Exploring and modelling colon cancer inter-tumour heterogeneity: opportunities and challenges

Self Cite

Colorectal cancer (CRC) is a heterogeneous disease that can currently be subdivided into four distinct consensus molecular subtypes (CMS) based on gene expression profiling. The CMS4 subtype is marked by high expression of mesenchymal genes and is associated with a worse overall prognosis compared to other CMSs. Importantly, this subtype responds poorly to the standard therapies currently used to treat CRC. We set out to explore what regulatory signalling networks underlie the CMS4 phenotype of cancer cells, specifically, by analysing which kinases were more highly expressed in this subtype compared to others. We found AKT3 to be expressed in the cancer cell epithelium of CRC specimens, patient derived xenograft (PDX) models and in (primary) cell cultures representing CMS4. Importantly, chemical inhibition or knockout of this gene hampers outgrowth of this subtype, as AKT3 controls expression of the cell cycle regulator p27KIP1. Furthermore, high AKT3 expression was associated with high expression of epithelial-mesenchymal transition (EMT) genes, and this observation could be expanded to cell lines representing other carcinoma types. More importantly, this association allowed for the identification of CRC patients with a high propensity to metastasise and an associated poor prognosis. High AKT3 expression in the tumour epithelial compartment may thus be used as a surrogate marker for EMT and may allow for a selection of CRC patients that could benefit from AKT3-targeted therapy.

Section: Introductionmentioning

confidence: 99%

AKT3 Expression in Mesenchymal Colorectal Cancer Cells Drives Growth and Is Associated with Epithelial-Mesenchymal Transition

Buikhuisen

Barila

Torang

et al. 2021

Self Cite

“…These two categories are good candidates to explain interval cancers for several reasons. First, both types are proposed to arise from serrated lesions [ 98 ]. However, CMS1 tumors mainly comprise MSI tumors enriched in the interval tumor setting [ 77 ].…”

Section: Discussionmentioning

confidence: 99%

Future Prospects of Colorectal Cancer Screening: Characterizing Interval Cancers

Ibáñez‐Sanz

Sanz‐Pamplona

Garcia

2021

Tumors that are not detected by screening tests are known as interval cancers and are diagnosed clinically after a negative result in the screening episode but before the next screening invitation. Clinical characteristics associated with interval colorectal cancers have been studied, but few molecular data are available that describe interval colorectal cancers. A better understanding of the clinical and biological characteristics associated with interval colorectal cancer may provide new insights into how to prevent this disease more effectively. This review aimed to summarize the current literature concerning interval colorectal cancer and its epidemiological, clinical, and molecular features.

“…While the SW480-SW620-LiM2 same-patient-derived model is uniquely suited to characterise the metabolic reprogramming underlying mCRC, colorectal cancer is a heterogeneous disease and the findings and vulnerabilities here reported might only apply to a subset of colorectal cancer tumours. Future works should explore the genetic histopathological and metabolic markers that can identify the CRC patients that could benefit the most by the putative drug or drug combinations here identified, thus paving the way for personalized therapies against mCRC [ 67 ]. Remarkably, methotrexate [ 37 ] and sulfasalazine [ 29 ] are already approved for clinical use and could be easily repositioned against susceptible subtypes of mCRC.…”

Section: Discussionmentioning

confidence: 99%

Cysteine and Folate Metabolism Are Targetable Vulnerabilities of Metastatic Colorectal Cancer

Tarragó-Celada

Foguet

Tarrado‐Castellarnau

et al. 2021

With most cancer-related deaths resulting from metastasis, the development of new therapeutic approaches against metastatic colorectal cancer (mCRC) is essential to increasing patient survival. The metabolic adaptations that support mCRC remain undefined and their elucidation is crucial to identify potential therapeutic targets. Here, we employed a strategy for the rational identification of targetable metabolic vulnerabilities. This strategy involved first a thorough metabolic characterisation of same-patient-derived cell lines from primary colon adenocarcinoma (SW480), its lymph node metastasis (SW620) and a liver metastatic derivative (SW620-LiM2), and second, using a novel multi-omics integration workflow, identification of metabolic vulnerabilities specific to the metastatic cell lines. We discovered that the metastatic cell lines are selectively vulnerable to the inhibition of cystine import and folate metabolism, two key pathways in redox homeostasis. Specifically, we identified the system xCT and MTHFD1 genes as potential therapeutic targets, both individually and combined, for combating mCRC.