Identification of the precise molecular pathways involved in oncogene-induced transformation may help us gain a better understanding of tumor initiation and promotion. Here, we demonstrate that SOX2^+ foregut epitheli...Identification of the precise molecular pathways involved in oncogene-induced transformation may help us gain a better understanding of tumor initiation and promotion. Here, we demonstrate that SOX2^+ foregut epithelial cells are prone to oncogenic transformation upon mutagenic insults, such as Kras^G12D and p53 deletion. GFP-based lineage-tracing experiments indicate that SOX2^+ cells are the cells-of-origin of esophagus and stomach hyperplasia. Our observations indicate distinct roles for oncogenic KRAS mutation and P53 deletion. p53 homozygous deletion is required for the acquisition of an invasive potential, and Kras^G12D expression, but not p53 deletion, suffices for tumor formation. Global gene expression analysis reveals secreting factors upregulated in the hyperplasia induced by oncogenic KRAS and highlights a crucial role for the CXCR2 pathway in driving hyperplasia. Collectively, the array of genetic models presented here demonstrate that stratified epithelial cells are susceptible to oncogenic insults, which may lead to a better understanding of tumor initiation and aid in the design of new cancer therapeutics.展开更多
Human embryonic stem cells(ESCs)have the capability to differentiate into all somatic cell types,a process that recapitu-lates the early stages of human develop-ment.However,the use of ESCs raises several controversie...Human embryonic stem cells(ESCs)have the capability to differentiate into all somatic cell types,a process that recapitu-lates the early stages of human develop-ment.However,the use of ESCs raises several controversies,particularly concern-ing the ethical dilemma regarding the use of human embryonic material and the need for embryo destruction.The discov-ery of induced pluripotent stem cell(iPSC)technology in 2006(Takahashi and Yamanaka,2006)opened the door for possible application of pluripotent stem-cell-related therapies in the clinic as well as for the generation of patient-derived pluripotent stem cells suitable for disease modeling in vitro.展开更多
基金National Key Research and Development Program of China (2015CB964800)the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010100)+6 种基金the National Natural Science Foundation of China (81625009, 81330008, 91749202, 81861168034)Program of Beijing Municipal Science and Technology Commission (Z151100003915072)Advanced Innovation Center for Human Brain Protection (117212, 3500-1192012)Beijing Municipal Commissio n of Health and Family Planning PXM2018_026283_000002)Work in the laboratory of J.C.I.B was supported by a Cancer Center Support Grant, the G. Harold and Leila Y, Mathers Charitable Foundation, The Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002)The Moxie Foundation, Fundacion Dr. Pedro Guillen and Universidad Catdlica San Antonio de Murcia (UCAM). T.H. was supported by a Pioneer Fund Postdoctoral Scholar Award, Nomis FellowshipUehara Memorial Foundation research fellowship.
文摘Identification of the precise molecular pathways involved in oncogene-induced transformation may help us gain a better understanding of tumor initiation and promotion. Here, we demonstrate that SOX2^+ foregut epithelial cells are prone to oncogenic transformation upon mutagenic insults, such as Kras^G12D and p53 deletion. GFP-based lineage-tracing experiments indicate that SOX2^+ cells are the cells-of-origin of esophagus and stomach hyperplasia. Our observations indicate distinct roles for oncogenic KRAS mutation and P53 deletion. p53 homozygous deletion is required for the acquisition of an invasive potential, and Kras^G12D expression, but not p53 deletion, suffices for tumor formation. Global gene expression analysis reveals secreting factors upregulated in the hyperplasia induced by oncogenic KRAS and highlights a crucial role for the CXCR2 pathway in driving hyperplasia. Collectively, the array of genetic models presented here demonstrate that stratified epithelial cells are susceptible to oncogenic insults, which may lead to a better understanding of tumor initiation and aid in the design of new cancer therapeutics.
文摘Human embryonic stem cells(ESCs)have the capability to differentiate into all somatic cell types,a process that recapitu-lates the early stages of human develop-ment.However,the use of ESCs raises several controversies,particularly concern-ing the ethical dilemma regarding the use of human embryonic material and the need for embryo destruction.The discov-ery of induced pluripotent stem cell(iPSC)technology in 2006(Takahashi and Yamanaka,2006)opened the door for possible application of pluripotent stem-cell-related therapies in the clinic as well as for the generation of patient-derived pluripotent stem cells suitable for disease modeling in vitro.
