Metastatic heterogeneity of the consensus molecular subtypes of colorectal cancer

Eide, Peter W.; Moosavi, Seyed H.; Eilertsen, Ina A.; Brunsell, Tuva H.; Langerud, Jonas; Berg, Kaja Christine Graue; Røsok, Bård I.; Bjørnbeth, Bjørn Atle; Nesbakken, Arild; Lothe, Ragnhild A.; Sveen, Anita

doi:10.1038/s41525-021-00223-7

Cited by 40 publications

(37 citation statements)

References 47 publications

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“…By adapting CMS classification to liver metastases and developing a new version of the R package CMScaller [ 38 ] (v2.0.1), we have shown that CMS has limited discriminatory power in CRLM [ 34 ]. Most metastatic lesions were classified into one of only two subtypes, based on epithelial-mesenchymal characteristics (Additional file 1 : Fig.…”

Section: Resultsmentioning

confidence: 99%

“…6 . LMS showed only a moderate level of classification concordance with CMS, despite comparison with CMS classes obtained from a tailored classification of resected CRLM tissue samples [ 34 ]. LMS provided stronger biological and prognostic discriminatory power than CMS in this setting.…”

Section: Discussionmentioning

confidence: 99%

“…One randomly selected CRLM sample from each patient in the in-house series was classified according to both the CMS and CRIS transcriptomic frameworks. For CMS classification, we have recently developed an algorithm tailored to CRLMs, taking into consideration the different distribution of clinicopathological factors and molecular subgroups in the primary and metastatic settings, as well as the different tumor microenvironment in the liver [ 34 ]. The tailored classifier is available in an updated version (v2.0.1) of the R package CMScaller ( https://github.com/Lothelab/CMScaller ).…”

Section: Methodsmentioning

confidence: 99%

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De novo transcriptomic subtyping of colorectal cancer liver metastases in the context of tumor heterogeneity

et al. 2021

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Background Gene expression-based subtyping has the potential to form a new paradigm for stratified treatment of colorectal cancer. However, current frameworks are based on the transcriptomic profiles of primary tumors, and metastatic heterogeneity is a challenge. Here we aimed to develop a de novo metastasis-oriented framework. Methods In total, 829 transcriptomic profiles from patients with colorectal cancer were analyzed, including primary tumors, liver metastases, and non-malignant liver samples. High-resolution microarray gene expression profiling was performed of 283 liver metastases from 171 patients treated by hepatic resection, including multiregional and/or multi-metastatic samples from each of 47 patients. A single randomly selected liver metastasis sample from each patient was used for unsupervised subtype discovery by nonnegative matrix factorization, and a random forest prediction model was trained to classify multi-metastatic samples, as well as liver metastases from two independent series of 308 additional patients. Results Initial comparisons with non-malignant liver samples and primary colorectal tumors showed a highly variable degree of influence from the liver microenvironment in metastases, which contributed to inter-metastatic transcriptomic heterogeneity, but did not define subtype distinctions. The de novo liver metastasis subtype (LMS) framework recapitulated the main distinction between epithelial-like and mesenchymal-like tumors, with a strong immune and stromal component only in the latter. We also identified biologically distinct epithelial-like subtypes originating from different progenitor cell types. LMS1 metastases had several transcriptomic features of cancer aggressiveness, including secretory progenitor cell origin, oncogenic addictions, and microsatellite instability in a microsatellite stable background, as well as frequent RAS/TP53 co-mutations. The poor-prognostic association of LMS1 metastases was independent of mutation status, clinicopathological variables, and current subtyping frameworks (consensus molecular subtypes and colorectal cancer intrinsic subtypes). LMS1 was also the least heterogeneous subtype in comparisons of multiple metastases per patient, and tumor heterogeneity did not confound the prognostic value of LMS1. Conclusions We report the first large study of multi-metastatic gene expression profiling of colorectal cancer. The new metastasis-oriented subtyping framework showed potential for clinically relevant transcriptomic classification in the context of metastatic heterogeneity, and an LMS1 mini-classifier was constructed to facilitate prognostic stratification and further clinical testing.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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De novo transcriptomic subtyping of colorectal cancer liver metastases in the context of tumor heterogeneity

et al. 2021

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“…Another layer of complexity could be represented by the presence of intrapatient tumor heterogeneity. 77 In this regard, an analysis of the transcriptomic profiles from 317 primary tumors and 295 liver metastases indicated that metastases were classified more frequently as CMS2 or CMS4 and less frequently as CMS1 or CMS3 compared with primary tumors. This heterogeneity may be a consequence of the complex tumor biology and of the interaction between cancer cells and the microenvironment.…”

