Implementing Systems Modelling and Molecular Imaging to Predict the Efficacy of BCL-2 Inhibition in Colorectal Cancer Patient-Derived Xenograft Models

O’Farrell, Alice C.; Jarzabek, Monika A.; Lindner, Andreas U.; Carberry, Steven; Conroy, Emer; Miller, Ian S.; Connor, Kate; Shiels, Liam; Zanella, Eugenia R.; Lucantoni, Federico; Lafferty, Adam; White, Kieron; Villamandos, Mariangela Meyer Meyer; Gallagher, William M.; Keek, Simon; Sanduleanu, Sebastian; Lambin, Philippe; Woodruff, Henry C.; Bertotti, Andrea; Trusolino, Livio; Byrne, Annette T.; Prehn, Jochen H M

doi:10.3390/cancers12102978

Cited by 11 publications

(10 citation statements)

References 47 publications

(87 reference statements)

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“…We next showed that modelling the interactions of the BCL-2 protein family upstream of MOMP could also accurately predict sensitivity of medulloblastoma cells to cisplatin-induced apoptosis, with similar results previously observed in colorectal and breast cancer [ 27 , 48 ]. Anti-apoptotic BCL-2 proteins are commonly highly expressed in cancer and are readily targetable by a suite of BH3 mimetics [ 49 ].…”

Section: Discussionsupporting

confidence: 77%

The identification of BCL-XL and MCL-1 as key anti-apoptotic proteins in medulloblastoma that mediate distinct roles in chemotherapy resistance

Fitzgerald,

O’Halloran,

Kerrane

et al. 2023

Cell Death Dis

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Medulloblastoma is the most common malignant paediatric brain tumour, representing 20% of all paediatric intercranial tumours. Current aggressive treatment protocols and the use of radiation therapy in particular are associated with high levels of toxicity and significant adverse effects, and long-term sequelae can be severe. Therefore, improving chemotherapy efficacy could reduce the current reliance on radiation therapy. Here, we demonstrated that systems-level analysis of basal apoptosis protein expression and their signalling interactions can differentiate between medulloblastoma cell lines that undergo apoptosis in response to chemotherapy, and those that do not. Combining computational predictions with experimental BH3 profiling, we identified a therapeutically-exploitable dependence of medulloblastoma cells on BCL-XL, and experimentally validated that BCL-XL targeting, and not targeting of BCL-2 or MCL-1, can potentiate cisplatin-induced cytotoxicity in medulloblastoma cell lines with low sensitivity to cisplatin treatment. Finally, we identified MCL-1 as an anti-apoptotic mediator whose targeting is required for BCL-XL inhibitor-induced apoptosis. Collectively, our study identifies that BCL-XL and MCL-1 are the key anti-apoptotic proteins in medulloblastoma, which mediate distinct protective roles. While BCL-XL has a first-line role in protecting cells from apoptosis basally, MCL-1 represents a second line of defence that compensates for BCL-XL upon its inhibition. We provide rationale for the further evaluation of BCL-XL and MCL-1 inhibitors in the treatment of medulloblastoma, and together with current efforts to improve the cancer-specificity of BCL-2 family inhibitors, these novel treatment strategies have the potential to improve the future clinical management of medulloblastoma.

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Section: Discussionsupporting

confidence: 77%

The identification of BCL-XL and MCL-1 as key anti-apoptotic proteins in medulloblastoma that mediate distinct roles in chemotherapy resistance

Fitzgerald,

O’Halloran,

Kerrane

et al. 2023

Cell Death Dis

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“…APOPTO-CELL has also been extensively validated in-house using single cell imaging and population-based approaches in cervical, colorectal and glioblastoma cells (Murphy et al, 2013;Salvucci et al, 2019a;Salvucci et al, 2017;Schmid et al, 2012). Both models have also been shown to predict responses to apoptosis sensitizers in preclinical settings (Lucantoni et al, 2018;O'Farrell et al, 2020). Our study supports the previously developed concept that tumor cells are indeed 'primed' to undergo mitochondrial apoptosis (Llambi et al, 2011;Ni Chonghaile et al, 2011).…”

