bims-instec 2023-04-23 papers

Cell Mol Gastroenterol Hepatol. 2023 Apr 19. pii: S2352-345X(23)00055-3. [Epub ahead of print]

Cancer-associated fibroblasts are key determinants of cancer cell invasion in the earliest stage of colorectal cancer.

Hao Dang, Tom J Harryvan, Chen-Yi Liao, Erik H J Danen, Vienna N L N Spalburg, Szymon M Kielbasa, Hailiang Mei, Jelle J Goeman, Eveline S de Jonge-Muller, Stefanus G T Janson, Johan J van der Reijden, Stijn Crobach, James C H Hardwick, Jurjen J Boonstra, Noel F C C de Miranda, Lukas J A C Hawinkels.

BACKGROUND AND AIMS: Improving clinical management of early-stage colorectal cancers (T1CRCs) requires a better understanding of their underlying biology. Accumulating evidence shows that cancer-associated fibroblasts (CAFs) are important determinants of tumor progression in advanced colorectal cancer (CRC), but their role in the initial stages of CRC tumorigenesis is unknown. Therefore, we investigated the contribution of T1CAFs to early CRC progression.
METHODS: Primary T1CAFs and patient-matched normal fibroblasts (NFs) were isolated from endoscopic biopsies of histologically confirmed T1CRCs and normal mucosa, respectively. The impact of T1CAFs and NFs on tumor behavior was studied using 3D co-culture systems with primary T1CRC organoids and extracellular matrix (ECM) remodeling assays. Whole transcriptome sequencing and gene silencing were used to pinpoint mediators of T1CAF functions.
RESULTS: In 3D multicellular cultures, matrix invasion of T1CRC organoids was induced by T1CAFs, but not by matched NFs. Enhanced T1CRC invasion was accompanied by T1CAF-induced ECM remodeling and upregulation of CD44 in epithelial cells. RNA sequencing of 10 NF-T1CAF pairs revealed 404 differentially expressed genes, with significant enrichment for ECM-related pathways in T1CAFs. Cathepsin H, a cysteine-type protease that was specifically upregulated in T1CAFs but not in fibroblasts from pre-malignant lesions or advanced CRCs, was identified as a key factor driving matrix remodeling by T1CAFs. Finally, we showed high abundance of Cathepsin H-expressing T1CAFs at the invasive front of primary T1CRC sections.
CONCLUSION: Already in the earliest stage of CRC, cancer cell invasion is promoted by CAFs via direct interactions with epithelial cancer cells and stage-specific, Cathepsin H-dependent ECM remodeling.

Keywords: T1 colorectal cancer; cancer-associated fibroblast; tumor microenvironment

DOI: https://doi.org/10.1016/j.jcmgh.2023.04.004

Development. 2023 Apr 18. pii: dev.201416. [Epub ahead of print]

Transplanted human intestinal organoids: A resource for modeling human intestinal development.

Akaljot Singh, Holly M Poling, Praneet Chaturvedi, Konrad Thorner, Nambirajan Sundaram, Daniel O Kechele, Charlie J Childs, Heather A McCauley, Garrett W Fisher, Nicole E Brown, Jason R Spence, James M Wells, Michael A Helmrath.

The in vitro differentiation of pluripotent stem cells into human intestinal organoids (HIOs) has served as a powerful means for creating complex three-dimensional intestinal structures. Due to their diverse cell populations, transplantation into an animal host is supported with this system and allows for the temporal formation of fully laminated structures, including crypt-villus architecture and smooth muscle layers which resemble native human intestine. While the endpoint of HIO engraftment has been well described, here, we aim to elucidate the developmental stages of HIO engraftment and establish if it parallels fetal human intestinal development. We analyzed a timecourse of transplanted HIOs histologically at two, four, six and eight weeks post-transplantation and demonstrated that HIO maturation closely resembles key stages of fetal human intestinal development. We also utilized single nuclear RNA sequencing to determine and track the emergence of distinct cell populations over time and validated our transcriptomic data through in situ protein expression. These observations suggest that transplanted HIOs indeed recapitulate early intestinal development, solidifying their value as a human intestinal model system.

Keywords: Development; Fetal; Human; Intestine; Organoid

DOI: https://doi.org/10.1242/dev.201416

Cell Rep. 2023 Apr 21. pii: S2211-1247(23)00434-5. [Epub ahead of print]42(5): 112423

UTP18-mediated p21 mRNA instability drives adenoma-carcinoma progression in colorectal cancer.

Meng Pan, Tixian Xiao, Lai Xu, Yong Xie, Wei Ge.

Colorectal cancer (CRC) often develops slowly from adenoma, but the underlying mechanism remains unclear, hampering the prevention or treatment of colorectal adenoma-carcinoma progression. In this study, we use in-depth quantitative proteomics combined with survival analysis, revealing that the ribosome protein U3 small nucleolar RNA-associated protein 18 homolog (UTP18) is consistently upregulated in the progression of colorectal adenoma to carcinoma and is associated with adenoma recurrence, effective serodiagnosis, and poor prognosis of CRC. Furthermore, deSUMOylation induces the nucleocytoplasmic transport of UTP18, driving cell-cycle progression and tumorigenesis via mediation of the instability of p21 mRNA. In addition, the growth and ribosome biogenesis of adenoma organoids is found to be promoted by overexpression of UTP18. Thus, UTP18 contributes to multiple roles in adenogenesis and malignancy of CRC, suggesting that it could be a potential biomarker and drug target for colorectal adenoma and cancer.

Keywords: CP: Cancer; UTP18; adenoma-carcinoma progression; colorectal cancer; nuclear export; p21

DOI: https://doi.org/10.1016/j.celrep.2023.112423

Nat Commun. 2023 Apr 21. 14(1): 2307

The small and large intestine contain related mesenchymal subsets that derive from embryonic Gli1+ precursors.

Simone Isling Pærregaard, Line Wulff, Sophie Schussek, Kristoffer Niss, Urs Mörbe, Johan Jendholm, Kerstin Wendland, Anna T Andrusaite, Kevin F Brulois, Robert J B Nibbs, Katarzyna Sitnik, Allan McI Mowat, Eugene C Butcher, Søren Brunak, William W Agace.

The intestinal lamina propria contains a diverse network of fibroblasts that provide key support functions to cells within their local environment. Despite this, our understanding of the diversity, location and ontogeny of fibroblasts within and along the length of the intestine remains incomplete. Here we show that the small and large intestinal lamina propria contain similar fibroblast subsets that locate in specific anatomical niches. Nevertheless, we find that the transcriptional profile of similar fibroblast subsets differs markedly between the small intestine and colon suggesting region specific functions. We perform in vivo transplantation and lineage-tracing experiments to demonstrate that adult intestinal fibroblast subsets, smooth muscle cells and pericytes derive from Gli1-expressing precursors present in embryonic day 12.5 intestine. Trajectory analysis of single cell RNA-seq datasets of E12.5 and adult mesenchymal cells suggest that adult smooth muscle cells and fibroblasts derive from distinct embryonic intermediates and that adult fibroblast subsets develop in a linear trajectory from CD81+ fibroblasts. Finally, we provide evidence that colonic subepithelial PDGFRαhi fibroblasts comprise several functionally distinct populations that originate from an Fgfr2-expressing fibroblast intermediate. Our results provide insights into intestinal stromal cell diversity, location, function, and ontogeny, with implications for intestinal development and homeostasis.

DOI: https://doi.org/10.1038/s41467-023-37952-5