Targeting the mechano-microenvironment and liver cancer stem cells:a promising therapeutic strategy for liver cancer

Over the past 2 decades,cancer stem cells(CSCs)have been identified as the root cause of cancer occurrence,progression,chemoradioresistance,recurrence,and metastasis.Targeting CSCs is a novel therapeutic strategy for cancer management and treatment.Liver cancer(LC)is a malignant disease that can endanger human health.Studies are increasingly suggesting that changes in the liver mechanical microenvironment are a primary driver triggering the occurrence and development of liver cancer.In this review,we summarize current understanding of the roles of the liver mechano-microenvironment and liver cancer stem cells(LCSCs)in liver cancer progression.We also discuss the relationship between the mechanical heterogeneity of liver cancer tissues and LCSC recruitment and metastasis.Finally,we highlight potential mechanosensitive molecules in LCSCs and mechanotherapy in liver cancer.Understanding the roles and regulatory mechanisms of the mechano-microenvironment and LCSCs may provide fundamental insights into liver cancer progression and aid in further development of novel therapeutic strategies.

Biomaterial-based platforms for cancer stem cell enrichment and study

Cancer stem cells(CSCs)are a relatively rare subpopulation of tumor cell with self-renewal and tumorigenesis capabilities.CSCs are associated with cancer recurrence,progression,and chemoradiotherapy resistance.Establishing a reliable platform for CSC enrichment and study is a prerequisite for understanding the characteristics of CSCs and discovering CSC-related therapeutic strategies.Certain strategies for CSC enrichment have been used in laboratory,particularly fluorescence-activated cell sorting(FACS)and mammosphere culture.However,these methods fail to recapitulate the in vivo chemical and physical conditions in tumors,thus potentially decreasing the malignancy of CSCs in culture and yielding unreliable research results.Accumulating research suggests the promise of a biomaterial-based three-dimensional(3 D)strategy for CSC enrichment and study.This strategy has an advantage over conventional methods in simulating the tumor microenvironment,thus providing a more effective and predictive model for CSC laboratory research.In this review,we first briefly discuss the conventional methods for CSC enrichment and study.We then summarize the latest advances and challenges in biomaterial-based 3 D CSC platforms.Design strategies for materials,morphology,and chemical and physical cues are highlighted to provide direction for the future construction of platforms for CSC enrichment and study.

Role of the mechanical microenvironment in cancer development and progression

Cross-talk between tumor cells and mechanical stress in the tumor microenvironment has been shown to be involved in carcinogenesis.High mechanical stress in tumors can alter the metabolism and behaviors of cancer cells and cause cancer cells to attain cancer stem-like cell properties,thus driving tumor progression and promoting metastasis.The mechanical signal is converted into a biochemical signal that activates tumorigenic signaling pathways through mechanotransduction.Herein,we describe the physical changes occurring during reprogramming of cancer cell metabolism,which regulate cancer stem cell functions and promote tumor progression and aggression.Furthermore,we highlight emerging therapeutic strategies targeting mechanotransduction signaling pathways.

Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin

Therapeutic targeting FOxO3A(a forkhead transcription factor)represents a prom-ising strategy to suppress acute myeloid leukemia(AML).However,the effective inhibitors that target FOXO3A are lacking and the adaptive response signaling weakens the cytotoxic effect of FOxO3A depletion on AML cells.Here,we show that FOxO3A deficiency induces a compensa-tory response involved in the reactive activation of mTOR that leads to signaling rebound and adaptive resistance.Mitochondrial metabolism acts downstream of mTOR to provoke activa-tion of JNK/c-JUN via reactive oxygen species(ROS).At the molecular level,FOXO3A directly binds to the promoter of G protein gamma subunit 7(GNG7)and preserves its expression,while GNG7 interacts with mTOR and restricts phosphorylated activation of mTOR.Consequently,combinatorial inhibition of FOXO3A and mTOR show a synergistic cytotoxic effect on AML cells and prolongs survival in a mouse model of AML.Through a structure-based virtual screening,we report one potent small-molecule FOxO3A inhibitor(Gardenoside)that exhibits a strong effect of anti-FOXO3A DNA binding.Gardenoside synergizes with rapamycin to substantially reduce tumor burden and extend survival in AML patient-derived xenograft model.These results demonstrate that mTOR can mediate adaptive resistance to FOxO3A inhibition and validate a combinatorial approach for treating AML.