Oxidative stress-triggered Wnt signaling perturbation characterizes the tipping point of lung adeno-to-squamous transdifferentiation

Lkb1 deficiency confers the Kras-mutant lung cancer with strong plasticity and the potential for adeno-to-squamous transdifferentiation(AST).However,it remains largely unknown how Lkb1 deficiency dynamically regulates AST.Using the classical AST mouse model(Kras LSL-G12D/+;Lkb1flox/flox,KL),we here comprehensively analyze the temporal transcriptomic dynamics of lung tumors at different stages by dynamic network biomarker(DNB)and identify the tipping point at which the Wnt signaling is abruptly suppressed by the excessive accumulation of reactive oxygen species(ROS)through its downstream effector FOXO3A.Bidirectional genetic perturbation of the Wnt pathway using two different Ctnnb1 conditional knockout mouse strains confirms its essential role in the negative regulation of AST.Importantly,pharmacological activation of the Wnt pathway before but not after the tipping point inhibits squamous transdifferentiation,highlighting the irreversibility of AST after crossing the tipping point.Through comparative transcriptomic analyses of mouse and human tumors,we find that the lineage-specific transcription factors(TFs)of adenocarcinoma and squamous cell carcinoma form a“Yin-Yang”counteracting network.Interestingly,inactivation of the Wnt pathway preferentially suppresses the adenomatous lineage TF network and thus disrupts the“Yin-Yang”homeostasis to lean towards the squamous lineage,whereas ectopic expression of NKX2-1,an adenomatous lineage TF,significantly dampens such phenotypic transition accelerated by the Wnt pathway inactivation.The negative correlation between the Wnt pathway and AST is further observed in a large cohort of human lung adenosquamous carcinoma.Collectively,our study identifies the tipping point of AST and highlights an essential role of the ROS-Wnt axis in dynamically orchestrating the homeostasis between adeno-and squamous-specific TF networks at the AST tipping point.

Mutually exclusive epigenetic modification on SIX6 with hypermethylation for precancerous stage and metastasis emergence tracing

Dear Editor,Aberrant DNA methylation gets involved in cancer initiation,progression,and recurrence,which in turn makes it an ideal cancer biomarker.Various methylation markers or their panels have been developed in diverse cancer types.However,the model-constructing based marker mining strategy and incompatibility of application have greatly impeded their ways to clinic.Thus,single methylation marker applicable to all/most cancer types and multiple clinical scenarios is desperately needed.The hope came from the unexpected observation that HIST1H4F was universally hypermethylated in all 17 cancer types;thus,we raised the concept of“Universal Cancer Only Marker(UCOM)”and established a paradigm for discovery and clinical application of UCOM.1 Recently,a novel UCOM,hypermethylated PCDHGB7,was identified and found to advance cervical cancer(CC)screening to the precancerous stage.2 During the screening of UCOM,we discerned a bunch of cancer cell-differentially methylated regions.1 Among them,sine oculis(SIX)homeobox family of transcription factors,which were found to function as tumorigenesis regulator by promoting epithelial-to-mesenchymal transition and metastasis recently in addition to their traditional roles in tissue formation and organogenesis,3 sparked our special attention.Herein,we interrogate whether SIX6 methylation could serve as a novel UCOM and its potential applications.

CACA guidelines for holistic integrative management of esophageal carcinoma

Esophageal carcinoma(EC)is a common malignant tumor of the upper digestive tract worldwide.An analysis of the latest data from cancer centers in China showed that the incidence of EC and the number of deaths due to EC in China in 2015 were 266,000 and 188,000,respectively,ranking sixth(6.3%)and fourth(8.0%)among all malignant tumors.The early diagnosis and treatment of EC and standardized diagnosis and treatment are important tasks for EC healthcare professionals in various centers across the country.At present,the 8th edition of the EC staging system jointly released by Union for International Cancer Control(UICC)and American Joint Committee on Cancer(AJCC)is the most recent,authoritative and widely used EC staging standard.The EC professional committee of the Chinese Anti-Cancer Association also organizes the"EC Standardization Campaign in China"every year to promote the development of EC diagnostic and treatment norms throughout the country.Since 2011,the EC Committee of the Chinese Anti-Cancer Association has published the Guidelines for Standardized Diagnosis and Treatment of EC.Considering the increasing number of EC clinical studies and the continuous progress in diagnostic and treatment technologies in recent years,the updated Guidelines will include the latest progress in the diagnosis and treatment of EC,with a goal of promoting the forward development of EC diagnosis and treatment in clinical practice.