LAMC2 Regulates Key Transcriptional and Targetable Effectors to Support Pancreatic Cancer Growth

被引:16
作者
Erice, Oihane [1 ]
Narayanan, Shruthi [2 ]
Feliu, Iker
Entrialgo-Cadierno, Rodrigo
Malinova, Antonia [3 ]
Vicentini, Caterina [3 ]
Guruceaga, Elizabeth [1 ,4 ]
No, Pietro Del fi [3 ]
Trajkovic-Arsic, Marija [5 ,6 ]
Moreno, Haritz
Valencia, Karmele [1 ]
Blanco, Ester
Macaya, Irati
Ohlund, Daniel [7 ,8 ,9 ]
Khatri, Purvesh [10 ,11 ]
Lecanda, Fernando [1 ]
Scarpa, Aldo [3 ]
Siveke, Jens T.
Corbo, Vincenzo [3 ]
Ponz-Sarvise, Mariano [1 ,2 ,13 ]
Vicent, Silve [1 ,2 ,12 ]
机构
[1] Univ Navarra, Ctr Appl Med Res, Program Solid Tumors, Pamplona, Spain
[2] Navarra Inst Hlth Res, IdiSNA, Pamplona, Spain
[3] Clin Univ Navarra, Med Oncol Dept, Pamplona, Spain
[4] Univ Verona, Dept Diagnost & Publ Hlth, Verona, Italy
[5] Univ Navarra, Ctr Appl Med Res, Computat Biol Program, Pamplona, Spain
[6] Univ Hosp Essen, Bridge Inst Expt Tumor Therapy, West German Canc Ctr, Essen, Germany
[7] German Canc Consortium, DKTK, Partner Site Univ Hosp Essen, Div Solid Tumor Translat Oncol, Heidelberg, Germany
[8] German Canc Res Ctr, DKFZ, Heidelberg, Germany
[9] Umea Univ, Dept Radiat Sci, Umea, Sweden
[10] Umea Univ, Wallenberg Ctr Mol Med, Umea, Sweden
[11] Stanford Inst Immun, Transplantat & Infect, Stanford, CA USA
[12] Univ Navarra, Ctr Appl Med Res CIMA, 55 Pio XII Ave, Pamplona 31008, Spain
[13] Clin Univ Navarra, CUN, 55 Pio XII Ave, Pamplona 31008, Spain
关键词
EGF RECEPTOR; INHIBITION; ADENOCARCINOMA; METASTASIS; SUBTYPES; KINASE; LIVER;
D O I
10.1158/1078-0432.CCR-22-0794
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: The identification of pancreatic ductal adenocarcino-ma (PDAC) dysregulated genes may unveil novel molecular targets entering inhibitory strategies. Laminins are emerging as potential targets in PDAC given their role as diagnostic and prognostic markers. Here, we investigated the cellular, functional, and clinical relevance of LAMC2 and its regulated network, with the ultimate goal of identifying potential therapies. Experimental Design: LAMC2 expression was analyzed in PDAC tissues, a panel of human and mouse cell lines, and a genetically engineered mouse model. Genetic perturbation in 2D, 3D, and in vivo allograft and xenograft models was done. Expression profiling of a LAMC2 network was performed by RNA-sequencing, and publicly available gene expression datasets from experimental and clinical studies examined to query its human relevance. Dual inhibition of pharmacologically targetable LAMC2-regulated effec-tors was investigated. Results: LAMC2 was consistently upregulated in human and mouse experimental models as well as in human PDAC specimens, and associated with tumor grade and survival. LAMC2 inhibition impaired cell cycle, induced apoptosis, and sensitized PDAC to MEK1/2 inhibitors (MEK1/2i). A LAMC2-regulated network was featured in PDAC, including both classical and quasi-mesenchymal subtypes, and contained downstream effectors transcriptionally shared by the KRAS signaling pathway. LAMC2 regulated a func-tional FOSL1-AXL axis via AKT phosphorylation. Furthermore, genetic LAMC2 or pharmacological AXL inhibition elicited a synergistic antiproliferative effect in combination with MEK1/2is that was consistent across 2D and 3D human and mouse PDAC models, including primary patient-derived organoids. Conclusions: LAMC2 is a molecular target in PDAC that regulates a transcriptional network that unveils a dual drug com-bination for cancer treatment.
引用
收藏
页码:1137 / 1154
页数:18
相关论文
共 60 条
[21]   Core signaling pathways in human pancreatic cancers revealed by global genomic analyses [J].
Jones, Sian ;
Zhang, Xiaosong ;
Parsons, D. Williams ;
Lin, Jimmy Cheng-Ho ;
Leary, Rebecca J. ;
Angenendt, Philipp ;
Mankoo, Parminder ;
Carter, Hannah ;
Kamiyama, Hirohiko ;
Jimeno, Antonio ;
Hong, Seung-Mo ;
Fu, Baojin ;
Lin, Ming-Tseh ;
Calhoun, Eric S. ;
Kamiyama, Mihoko ;
Walter, Kimberly ;
Nikolskaya, Tatiana ;
Nikolsky, Yuri ;
Hartigan, James ;
Smith, Douglas R. ;
Hidalgo, Manuel ;
Leach, Steven D. ;
Klein, Alison P. ;
Jaffee, Elizabeth M. ;
Goggins, Michael ;
Maitra, Anirban ;
Iacobuzio-Donahue, Christine ;
Eshleman, James R. ;
Kern, Scott E. ;
Hruban, Ralph H. ;
Karchin, Rachel ;
Papadopoulos, Nickolas ;
Parmigiani, Giovanni ;
Vogelstein, Bert ;
Velculescu, Victor E. ;
Kinzler, Kenneth W. .
