2016

J Mol Med

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The chemotherapeutic Doxorubicin (DOX) has significantly increased survival rates of pediatric and adult cancer patients. However, 10 % of pediatric cancer survivors will 10-20 years later develop severe Dilated Cardiomyopathy (DCM) and the exact molecular mechanisms of disease progression after this long latency time remain puzzling. We here revisit the hypothesis that elevated apoptosis signaling or its increased likelihood after DOX exposure can lead to an impairment of cardiac function and cause a cardiac dilation. Based on recent literature evidences, we first argue why even little detectable apoptosis may be sufficient to cause a dilated phenotype. We then review findings suggesting that mature cardiomyocytes are protected against DOX-induced apoptosis downstream, but not upstream to Mitochondrial Outer Membrane Permeabilisation (MOMP). This lack of prevention of MOMP-induction then is proposed to alter the metabolic phenotype, induce hypertrophic remodeling and lead to functional cardiac impairment even in absence of cardiomyocyte apoptosis. We further discuss findings that DOX exposure can lead to increased sensitivity to further cardiomyocyte apoptosis, which may cause a gradual loss in cardiomyocytes over time and a compensatory hypertrophic remodeling after treatment, potentially explaining the long lag time in disease onset. We finally note similarities between DOX-exposed cardiomyocytes and apoptosisprimed cancer cells and propose computational systems biology as tool to predict patient individual DOX doses. In conclusion, combining recent findings in rodent hearts and cardiomyocytes exposed to DOX with insights from apoptosis signal transduction allowed us to obtain a molecularly deeper insight in this delayed and still enigmatic pathology of DCM. Key messages1. Differentiated cardiomyocyte are protected to post but not pre-MOMP apoptosis 2. MOMP-induction can lead to cardiac hypertrophy and metabolic remodeling after DOX 3. DOX-exposed cardiomyocytes may be more sensitive to apoptosis over life time 4. DOX-exposed cardiomyocytes show similarities to apoptosis-primed cancer cells

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“…However, to better assess the predictive power of APOPTO-CELL, additional, prospective validations to other cell lines would be necessary. Nevertheless, this work along with previous studies from our laboratory suggests that APOPTO-CELL explains cancer cell death or apoptosis resistance subsequent to MOMP in several cancer cells with sufficient accuracy (17,43). In conclusion, our study is the first systems analysis of heterogeneity and impairment of apoptosis subsequent to MOMP, emphasizing the importance of this pathway component in determining the efficacy of apoptosisinducing chemotherapy.…”

Section: Optimization Of Apopto-cell For Uses As a Clinical Tool To Smentioning

confidence: 81%

“…Therefore, in the context of our work, the decision as to whether or not apoptosis is executed subsequent to MOMP is assumed to be dose-independent. This decision is therefore considered to depend solely on the expression levels of the pro-and anti-apoptotic proteins during apoptosis execution during this phase (17,43). Due to these specificities, independent studies of processes prior and subsequent to MOMP can bring more context-dependent and potentially complementary insights into mechanisms of impairment of cancer cell death and its therapeutic implications.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, loss of APAF-1, overexpression of XIAP, or down-regulation of Smac, which are likely to attenuate the apoptotic pathway subsequent to MOMP, have been linked to carcinogenesis and to mediating chemo-resistance (26 -29). To this end, we recently demonstrated that APOPTO-CELL can predict responsiveness to MOMP-inducing, chemotherapeutic stimuli using patient-individual protein profiles as input (17,43).…”

Section: Apoptosis Can Be Impaired Subsequent To Momp and Can Be Explmentioning

confidence: 99%

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Systems Analysis of Cancer Cell Heterogeneity in Caspase-dependent Apoptosis Subsequent to Mitochondrial Outer Membrane Permeabilization

Schmid

Düßmann

Boukes

et al. 2012

Journal of Biological Chemistry

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Background: Computational systems models may allow understanding of progression and impairment of apoptosis based on quantitative protein profiles. Results: We found apoptosis to be impaired in some cell lines after MOMP, which can be understood by our systems model "APOPTO-CELL". Conclusion: APOPTO-CELL helps to understand heterogeneity in apoptosis execution after MOMP. Significance: APOPTO-CELL may help to assess cancer-specific efficacy of chemotherapeutics that induce apoptosis.

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Clinical application of a systems model of apoptosis execution for the prediction of colorectal cancer therapy responses and personalisation of therapy

Abstract: Our study represents the first proof-of-concept example demonstrating the significant clinical potential of systems biology-based approaches for predicting patient outcome and responsiveness to novel targeted treatment paradigms.

Cited by 49 publications

References 44 publications

Systems analysis of apoptosis protein expression allows the case-specific prediction of cell death responsiveness of melanoma cells

Systems analysis of apoptosis protein expression allows the case-specific prediction of cell death responsiveness of melanoma cells

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Systems Analysis of Cancer Cell Heterogeneity in Caspase-dependent Apoptosis Subsequent to Mitochondrial Outer Membrane Permeabilization

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