Loss of cadherin 17 downregulates LGR5 expression, stem cell properties and drug resistance in metastatic colorectal cancer cells

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Abstract
Cadherin 17 (CDH17) plays a crucial role in the metastatic progression of colorectal cancer (CRC) through its interaction with α2β1 integrin and desmocollin 1. To further elucidate the molecular mechanisms involving CDH17 functions in CRC, we examined global expression alterations following CDH17 silencing in various metastatic cell lines. Loss of CDH17 resulted in a marked down-regulation of the intestinal cancer stem cell (CSC) marker LGR5, leading to the inhibition of Wnt/β-catenin signaling, suppression of pluripotency genes such as MYC, and a subsequent reduction in stemness properties. Treatment with CDH17/integrin blocking antibodies produced similar effects, decreasing both, LGR5 expression and Wnt signaling. CDH17 silencing also down-regulated various transporters associated with drug-resistance, including the glutamine-transporter SLC38A5. Consequently, the loss of CDH17 increased sensitivity to 5-FU, irinotecan, oxidative stress and anoikis in CRC cells. Notably, SLC38A5 silencing was necessary for CDH17-driven effects on drug resistance and survival. Pharmacological inhibition of SLC38A5 with amiloride, significantly increased cell sensitivity to 5-FU and irinotecan, and improved mouse survival in metastasis models. In conclusion, CDH17 plays a crucial role in maintaining colorectal cancer cell stemness and chemoresistance via LGR5/Wnt/MYC signaling and SLC38A5 expression. These findings underscore the therapeutic potential of CDH17 targeting in metastatic CRC, and support the use of amiloride for inhibiting liver metastasis.

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