SCIENCE, 2008, 321 (5897) :1801-1806
[22]   Presence of Somatic Mutations in Most Early-Stage Pancreatic Intraepithelial Neoplasia [J].
Kanda, Mitsuro ;
Matthaei, Hanno ;
Wu, Jian ;
Hong, Seung-Mo ;
Yu, Jun ;
Borges, Michael ;
Hruban, Ralph H. ;
Maitra, Anirban ;
Kinzler, Kenneth ;
Vogelstein, Bert ;
Goggins, Michael .
GASTROENTEROLOGY, 2012, 142 (04) :730-U129
[23]   Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer [J].
Kapoor, Avnish ;
Yao, Wantong ;
Ying, Haoqiang ;
Hua, Sujun ;
Liewen, Alison ;
Wang, Qiuyun ;
Zhong, Yi ;
Wu, Chang-Jiun ;
Sadanandam, Anguraj ;
Hu, Baoli ;
Chang, Qing ;
Chu, Gerald C. ;
Al-Khalil, Ramsey ;
Jiang, Shan ;
Xia, Hongai ;
Fletcher-Sananikone, Eliot ;
Lim, Carol ;
Horwitz, Gillian I. ;
Viale, Andrea ;
Pettazzoni, Piergiorgio ;
Sanchez, Nora ;
Wang, Huamin ;
Protopopov, Alexei ;
Zhang, Jianhua ;
Heffernan, Timothy ;
Johnson, Randy L. ;
Chin, Lynda ;
Wang, Y. Alan ;
Draetta, Giulio ;
DePinho, Ronald A. .
CELL, 2014, 158 (01) :185-197
[24]   Extracellular matrix-based cancer targeting [J].
Karamanos, Nikos K. ;
Piperigkou, Zoi ;
Passi, Alberto ;
Gotte, Martin ;
Rousselle, Patricia ;
Vlodavsky, Israel .
TRENDS IN MOLECULAR MEDICINE, 2021, 27 (10) :1000-1013
[25]   Pancreatic cancer [J].
Kleeff, Jorg ;
Korc, Murray ;
Apte, Minoti ;
La Vecchia, Carlo ;
Johnson, Colin D. ;
Biankin, Andrew V. ;
Neale, Rachel E. ;
Tempero, Margaret ;
Tuveson, David A. ;
Hruban, Ralph H. ;
Neoptolemos, John P. .
NATURE REVIEWS DISEASE PRIMERS, 2016, 2
[26]   Dual Inhibition of MEK and AXL Targets Tumor Cell Heterogeneity and Prevents Resistant Outgrowth Mediated by the Epithelial-to-Mesenchymal Transition in NSCLC [J].
Konen, Jessica M. ;
Rodriguez, B. Leticia ;
Padhye, Aparna ;
Ochieng, Joshua K. ;
Gibson, Laura ;
Diao, Lixia ;
Fowlkes, Natalie W. ;
Fradette, Jared J. ;
Peng, David H. ;
Cardnell, Robert J. ;
Kovacs, Jeffrey J. ;
Wang, Jing ;
Byers, Lauren A. ;
Gibbons, Don L. .
CANCER RESEARCH, 2021, 81 (05) :1398-1412
[27]   Laminin, gamma 2 (LAMC2): A Promising New Putative Pancreatic Cancer Biomarker Identified by Proteomic Analysis of Pancreatic Adenocarcinoma Tissues [J].
Kosanam, Hari ;
Prassas, Ioannis ;
Chrystoja, Caitlin C. ;
Soleas, Ireena ;
Chan, Alison ;
Dimitromanolakis, Apostolos ;
Blasutig, Ivan M. ;
Rueckert, Felix ;
Gruetzmann, Robert ;
Pilarsky, Christian ;
Maekawa, Masato ;
Brand, Randall ;
Diamandis, Eleftherios P. .
MOLECULAR & CELLULAR PROTEOMICS, 2013, 12 (10) :2820-2832
[28]   GLI2-dependent c-MYC upregulation mediates resistance of pancreatic cancer cells to the BET bromodomain inhibitor JQ1 [J].
Kumar, Krishan ;
Raza, Sania S. ;
Knab, Lawrence M. ;
Chow, Christina R. ;
Kwok, Benjamin ;
Bentrem, David J. ;
Popovic, Relja ;
Ebine, Kazumi ;
Licht, Jonathan D. ;
Munshi, Hidayatullah G. .
SCIENTIFIC REPORTS, 2015, 5
[29]  
lanevski A., 2020, Nucleic Acids Research, V48, pW488, DOI [DOI 10.1093/NAR/GKAA216, 10.1093/nar/gkaa216]
[30]   Preclinical validation of AXL receptor as a target for antibody-based pancreatic cancer immunotherapy [J].
Leconet, W. ;
Larbouret, C. ;
Chardes, T. ;
Thomas, G. ;
Neiveyans, M. ;
Busson, M. ;
Jarlier, M. ;
Radosevic-Robin, N. ;
Pugniere, M. ;
Bernex, F. ;
Penault-Llorca, F. ;
Pasquet, J-M ;
Pelegrin, A. ;
Robert, B. .
ONCOGENE, 2014, 33 (47) :5405-5414