At numerous locations of the body, transition zones are localized at the crossroad between two types of epithelium and are frequently associated with neoplasia involving both type of tissues. These transition zones contain cells expressing markers of adult stem cells that can be the target of early transformation. The mere fact that transition zone cells can merge different architecture with separate functions implies for a unique plasticity that these cells must display in steady state. However, their roles during tissue regeneration in normal and injured state remain unknown. Here, by using in vivo lineage tracing, single-cell transcriptomics, computational modeling and a three-dimensional organoid culture system of transition zone cells, we identify a population of Krt17+ basal cells with multipotent properties at the squamo-columnar anorectal junction that maintain a squamous epithelium during normal homeostasis and can participate in the repair of a glandular epithelium following tissue injury.

Circulating tumor cells (CTCs) are promising diagnostic and prognostic tools for clinical use. In several cancers, including colorectal and breast, the CTC load has been associated with a therapeutic response as well as progression-free and overall survival. However, counting and isolating CTCs remains sub-optimal because they are currently largely identified by epithelial markers such as EpCAM. New, complementary CTC surface markers are therefore urgently needed. We previously demonstrated that a splice variant of CD44, CD44 variable alternative exon 6 (CD44v6), is highly and specifically expressed by CTC cell lines derived from blood samples in colorectal cancer (CRC) patients. Two different approaches—immune detection coupled with magnetic beads and fluorescence-activated cell sorting—were optimized to purify CTCs from patient blood samples based on high expressions of CD44v6. We revealed the potential of the CD44v6 as a complementary marker to EpCAM to detect and purify CTCs in colorectal cancer blood samples. Furthermore, this marker is not restricted to colorectal cancer since CD44v6 is also expressed on CTCs from breast cancer patients. Overall, these results strongly suggest that CD44v6 could be useful to enumerate and purify CTCs from cancers of different origins, paving the way to more efficacious combined markers that encompass CTC heterogeneity.

Progastrin is an unprocessed soluble peptide precursor with a well-described tumor-promoting role in colorectal cancer. It is expressed at small levels in the healthy intestinal mucosa, and its expression is enhanced at early stages of intestinal tumor development, with high levels of this peptide in hyperplastic intestinal polyps being associated with poor neoplasm-free survival in patients. Yet, the precise type of progastrin-producing cells in the healthy intestinal mucosa and in early adenomas remains unclear. Here, we used a combination of immunostaining, RNAscope labelling and retrospective analysis of single cell RNAseq results to demonstrate that progastrin is produced within intestinal crypts by a subset of Bmi1+/Prox1+/LGR5low endocrine cells, previously shown to act as replacement stem cells in case of mucosal injury. In contrast, our findings indicate that intestinal stem cells, specified by expression of the Wnt signaling target LGR5, become the main source of progastrin production in early mouse and human intestinal adenomas. Collectively our results suggest that the previously identified feed-forward mechanisms between progastrin and Wnt signaling is a hallmark of early neoplastic transformation in mouse and human colonic adenomas.

Médecine/sciences (M/S), revue internationale dans le domaine de la recherche biologique, médicale et en santé

Étude de la dissémination précoce dans le cancer colorectal: La majorité des décès par cancer est attribuée aux métastases mais les mécanismes impliqués demeurent peu décrits. La littérature sur le sujet se concentre principalement sur les étapes tardives de la tumorigénèse, ignorant la dissémination précoce, en particulier dans le cancer colorectal (CCR). Par conséquent, notre étude a pour objectif d'étudier l'existence d'une dissémination tumorale précoce dans le cancer colorectal et le rôle des cellules disséminées dans les organes distants. Nous avons généré un modèle de souris inductible qui nous permet de suivre la dissémination à des stades très précoces du développement tumoral. En utilisant ce modèle, nous avons pu détecter la présence rare mais évidente de cellules disséminées intestinales dans le foie, le principal organe susceptible d'être colonisé par des cellules métastatiques du cancer colorectal. En parallèle, un niveau plasmatique élevé de TIMP1, principalement, ainsi que de TNF-α, SDF-1, CXCL2 et M-CSF a été détecté, un profil qui a également été observé dans le sang de patients avec des polypes intestinaux bénins. Dans le foie, la présence de cellules disséminées précoces, en synergie avec les facteurs systémiques détectés, était accompagnée d'une infiltration importante de cellules myéloïdes, y compris de macrophages et de neutrophiles. Cet enrichissement a un impact significatif sur la colonisation métastatique, en favorisant l'accueil des futures vagues de cellules métastatiques. En conclusion, ce projet valide fonctionnellement pour la première fois l'existence d'une dissémination précoce dans le CCR et propose un rôle causal de ces cellules dans une préparation précoce de la niche pré-métastatique.