title: Evidence, Mechanism, and Clinical Relevance of the Transdifferentiation from Lung Adenocarcinoma to Squamous Cell Carcinoma.
abstract: Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are two distinct subtypes of non-small-cell lung carcinoma. Interestingly, approximately 4% to 9% of human non-small-cell lung carcinoma tumors contain mixed adenomatous and squamous pathologies in a single lesion, clinically termed adenosquamous cell carcinoma. More important, these two different pathological components frequently share identical oncogenic mutations, indicative of a potential transition. Indeed, recent data have provided convincing evidence in supporting the ADC to SCC transdifferentiation in lungs. In the liver kinase B1 (official name STK11)-deficient mouse model, lung ADC can progressively transdifferentiate to SCC through pathologically mixed adenosquamous cell carcinoma as the intermediate status. Mechanistic studies further identify essential roles of extracellular matrix remodeling and metabolic reprogramming during this phenotypic transition. Small molecular compounds, including lysyl oxidase inhibitors and reactive oxygen species-inducing reagents such as phenformin, significantly accelerate the transition from lung ADC to SCC and thus confer lung tumors with drug resistance. Consistent with these findings, recent clinical studies have shown that epidermal growth factor receptor-mutant lung ADC can transdifferentiate to SCC in relapsed cancer patients. Together, these data support that this phenotypic transition from lung ADC to SCC might represent a novel mechanism for drug resistance. This review will summarize our current understanding of the transdifferentiation from lung ADC to SCC.
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Shenda
authors.initials: S
authors.lastname: Hou
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Shiyu
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xiangkun
authors.initials: X
authors.lastname: Han
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Shun
authors.initials: S
authors.lastname: Yao
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, Shanghai Tech University, Shanghai, China. Electronic address: hbji@sibcb.ac.cn.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D054338:Cell Transdifferentiation / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005109:Extracellular Matrix / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D010641:Phenotype; D011494:Protein Kinases / Q000378:metabolism
chemical_list: D011494:Protein Kinases