PI3K/Akt/mTOR signaling orchestrates the phenotypic transition and chemo-resistance of small cell lung cancer

Small cell lung cancer(SCLC)is a phenotypically heterogeneous disease with an extremely poor prognosis,which is mainly attributed to the rapid development of resistance to chemotherapy.However,the relation between the growth phenotypes and chemo-resistance of SCLC remains largely unclear.Through comprehensive bioinformatic analyses,we found that the heterogeneity of SCLC phenotype was significantly associated with different sensitivity to chemotherapy.Adherent or semiadherent SCLC cells were enriched with activation of the PI3K/Akt/mTOR pathway and were highly chemoresistant.Mechanistically,activation of the PI3K/Akt/mTOR pathway promotes the phenotypic transition from suspension to adhesion growth pattern and confers SCLC cells with chemo-resistance.Such chemo-resistance could be largely overcome by combining chemotherapy with PI3K/Akt/mTOR pathway inhibitors.Our findings support that the PI3K/Akt/mTOR pathway plays an important role in SCLC phenotype transition and chemo-resistance,which holds important clinical implications for improving SCLC treatment.

Evolution from genetics to phenotype： reinterpretation of NSCLC plasticity, heterogeneity, and drug resistance

Lung cancer is the leading cause of cancer-related deaths worldwide. Targeted therapy is beneficial in most cases, but the development of drug resistance stands as an obstacle to good prognosis. Multiple mechanisms were explored such as genetic alterations, activation of bypass signaling, and phenotypic transition. These intrinsic and/or extrinsic dynamic regulations facilitate tumor cell survival in meeting the demands of signaling under different stimulus. This review introduces lung cancer plasticity and heterogeneity and their correlation with drug resistance. While cancer plasticity and heterogeneity play an essential role in the development of drug resistance, the manipulation of them may bring some inspirations to cancer prognosis and treatment. That is to say, lung cancer plasticity and heterogeneity present us with not only challenges but also opportunities.

Modulating macrophage activities to promote endogenous bone regeneration: Biological mechanisms and engineering approaches

A coordinated interaction between osteogenesis and osteoimmune microenvironment is essential for successful bone healing.In particular,macrophages play a central regulatory role in all stages of bone repair.Depending on the signals they sense,these highly plastic cells can mediate the host immune response against the exterior signals of molecular stimuli and implanted scaffolds,to exert regenerative potency to a varying extent.In this article,we first encapsulate the immunomodulatory functions of macrophages during bone regeneration into three aspects,as sweeper,mediator and instructor.We introduce the phagocytic role of macrophages in different bone healing periods(‘sweeper’)and overview a variety of paracrine cytokines released by macrophages either mediating cell mobilisation,vascularisation and matrix remodelling(‘mediator’),or directly driving the osteogenic differentiation of bone progenitors and bone repair(‘instructor’).Then,we systematically classify and discuss the emerging engineering strategies to recruit,activate and modulate the phenotype transition of macrophages,to exploit the power of endogenous macrophages to enhance the performance of engineered bone tissue.