Intact regulation of G1/S transition renders esophageal squamous cell carcinoma sensitive to PI3Kαinhibitors

Phosphatidylinositol 3-kinase alpha(PI3Kα)inhibitors are currently evaluated for the therapy of esophageal squamous cell carcinoma(ESCC).It is of great importance to identify potential biomarkers to predict or monitor the efficacy of PI3Kαinhibitors in an aim to improve the clinical responsive rate in ESCC.Here,ESCC PDXs with CCND1 amplification were found to be more sensitive to CYH33,a novel PI3Kα-selective inhibitor currently in clinical trials for the treatment of advanced solid tumors including ESCC.Elevated level of cyclin D1,p21 and Rb was found in CYH33-sensitive ESCC cells compared to those in resistant cells.CYH33 significantly arrested sensitive cells but not resistant cells at G1 phase,which was associated with accumulation of p21 and suppression of Rb phosphorylation by CDK4/6 and CDK2.Hypo-phosphorylation of Rb attenuated the transcriptional activation of SKP2 by E2F1,which in turn hindered SKP2-mediated degradation of p21 and reinforced accumulation of p21.Moreover,CDK4/6 inhibitors sensitized resistant ESCC cells and PDXs to CYH33.These findings provided mechanistic rationale to evaluate PI3Kαinhibitors in ESCC patients harboring amplified CCND1 and the combined regimen with CDK4/6 inhibitors in ESCC with proficient Rb.

Type IV collagen α5 chain promotes luminal breast cancer progression through c-Myc-driven glycolysis

Cancer cell metabolism reprogramming is one of the hallmarks of cancer.Cancer cells preferentially utilize aerobic glycolysis,which is regulated by activated oncogenes and the tumor microenvironment.Extracellular matrix(ECM)in the tumor microenvironment,including the basement membranes(BMs),is dynamically remodeled.However,whether and how ECM regulates tumor glycolysis is largely unknown.We show that type IV collagens,components of BMs essential for the tissue integrity and proper function,are differentially expressed in breast cancer subtypes thatα5 chain(α5(IV))is preferentially expressed in the luminal-type breast cancer and is regulated by estrogen receptor-α.α5(IV)is indispensable for luminal breast cancer development.Ablation ofα5(IV)significantly reduces the growth of luminal-type breast cancer cells and impedes the development of luminal-type breast cancer.Impaired cell growth and tumor development capability ofα5(IV)-ablated luminal breast cancer cells is attributed to the reduced expression of glucose transporter and glycolytic enzymes and impaired glycolysis in luminal breast cancer cells.Non-integrin collagen receptor discoidin domain receptor-1(DDR1)expression and p38 mitogen-activated protein kinase activation are attenuated inα5(IV)-ablated luminal breast cancer cells,resulting in reduced c-Myc oncogene expression and phosphorylation.Ectopic expression of constitutively active DDR1 or c-Myc restores the expression of glucose transporter and glycolytic enzymes,and thereafter restores aerobic glycolysis,cell proliferation,and tumor growth of luminal breast cancer.Thus,type IV collagenα5 chain is a luminal-type breast cancer-specific microenvironmental regulator modulating cancer cell metabolism.

Basement membrane promotes tumor development by attenuating T cell activation

Dear Editor,T cells recognize and eliminate cancer cells.Prolonged survival of cancer patients is associated with not only intratumoral T cell infiltration but also the functional status of infiltrated T cells(Galon and Bruni,2020).The immune contexture,including the number and functionality of T cells,is modulated by the tumor microenvironment(Joyce and Fearon,2015;Galon and Bruni,2020).