Multi-biotics have shown promise in enhancing the sensitivity of metabolic dysfunction-associated steatohepatitis (MASH)-related hepatocellular carcinoma (HCC) organoids to Lenvatinib, a first-line treatment for HCC, according to a new study published in Scientific Reports. The research, which focused on establishing and characterizing mouse MASH-HCC organoids, suggests that multi-biotics may modulate cellular pathways affecting drug sensitivity.
The researchers developed MASH-HCC mouse models by feeding mice a choline-deficient L-amino acid-defined high-fat diet (CDAHFD) for 30 weeks, confirming the induction of MASH-related HCC. They then evaluated the effects of multi-biotics on MASH-HCC organoids, specifically in relation to their response to Lenvatinib.
Multi-biotics and Lenvatinib Response
While multi-biotics did not significantly reduce tumor burden in the MASH-HCC mouse model, they enhanced the response of HCC organoids to Lenvatinib. This suggests that multi-biotics may modulate pathways that improve sensitivity to Lenvatinib, potentially delaying or reducing the onset of drug resistance. RNA-sequencing identified 30 differentially expressed genes (DEGs) between the control and multi-biotics groups, with several implicated in metabolic regulation and cancer biology.
"We observed that multi-biotics enhanced the initial response of MASH-HCC organoids to Lenvatinib compared to the control group," the researchers noted. "This suggests that multi-biotics may modulate pathways that improve sensitivity to Lenvatinib, which could potentially delay or reduce the onset of drug resistance."
Transcriptomic Analysis
Among the identified genes, Slc5a8, which is significantly upregulated, has been shown to act as a tumor suppressor by facilitating the transport of short-chain fatty acids. Vnn3 and Mcm5 are associated with cell proliferation and inflammatory responses, suggesting that the differences between the control and multi-biotics groups may be linked to alterations in metabolic and immune-related pathways. Enriched pathways, such as adipogenesis and IL-2-STAT5 signaling, may play a crucial role in modulating the response of organoids to Lenvatinib by influencing tumor cell growth and survival under treatment conditions.
Resistance Mechanisms
The study also identified pathways enriched in Lenvatinib-resistant organoids, including inflammatory response, TNF-α signaling via NF-κB, upregulated KRAS signaling, and epithelial-mesenchymal transition (EMT). Activation of the NF-κB signaling pathway has been widely reported to contribute to resistance by promoting survival and proliferation in various cancer types, including HCC. EMT is a key process driving metastasis and resistance to targeted therapies, including Lenvatinib.
Potential Therapeutic Targets
Several genes, including Itga7, Col7a1, and Slpi, were identified as potential therapeutic targets. Itga7 (integrin alpha-7), downregulated in the Lenvatinib-resistant group, has been linked to adipogenesis and cellular adhesion processes. Col7a1 (collagen type VII alpha 1), upregulated in the resistant group, plays a key role in the EMT process. Slpi (secretory leukocyte protease inhibitor), associated with KRAS signaling, was also upregulated in the Lenvatinib-resistant group.
Implications and Future Directions
This study provides novel insights into the effects of multi-biotics on MASH-related HCC and drug resistance, specifically Lenvatinib resistance, using mouse-derived organoid models. The establishment of Lenvatinib-resistant MASH-related HCC organoids and the identification of transcriptomic changes associated with resistance are significant contributions. The enhanced response of MASH-HCC organoids to Lenvatinib in the presence of multi-biotics suggests that similar approaches could be applied to other therapeutic agents, potentially broadening the scope of treatment options for patients with drug-resistant HCC.
"The use of organoid models in this study also highlights the potential of patient-derived organoids as a personalized medicine tool," the researchers concluded. "By generating organoids from individual patients with MASH-related HCC, it may be possible to predict responses to multi-biotics and other interventions, thus tailoring treatment strategies to individual patients’ unique genetic and molecular profiles."
