Nanog maintains stemness of Lkb1 ‐deficient lung adenocarcinoma and prevents gastric differentiation
Authors: Peng Zhang
Haiquan Chen
Xinsheng Zhu
Yueqing Chen
Yi Ye
Yun Xue
Wenjing Zhang
Yijun Gao
Xinyuan Tong
Hongbin Ji
Rui Wang
Lei Xiao
Weiqiang Gao
Journal: EMBO Molecular Medicine (2021)
Discipline: CLINICAL MEDICINE
Keywords: Nanog; LKB1; Notch; drug resistance; gastric differentiation.
Affiliations: State Key Laboratory of Cell Biology Shanghai Institute of Biochemistry and Cell Biology Center for Excellence in Molecular Cell Science Chinese Academy of Sciences  Shanghai China, University of Chinese Academy of Sciences  Beijing China, Department of Thoracic Surgery Shanghai Pulmonary Hospital Tongji University School of Medicine  Shanghai China, School of Life Science and Technology Shanghai Tech University  Shanghai China, Department of Thoracic Surgery Fudan University Shanghai Cancer Center  Shanghai China, Department of Oncology Shanghai Medical College Fudan University  Shanghai China, State Key Laboratory of Oncogenes and Related Genes Shanghai Cancer Institute Renji Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China, Med‐X Research Institute Shanghai Jiao Tong University  Shanghai China, College of Animal Science and Zhejiang University School of Medicine Zhejiang University  Hangzhou China

Abstract:  Growing evidence supports that LKB1-deficient KRAS-driven lung tumors represent a unique therapeutic challenge, displaying strong cancer plasticity that promotes lineage conversion and drug resistance. Here we find that murine lung tumors from the KrasLSL-G12D/+ ; Lkb1flox/flox (KL) model show strong plasticity, which associates with up-regulation of stem cell pluripotency genes such as Nanog. Deletion of Nanog in KL model initiates a gastric differentiation program and promotes mucinous lung tumor growth. We find that NANOG is not expressed at a meaningful level in human lung adenocarcinoma (ADC), as well as in human lung invasive mucinous adenocarcinoma (IMA). Gastric differentiation involves activation of Notch signaling, and perturbation of Notch pathway by the γ-secretase inhibitor LY-411575 remarkably impairs mucinous tumor formation. In contrast to non-mucinous tumors, mucinous tumors are resistant to phenformin treatment. Such therapeutic resistance could be overcome through combined treatments with LY-411575 and phenformin. Overall, we uncover a previously unappreciated plasticity of LKB1-deficient tumors and identify the Nanog-Notch axis in regulating gastric differentiation, which holds important therapeutic implication for the treatment of mucinous lung cancer. 

Retracted: No

PubPeer comments:
 In this paper, there seems to be reuse of figures (potential data fabrication). Please see Figures 4B and 4I (sections in read squares). ![file] , 
 #1 Thanks for pointing out this mistake. Indeed, we have noticed this a couple of days ago and in the process of making corrigendum already. The bottom middle panel of NICD immunostaining for KLN IMA in Fig 4B contain similar field as the NICD immunostaining for KLN IMA (vehicle group) in Fig 4I. These two photos were inadvertently saved and named with different serial numbers in the process of photo taking. Although this unintentional mistake does not affect the interpretation of data or the conclusion of this study, we are extremely sorry for such oversight and apologize for any inconvenience it may have caused. , 
 #2 Dear Lecithocera Eumenopisuff1a Thanks for pointing out this mistake. After checking the original data, we did find the flow plots of pMSCV vector (left image) of Kyse510 cells was reused in the flow plots of pSuper-retro-puro vector (right image) of kyse510 cells. Although this unintentional mistake does not affect the interpretation of data or the conclusion of this study, which overexpressing either pMSCV vector or pSuper-retro-puro vector has no effect on the apoptosis in Kyse510 cells, we are extremely sorry for such oversight and apologize for any inconvenience it may have caused. We will make corrigendum as soon as possible. Jun Li , 
 Dear Dr. Li, Could you please also check two other sets of panels that appear to overlap? I have marked them below with green and blue boxes. The panels with the green boxes might be both showing the same sample, but the ones marked with blue appear to be differentially labeled - are these the same tissue? Found with the aid of ImageTwin. ![file] , 
 #4 Thanks for raising these concerns! We have now got chance to go through the raw data carefully. The human IMA HE staining in Figure 2A and Figure 3G are from a same sample. As for the issue regarding the similarity about the 10x HE photo in Figure 2B and the 40x HE photo in Figure 4I, we have mistakenly used au00a0photo from the KLN IMA vehicleu00a0treatment group for Figure 2B. As you can see from following image, the current inset (40x HE) in Figure 2B does not match the 10x HE photo. The 10x HE photo is from KLN IMA vehicle treatment group and the high magnification inset is from KLN IMA group. We have now located the low magnification photo which contains the area of current inset. We hope this clarify your concerns. We will contact the journal as soon as possible to replace the KLN IMA 10x HE photo in Figure 2B with the correct one. Again, although this mistake does not affect the interpretation of data or the conclusion of this study, we are really sorry for the oversight and apologize for any inconvenience it may have caused. , 
 #4 Thanks for raising these concerns! We have now got chance to go through the raw data carefully. The human IMA HE staining in Figure 2A and Figure 3G are from a same sample. As for the issue regarding the similarity about the 10x HE photo in Figure 2B and the 40x HE photo in Figure 4I, we have mistakenly used a photo from the KLN IMA vehicle treatment group for Figure 2B. As you can see from following image, the current inset (40x HE) in Figure 2B does not match the 10x HE photo. The 10x HE photo is from KLN IMA vehicle treatment group and the high magnification inset is from KLN IMA group. We have now located the low magnification photo which contains the area of current inset. We hope this clarify your concerns. We will contact the journal as soon as possible to replace the KLN IMA 10x HE photo in Figure 2B with the correct one. Again, although this mistake does not affect the interpretation of data or the conclusion of this study, we are really sorry for the oversight and apologize for any inconvenience it may have caused. ![file] , 
 Correction, 7 September 2021: https: www.embopress.org doi full 10.15252 emmm.202114795  The authors were alerted to duplicated images between Figures 2A and 3G, 2B and 4I, and 4B and 4I. The authors state that the human IMA HE stainings in Figure 2A and Figure 3G are from the same sample. The legend of Figure 3G is amended to indicate that the sample is also shown in Figure 2A. The 10x HE image in Figure 2B had been incorrectly displayed in the 40x HE image in Figure 4I. The authors state that they used the incorrect photograph from the KLN IMA vehicle treatment group in Figure 2B. The authors have identified the correct low-magnification image that corresponds to the magnification currently displayed in Figure 2B and herewith retract and replace this panel. The bottom middle panel of NICD immunostaining for KLN IMA in Figure 4B displayed an image from a similar field of the NICD immunostaining for KLN IMA (vehicle group) in Figure 4I. The authors state that these two photographs were mislabeled during the acquisition process. The authors have identified the correct image for NICD immunostaining for KLN IMA in Figure 4B in the original data and herewith retract and replace this panel. Lastly, the authors note that the labeling in Figure 4J had previously been inverted and this is herewith corrected. The authors state that these changes do not affect the interpretation of the data or the conclusions of the study. The authors apologize for this oversight and for any inconvenience it may have caused. ,