Section: Consensus Molecular Subtype Classification Of Colorectal Cancermentioning

confidence: 96%

“…Of note, intratumor heterogeneity was correlated with reduced disease‐free survival and with worse OS. Another layer of complexity could be represented by the presence of intrapatient tumor heterogeneity 77 . In this regard, an analysis of the transcriptomic profiles from 317 primary tumors and 295 liver metastases indicated that metastases were classified more frequently as CMS2 or CMS4 and less frequently as CMS1 or CMS3 compared with primary tumors.…”

Section: Consensus Molecular Subtype Classification Of Colorectal Cancermentioning

confidence: 99%

Clinical management of metastatic colorectal cancer in the era of precision medicine

Ciardiello

Martini

et al. 2022

CA A Cancer J Clinicians

290

161

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Colorectal cancer (CRC) represents approximately 10% of all cancers and is the second most common cause of cancer deaths. Initial clinical presentation as metastatic CRC (mCRC) occurs in approximately 20% of patients. Moreover, up to 50% of patients with localized disease eventually develop metastases. Appropriate clinical management of these patients is still a challenging medical issue. Major efforts have been made to unveil the molecular landscape of mCRC. This has resulted in the identification of several druggable tumor molecular targets with the aim of developing personalized treatments for each patient. This review summarizes the improvements in the clinical management of patients with mCRC in the emerging era of precision medicine. In fact, molecular stratification, on which the current treatment algorithm for mCRC is based, although it does not completely represent the complexity of this disease, has been the first significant step toward clinically informative genetic profiling for implementing more effective therapeutic approaches. This has resulted in a clinically relevant increase in mCRC disease control and patient survival. The next steps in the clinical management of mCRC will be to integrate the comprehensive knowledge of tumor gene alterations, of tumor and microenvironment gene and protein expression profiling, of host immune competence as well as the application of the resulting dynamic changes to a precision medicine-based continuum of care for each patient. This approach could result in the identification of individual prognostic and predictive parameters, which could help the clinician in choosing the most appropriate therapeutic program(s) throughout the entire disease journey for each patient with mCRC.

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KLK10 promotes the progression of KRAS mutant colorectal cancer via PAR1‐PDK1‐AKT signaling pathway

Wu,

Yan

et al. 2023

Cell Biology International

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Kirsten rat sarcoma virus (KRAS) gene mutation is common in colorectal cancer (CRC) and is often predictive of treatment failure and poor prognosis. To understand the mechanism, we compared the transcriptome of CRC patients with wild‐type and mutant KRAS and found that KRAS mutation is associated with the overexpression of a secreted serine protease, kallikrein‐related peptidase 10 (KLK10). Moreover, using in vitro and in vivo models, we found that KLK10 overexpression favors the rapid growth and liver metastasis of KRAS mutant CRC and can also impair the efficacy of KRAS inhibitors, leading to drug resistance and poor survival. Further functional assays revealed that the oncogenic role of KLK10 is mediated by protease‐activated receptor 1 (PAR1). KLK10 cleaves and activates PAR1, which further activates 3‐phosphoinositide‐dependent kinase 1 (PDK1)‐AKT oncogenic pathway. Notably, suppressing PAR1‐PDK1‐AKT cascade via KLK10 knockdown can effectively inhibit CRC progression and improve the sensitivity to KRAS inhibitor, providing a promising therapeutic strategy. Taken together, our study showed that KLK10 promotes the progression of KRAS mutant CRC via activating PAR1‐PDK1‐AKT signaling pathway. These findings expanded our knowledge of CRC development, especially in the setting of KRAS mutation, and also provided novel targets for clinical intervention.

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Metastatic heterogeneity of the consensus molecular subtypes of colorectal cancer

Cited by 40 publications

References 47 publications

De novo transcriptomic subtyping of colorectal cancer liver metastases in the context of tumor heterogeneity

De novo transcriptomic subtyping of colorectal cancer liver metastases in the context of tumor heterogeneity

Clinical management of metastatic colorectal cancer in the era of precision medicine

KLK10 promotes the progression of KRAS mutant colorectal cancer via PAR1‐PDK1‐AKT signaling pathway

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