Section: Priming Of Cancer Cells and The Degree Of Inter-individual Hsupporting

confidence: 79%

An atlas of inter- and intra-tumor heterogeneity of apoptosis competency in colorectal cancer tissue at single cell resolution

Lindner

Salvucci

McDonough

et al. 2021

Preprint

Self Cite

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Cancer cells' ability to inhibit apoptosis is key to malignant transformation and limits response to therapy. Here, we performed multiplexed immunofluorescence analysis on tissue microarrays with 373 cores from 168 patients, segmentation of 2.4 million individual cells and quantification of 20 cell lineage and apoptosis proteins. Ordinary differential equation-based modelling of apoptosis sensitivity at single cell resolution was conducted and an atlas of inter- and intra-tumor heterogeneity in apoptosis susceptibility generated. We identified an enrichment for BCL2 in immune, and BAK, SMAC and XIAP in cancer cells. ODE-based modelling at single cell resolution identified an enhanced sensitivity of cancer cells to mitochondrial permeabilization and executioner caspase activation compared to immune and stromal cells, with significant inter- and intra-tumor heterogeneity. However, we did not find increased spatial heterogeneity of apoptosis signaling in cancer cells, suggesting that such heterogeneity is an intrinsic, non-genomic property not increased by the process of malignant transformation.

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“… 120 , 122 The implementing systems and molecular images were established to predict the efficacy of BCL‐2 inhibition in CRC based on a PDX cohort. 123 PP2AC expression accurately indicates therapeutic response to p38 inhibitor in CRC PDX. 124 APC and TP53 mutation as convenient biomarkers predicts the sensitivity to EGFR‐targeted therapies.…”

Section: The Application Of Pdx In Crc Researchmentioning

confidence: 99%

“…The expression of EGFR ligands is associated with the sensitivity of CRC to cetuximab, and the gene copy number of some oncogenes ( BRAF , EGFR , and KRAS ) is correlated positively with cetuximab and erlotinib sensitivity 120,122 . The implementing systems and molecular images were established to predict the efficacy of BCL‐2 inhibition in CRC based on a PDX cohort 123 . PP2AC expression accurately indicates therapeutic response to p38 inhibitor in CRC PDX 124 .…”

Section: The Application Of Pdx In Crc Researchmentioning

confidence: 99%

Patient‐derived xenograft model in colorectal cancer basic and translational research

Liu

Xin

Wang

2022

Anim Models and Exp Med

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Colorectal cancer (CRC), one of the most deadly cancers, is the fourth most common cause of cancer-related deaths. 1 Currently, surgery is the main treatment option for primary and metastatic CRC, and chemotherapy and targeted drugs are regularly used as adjuvant regimens. [2][3][4] Despite improvements in screening and treatment, the number of individuals newly diagnosed is increasing rapidly. Moreover, metastasis, recurrence, and chemoresistance are common in CRC patients after treatment, which leads to the dismal prognosis and high mortality of CRC patients. [5][6][7] These issues lead to the need for more advancements in CRC treatment. About 5% of CRCs are hereditary tumor syndromes, such as familial adenomatous polyposis (FAP) and Lynch syndrome. 8 Most of the CRCs are sporadic as the comprehensive effects of various factors, including somatic genetic alterations, chronic inflammation, lifestyle, and environmental stimuli. 9 These genetic and nongenetic risk factors work together to promote CRC development and progression. [10][11][12][13] To date, the mechanisms involved in the interactions of these factors driving CRC development and progression are

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Implementing Systems Modelling and Molecular Imaging to Predict the Efficacy of BCL-2 Inhibition in Colorectal Cancer Patient-Derived Xenograft Models

Cited by 11 publications

References 47 publications

The identification of BCL-XL and MCL-1 as key anti-apoptotic proteins in medulloblastoma that mediate distinct roles in chemotherapy resistance

The identification of BCL-XL and MCL-1 as key anti-apoptotic proteins in medulloblastoma that mediate distinct roles in chemotherapy resistance

An atlas of inter- and intra-tumor heterogeneity of apoptosis competency in colorectal cancer tissue at single cell resolution

Patient‐derived xenograft model in colorectal cancer basic and translational research

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