An epigenetic signature of advanced colorectal cancer metastasis

Rodger, Euan J.; Gimenez, Grégory; Ajithkumar, Priyadarshana; Stockwell, Peter A.; Almomani, Suzan N.; Bowden, Sarah A.; Leichter, Anna L.; Ahn, Antonio; McCall, John; Schmeier, Sebastian; Frizelle, Frank; Eccles, Michael R.; Purcell, Rachel; Chatterjee, Aniruddha

doi:10.1016/j.isci.2023.106986

Cited by 15 publications

(14 citation statements)

References 80 publications

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“…Differences in the response of ptCRC11 and mCRC11 to epigenetic targeted therapies, suggested that epigenomic variations between primary tumours and metastases may had contributed to the differential sensitivity profiles of primary and metastatic tumours. Correspondingly, a recent study identified distinctions in the DNA methylation patterns between primary tumours and liver metastases of metCRC patients, resulting in functional changes in the transcriptome of both lesions 21 . The results thus collectively demonstrate that the FPO approach, when applied concurrently to both primary tumours and metastases, adds a new dimension to precision and personalised oncology for metCRC, complementing current genomics-driven systemic treatment of metCRC.…”

Section: Discussionmentioning

confidence: 91%

“…Recent epigenomic profiling, however, revealed distinct methylation patterns associated with functional regulatory changes between metCRC primary tumour and metastases 21 . Coupled with the heterogeneous nature of tumour cell evolution during metastasis dissemination, we postulate that primary and metastatic lesions may respond differentially to the same epigenetic combination therapy 22 , 23 .…”

Section: Introductionmentioning

confidence: 99%

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A functional personalised oncology approach against metastatic colorectal cancer in matched patient derived organoids

Thng,

Hooi,

Siew

et al. 2024

npj Precis. Onc.

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Globally, colorectal cancer (CRC) is the third most frequently occurring cancer. Progression on to an advanced metastatic malignancy (metCRC) is often indicative of poor prognosis, as the 5-year survival rates of patients decline rapidly. Despite the availability of many systemic therapies for the management of metCRC, the long-term efficacies of these regimens are often hindered by the emergence of treatment resistance due to intratumoral and intertumoral heterogeneity. Furthermore, not all systemic therapies have associated biomarkers that can accurately predict patient responses. Hence, a functional personalised oncology (FPO) approach can enable the identification of patient-specific combinatorial vulnerabilities and synergistic combinations as effective treatment strategies. To this end, we established a panel of CRC patient-derived organoids (PDOs) as clinically relevant biological systems, of which three pairs of matched metCRC PDOs were derived from the primary sites (ptCRC) and metastatic lesions (mCRC). Histological and genomic characterisation of these PDOs demonstrated the preservation of histopathological and genetic features found in the parental tumours. Subsequent application of the phenotypic-analytical drug combination interrogation platform, Quadratic Phenotypic Optimisation Platform, in these pairs of PDOs identified patient-specific drug sensitivity profiles to epigenetic-based combination therapies. Most notably, matched PDOs from one patient exhibited differential sensitivity patterns to the rationally designed drug combinations despite being genetically similar. These findings collectively highlight the limitations of current genomic-driven precision medicine in guiding treatment strategies for metCRC patients. Instead, it suggests that epigenomic profiling and application of FPO could complement the identification of novel combinatorial vulnerabilities to target synchronous ptCRC and mCRC.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

A functional personalised oncology approach against metastatic colorectal cancer in matched patient derived organoids

Thng,

Hooi,

Siew

et al. 2024

npj Precis. Onc.

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show abstract

“…Wu et al and Chen et al constructed methylation models to classify patients with potential lymph node metastasis in gastric cancer [122] , [123] . Other studies also revealed different methylation signatures associated with distant metastasis in cancers including the prostate, colon, and lung [124] , [125] , [126] , [127] .…”

Section: Dna Methylation Signature In Cancermentioning

confidence: 95%

A review on trends in development and translation of omics signatures in cancer

Ma,

Tang,

Kwok

et al. 2024

Computational and Structural Biotechnology Journal

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“…We have used the protocol described here for several human cancers 1 , 2 , 3 , 4 , 5 and have also successfully used it for DNA methylation analysis of other human diseases, 6 , 7 , 8 normal human cells, 9 , 10 mice, 11 zebrafish, 12 , 13 , 14 , 15 and mangrove rivulus. 16 …”

Section: Before You Beginmentioning

confidence: 99%

Protocol for generating high-quality genome-scale DNA methylation sequencing data from human cancer biospecimens

Rodger,

Stockwell,

Almomani

et al. 2023

STAR Protocols

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An epigenetic signature of advanced colorectal cancer metastasis

Cited by 15 publications

References 80 publications

A functional personalised oncology approach against metastatic colorectal cancer in matched patient derived organoids

A functional personalised oncology approach against metastatic colorectal cancer in matched patient derived organoids

A review on trends in development and translation of omics signatures in cancer

Protocol for generating high-quality genome-scale DNA methylation sequencing data from human cancer biospecimens

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