bims-instec 2022-07-17 papers

Nature. 2022 Jul 13.

Retrograde movements determine effective stem cell numbers in the intestine.

The morphology and functionality of the epithelial lining differ along the intestinal tract, but tissue renewal at all sites is driven by stem cells at the base of crypts1-3. Whether stem cell numbers and behaviour vary at different sites is unknown. Here we show using intravital microscopy that, despite similarities in the number and distribution of proliferative cells with an Lgr5 signature in mice, small intestinal crypts contain twice as many effective stem cells as large intestinal crypts. We find that, although passively displaced by a conveyor-belt-like upward movement, small intestinal cells positioned away from the crypt base can function as long-term effective stem cells owing to Wnt-dependent retrograde cellular movement. By contrast, the near absence of retrograde movement in the large intestine restricts cell repositioning, leading to a reduction in effective stem cell number. Moreover, after suppression of the retrograde movement in the small intestine, the number of effective stem cells is reduced, and the rate of monoclonal conversion of crypts is accelerated. Together, these results show that the number of effective stem cells is determined by active retrograde movement, revealing a new channel of stem cell regulation that can be experimentally and pharmacologically manipulated.

DOI: https://doi.org/10.1038/s41586-022-04962-0

Nat Cancer. 2022 Jul 13.

Colorectal cancer cells expressing Mex3a drive recurrence after chemotherapy.

DOI: https://doi.org/10.1038/s43018-022-00409-7

Nat Commun. 2022 Jul 09. 13(1): 3998

Acetyl-CoA-Carboxylase 1-mediated de novo fatty acid synthesis sustains Lgr5+ intestinal stem cell function.

Shuting Li, Chia-Wen Lu, Elia C Diem, Wang Li, Melanie Guderian, Marc Lindenberg, Friederike Kruse, Manuela Buettner, Stefan Floess, Markus R Winny, Robert Geffers, Hans-Hermann Richnow, Wolf-Rainer Abraham, Guntram A Grassl, Matthias Lochner.

Basic processes of the fatty acid metabolism have an important impact on the function of intestinal epithelial cells (IEC). However, while the role of cellular fatty acid oxidation is well appreciated, it is not clear how de novo fatty acid synthesis (FAS) influences the biology of IECs. We report here that interfering with de novo FAS by deletion of the enzyme Acetyl-CoA-Carboxylase (ACC)1 in IECs results in the loss of epithelial crypt structures and a specific decline in Lgr5+ intestinal epithelial stem cells (ISC). Mechanistically, ACC1-mediated de novo FAS supports the formation of intestinal organoids and the differentiation of complex crypt structures by sustaining the nuclear accumulation of PPARδ/β-catenin in ISCs. The dependency of ISCs on cellular de novo FAS is tuned by the availability of environmental lipids, as an excess delivery of external fatty acids is sufficient to rescue the defect in crypt formation. Finally, inhibition of ACC1 reduces the formation of tumors in colitis-associated colon cancer, together highlighting the importance of cellular lipogenesis for sustaining ISC function and providing a potential perspective to colon cancer therapy.

DOI: https://doi.org/10.1038/s41467-022-31725-2

Mol Cancer. 2022 Jul 14. 21(1): 144

Wnt signaling in colorectal cancer: pathogenic role and therapeutic target.

Hui Zhao, Tianqi Ming, Shun Tang, Shan Ren, Han Yang, Maolun Liu, Qiu Tao, Haibo Xu.

BACKGROUND: The Wnt signaling pathway is a complex network of protein interactions that functions most commonly in embryonic development and cancer, but is also involved in normal physiological processes in adults. The canonical Wnt signaling pathway regulates cell pluripotency and determines the differentiation fate of cells during development. The canonical Wnt signaling pathway (also known as the Wnt/β-catenin signaling pathway) is a recognized driver of colon cancer and one of the most representative signaling pathways. As a functional effector molecule of Wnt signaling, the modification and degradation of β-catenin are key events in the Wnt signaling pathway and the development and progression of colon cancer. Therefore, the Wnt signaling pathway plays an important role in the pathogenesis of diseases, especially the pathogenesis of colorectal cancer (CRC).
OBJECTIVE: Inhibit the Wnt signaling pathway to explore the therapeutic targets of colorectal cancer.
METHODS: Based on studying the Wnt pathway, master the biochemical processes related to the Wnt pathway, and analyze the relevant targets when drugs or inhibitors act on the Wnt pathway, to clarify the medication ideas of drugs or inhibitors for the treatment of diseases, especially colorectal cancer.
RESULTS: Wnt signaling pathways include: Wnt/β-catenin or canonical Wnt signaling pathway, planar cell polarity (Wnt-PCP) pathway and Wnt-Ca2+ signaling pathway. The Wnt signaling pathway is closely related to cancer cell proliferation, stemness, apoptosis, autophagy, metabolism, inflammation and immunization, microenvironment, resistance, ion channel, heterogeneity, EMT/migration/invasion/metastasis. Drugs/phytochemicals and molecular preparations for the Wnt pathway of CRC treatment have now been developed. Wnt inhibitors are also commonly used clinically for the treatment of CRC.
CONCLUSION: The development of drugs/phytochemicals and molecular inhibitors targeting the Wnt pathway can effectively treat colorectal cancer clinically.

Keywords: Biochemical process; Colorectal cancer; Drugs and inhibitors; Wnt pathway

DOI: https://doi.org/10.1186/s12943-022-01616-7

Ann Surg Oncol. 2022 Jul 13.

I've Got Bad News and Bad News: The Cost of Colorectal Cancer Care.

Alexander T Hawkins.

DOI: https://doi.org/10.1245/s10434-022-12172-1