Endothelial p130cas confers resistance to anti-angiogenesis therapy
Authors: Deanna Glassman
Yunfei Wen
Elaine Stur
Anil K Sood
Dahai Jiang
Anca Chelariu-Raicu
Xiuhui Chen
Nicholas B Jennings
Gabriel Lopez-Berestein
Pahul Hanjra
Sujanitha Umamaheswaran
Sara Corvigno
Mien-Chie Hung
Alpa M Nick
Jinsong Liu
Journal: Cell Reports (2022)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: TNKS1BP1; VEGFR2; adaptive resistance; angiogenesis; anti-angiogenic therapy
Affiliations: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Boulevard, Houston, TX 77030, USA. Electronic address: ., Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Boulevard, Houston, TX 77030, USA., Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Boulevard, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Department of Pathology/Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Graduate Institute of Biomedical Sciences, Center for Molecular Medicine, China Medical University, Taichung, Taiwan., Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Boulevard, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: .

Abstract:  Anti-angiogenic therapies, such as anti-VEGF antibodies (AVAs), have shown promise in clinical settings. However, adaptive resistance to such therapies occurs frequently. We use orthotopic ovarian cancer models with AVA-adaptive resistance to investigate the underlying mechanisms. Genomic profiling of AVA-resistant tumors guides us to endothelial p130cas. We find that bevacizumab induces cleavage of VEGFR2 in endothelial cells by caspase-10 and that VEGFR2 fragments internalize into the nucleus and autophagosomes. Nuclear VEGFR2 and p130cas fragments, together with TNKS1BP1 (tankyrase-1-binding protein), initiate endothelial cell death. Blockade of autophagy in AVA-resistant endothelial cells retains VEGFR2 at the membrane with bevacizumab treatment. Targeting host p130cas with RGD (Arg-Gly-Asp)-tagged nanoparticles or genomic ablation of vascular p130cas in p130casflox/floxTie2Cre mice significantly extends the survival of mice with AVA-resistant ovarian tumors. Higher vascular p130cas is associated with shorter survival of individuals with ovarian cancer. Our findings identify opportunities for new strategies to overcome adaptive resistance to AVA therapy. 

Retracted: No

PubPeer comments:
 ![file] ![file] , 
 Figure 4D and Suppl Figure 4B ![file] , 
 identified one more questionable picture on Figure 5A (short and longer exposure time on the same mouse) ![file] https: pubpeer.com publications D276671F20B2DF6F5D431BFC0FAEEC , 
 Addition to #1 s comment On figure 5A, 1st and 3rd mice at 35 days are the same mouse , 
 ![file] , 
 very similar cell location distribution ![file] , 
 Erratum, 21 June 2022: https: www.cell.com cell-reports fulltext S2211-1247(22)00788-4 The Erratum is not obvious from the article s landing page. The text reads:  *In the original version of the article that was published with the January 25, 2022 issue, there were inadvertent errors introduced during figure assembly in Figures 2, 4, and 5. The original Figure 2H contained an inversion of the first two images in the upper panel, the original Figure 4D contained duplicated Hoechst and VEGFR2 images in row 1 and row 2 as well as a duplicated cell cluster in row 3, and the original Figure 5A contained duplicated animal images in day 35 (first group, positions 1 and 3) and day 50 (second group, positions 2 and 3). The correct images for each case have been located, and the correct versions of the figures now appear online with the article; these errors did not affect the scientific conclusions drawn from the figures. The authors sincerely regret the errors and any confusion they may have caused.* , 
 Could the authors please also check Figures 2C and 2D? * Pink boxes: the left b-actin panel in Figure 2C (RF24-Bev) looks quite similar to the right LMNB1 panel in Figure 2D (RF24-par). ![file] * This similarity is confirmed by looking at the uncropped blots provided in the  Source Data document for Figure 2. ![file] , 
 Concern about Figure 4E: * Blue boxes: the Source Data file for Figure 4E appears to contain unexpected duplicated areas ![file] , 
 Concern about Supplemental Figure 1: * Purple boxes: Four lanes in the b-actin panel of Supplemental Figure 1B look remarkably similar to the b-actin panel in Supplemental Figure 1G, while the labels suggest that these represent different experiments. ![file] This similarity appears to also be visible in the Source Data file for this figure. ![file] , 
 Concerns about Supplemental Figure 2. A finding by ImageTwin. * Pink boxes: ImageTwin found a possible duplicated area in the pY1175-VEGFR2 panel in Figure S2E. * Red boxes: ImageTwin found a possible duplicated area in the pY1214-VEGFR2 panel in Figure S2I. ![file] A detailed look at these two panels reveals more potential duplicated areas. * Pink, orange, green, and brown boxes highlight several areas that look quite similar in the pY1175-VEGFR2 panel in Figure S2E. ![file] Some of these similarities are confirmed by Forensically: ![file] * Red and dark red boxes highlight several areas that look quite similar in the pY1214-VEGFR2 panel in Figure S2I. Image made a bit darker to bring out details. ![file] ,