Abstract
Emerging evidence suggests that cancer stemness plays a crucial role in tumor progression, metastasis, and chemoresistance. Upon exposure to internal or external stress, ribosomes stand sentinel and facilitate diverse biological processes, including oncological responses. In the present study, ribosome-inactivating stress (RIS) was evaluated for its modulation of cancer cell stemness as a pivotal factor of tumor cell reprogramming. Based on the concept of stress-responsive cancer cell stemness, we addressed human intestinal cancer cell line-based off-the-shelf spheroid cultures. Intestinal cancer cell line-based spheroids exhibited heightened levels of CD44+CD133+ cancer stemness, which was improved by chemical-induced RIS. Further evaluations revealed the potential of these stress-imprinted spheroids as a platform for chemoresistance screening. Compared to adherent cells, stemness-improved spheroid cultures displayed reduced apoptosis in response to 5-fluorouracil (5-FU), a frontline chemotherapeutic agent against colorectal cancer. Moreover, serial subcultures with repeated RIS exposure maintained and even enhanced cancer stemness and chemoresistance patterns. In particular, isolated CD44+CD133+ cancer stem cells exhibited higher chemoresistance compared to unsorted cells. To elucidate the mechanisms underlying RIS-induced stemness, RNA-seq analysis identified Wnt signaling pathways and stemness-associated signals as notable features in spheroids exposed to RIS. Loss-of-function studies targeting connective tissue growth factor (CTGF), a negative regulator of Wnt signaling, revealed that CTGF-deficient spheroids exhibited improved cancer stemness and resistance to 5-FU, with RIS further enhancing these effects. In conclusion, this proof-of-concept study demonstrates the feasibility of leveraging stress-responsive cancer stemness for the development of spheroid-based platforms for chemoresistance evaluation and elucidation of pathophysiological processes of colorectal tumorigenesis under environmental stress.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
