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Colorectal Cancer Is Borrowing Blueprints from Intestinal Ontogenesis

SIMPLE SUMMARY: A critical relationship was recently identified between fetal gene expression and aberrant stem cell properties in precancerous intestinal lesions. The reported findings show that developmental reprogramming, or the reactivation of genes expressed at the embryonic stage, precedes the...

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Detalles Bibliográficos
Autores principales: Billingsley, Jacob L., Yevdokimova, Veronika, Ayoub, Kristina, Benoit, Yannick D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10604965/
https://www.ncbi.nlm.nih.gov/pubmed/37894295
http://dx.doi.org/10.3390/cancers15204928
Descripción
Sumario:SIMPLE SUMMARY: A critical relationship was recently identified between fetal gene expression and aberrant stem cell properties in precancerous intestinal lesions. The reported findings show that developmental reprogramming, or the reactivation of genes expressed at the embryonic stage, precedes the initiation of colorectal cancer. Hence, harnessing such gene networks in future drug discovery endeavors has been proposed to suppress the initiation of colorectal tumors. In a recent drug discovery-oriented study, it was determined that stem-like functions in cancer, such as tumor initiation and self-renewal, can be suppressed by targeting gene signatures specific to germ layer commitment. Specifically, drugs with the capacity to induce endoderm, ectoderm, or mesoderm differentiation in human embryonic stem cells were also effective at suppressing the initiation of tumors from the same developmental origins. Altogether, the two cutting-edge studies showcased in this article reinforce the concept of oncogenic reprogramming as an early step in tumorigenesis. These studies are paving the way for new drug discovery efforts focused on suppressing fetal gene networks and fostering the differentiation of stem-like cells in colorectal cancer. ABSTRACT: Colorectal tumors are heterogenous cellular systems harboring small populations of self-renewing and highly tumorigenic cancer stem cells (CSCs). Understanding the mechanisms fundamental to the emergence of CSCs and colorectal tumor initiation is crucial for developing effective therapeutic strategies. Two recent studies have highlighted the importance of developmental gene expression programs as potential therapeutic targets to suppress pro-oncogenic stem cell populations in the colonic epithelium. Specifically, a subset of aberrant stem cells was identified in preneoplastic intestinal lesions sharing significant transcriptional similarities with fetal gut development. In such aberrant stem cells, Sox9 was shown as a cornerstone for altered cell plasticity, the maintenance of premalignant stemness, and subsequent colorectal tumor initiation. Independently, chemical genomics was used to identify FDA-approved drugs capable of suppressing neoplastic self-renewal based on the ontogenetic root of a target tumor and transcriptional programs embedded in pluripotency. Here, we discuss the joint conclusions from these two approaches, underscoring the importance of developmental networks in CSCs as a novel paradigm for identifying therapeutics targeting colorectal cancer stemness.