PubMed · 1590327
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R L Grotz, J H Pemberton. 1992. Second look surgery--a shell game?. https://pubmed.ncbi.nlm.nih.gov/1590327/
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In their recent article, Moore and colleagues demonstrate that, upon KRAS hyperactivation, colorectal cancer growth is driven by a reprogramming of Lgr5+ intestinal stem cell (ISC) progeny towards the acquisition of a regenerative phenotype. They find that this phenotype is regulated by a balance between WNT-related ISCs and MAPK-related regenerative and proliferative transcriptional programs. By targeting both pathways, they are able to suppress this dynamic plasticity and achieve tumor regression in cell line and mouse models. The antagonistic relationship between these central pathways defined here provides key insights into genomic patterns of colorectal cancer and targeted therapy strategies.
Mutational signature analysis has enhanced our understanding of mutagenic processes. In a recent study, we analyzed 802 microsatellite-stable colorectal cancers (CRC) and identified a de novo signature, SBS_D, which was decomposed into SBS18. Here, we re-evaluate this decomposition and provide evidence that SBS_D represents a distinct mutational process from SBS18. Through an analysis of 2,616 CRCs across three independent cohorts, we demonstrate that SBS_D is consistently present, suggesting this signature may have been previously overlooked. We illustrate that the pattern of SBS_D better aligns with signatures associated with deficiencies in DNA repair, despite evidence that SBS_D is not driven by canonical defects in these DNA repair pathways. Overall, this study identifies a previously unrecognized mutational signature in DNA repair-proficient CRC and proposes that its etiology may be linked to DNA repair infidelity emerging late in tumor development. SBS_D has been submitted to the COSMIC database and provisionally designated as SBS111.
In this issue of Cancer Cell, Liu et al. apply spatial multi-omics to map colorectal cancer micrometastases across primary tumors and matched liver and lung metastases, revealing liver micrometastases as an early evolved, stem-like, immune-suppressed residual disease state linked to a six-gene recurrence signature.