Review
Oncology
Chandra K. Maharjan, Po Hien Ear, Catherine G. Tran, James R. Howe, Chandrikha Chandrasekharan, Dawn E. Quelle
Summary: Pancreatic neuroendocrine tumors (pNETs) are rare, slow-growing malignancies with incompletely understood molecular pathogenesis. Current therapies can effectively slow disease progression, but resistance often develops, highlighting the need for a better understanding of disease mechanisms to develop new treatments. Research efforts have identified potential therapeutic targets and expanded model systems for investigating pNETs, with advancements expected to improve patient treatments.
Review
Biology
Manuel Ramos-Kuri, Sri Harika Meka, Fabio Salamanca-Buentello, Roger J. Hajjar, Larissa Lipskaia, Elie R. Chemaly
Summary: The Ras family of G proteins plays a crucial role in cardiac diseases, with H-Ras regulating cardiomyocyte size and K-Ras controlling cardiomyocyte proliferation. Pathogenic Ras variations can lead to hypertrophic cardiomyopathy and various cardiac defects.
BIOLOGICAL RESEARCH
(2021)
Article
Pharmacology & Pharmacy
Linlin Zhang, Yuanyuan Wang, Dengjin Li, Liang Wang, Zhenzhou Li, Fei Yan
Summary: A dual-modal imaging tumor-homing bacteria (GVs-miRFP680 MG1655) has been developed, allowing optical and acoustic imaging capabilities in vivo. The engineered bacteria effectively integrate the advantages of near-infrared fluorescent proteins and gas vesicles for imaging, with signals lasting up to 25 minutes and 96 hours, respectively. The combination of different imaging modalities in tumor-homing bacteria may contribute to non-invasive monitoring of the therapeutic effect of bacterial therapy in the future.
Article
Immunology
Ana Alcaraz-Sanabria, Esther Cabanas Morafraile, Gonzalo Fernandez-Hinojal, Guillermo Velasco, Pedro Perez-Segura, Atanasio Pandiella, Balazs Gyorffy, Alberto Ocana
Summary: This study identified genes coding for selectively expressed surface membrane proteins in K-RAS mutated NSCLC and discovered immune correlates related to this tumor type. These findings could be used to select and optimize current therapies.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Multidisciplinary Sciences
Dae Gyu Kim, Yongseok Choi, Yuno Lee, Semi Lim, Jiwon Kong, JaeHa Song, Younah Roh, Dipesh S. Harmalkar, Kwanshik Lee, Ja-il Goo, Hye Young Cho, Ameeq Ul Mushtaq, Jihye Lee, Song Hwa Park, Doyeun Kim, Byung Soh Min, Kang Young Lee, Young Ho Jeon, Sunkyung Lee, Kyeong Lee, Sunghoon Kim
Summary: AIMP2-DX2 acts as a cancer-specific regulator of KRAS stability and enhances KRAS-driven tumorigenesis by blocking ubiquitin-mediated degradation of KRAS. A small molecule that inhibits the interaction between AIMP2-DX2 and KRAS reduces KRAS levels and suppresses KRAS-dependent cancer cell growth in vitro and in vivo.
NATURE COMMUNICATIONS
(2022)
Review
Oncology
Chengcheng Liao, Qian Wang, Jiaxing An, Minglin Zhang, Jie Chen, Xiaolan Li, Linlin Xiao, Jiajia Wang, Qian Long, Jianguo Liu, Xiaoyan Guan
Summary: The serine protease inhibitor Kazal type (SPINK) family is the largest branch in the serine protease inhibitor family. Different SPINK members exhibit various regulatory modes in tumor progression and can be used as tumor prognostic markers and treatment targets.
FRONTIERS IN ONCOLOGY
(2022)
Review
Oncology
Yuriko Saiki, Can Jiang, Masaki Ohmuraya, Toru Furukawa
Summary: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy and a major cause of cancer-related deaths worldwide. Recent multi-gene analysis methods have provided valuable insight into the molecular characteristics of pancreatic tumors, with different types of pancreatic cancer and precursor lesions showing specific molecular alterations. Genetically engineered mouse models (GEMMs) driven by oncogenic Kras have proven to be useful in understanding the roles of altered genes and recapitulating key features of human PDAC.
Article
Multidisciplinary Sciences
Fernando C. Baltanas, Rosula Garcia-Navas, Pablo Rodriguez-Ramos, Nuria Calzada, Cristina Cuesta, Javier Borrajo, Rocio Fuentes-Mateos, Andrea Olarte-San Juan, Nerea Vidana, Esther Castellano, Eugenio Santos
Summary: The impact of genetic ablation of SOS1 or SOS2 was evaluated in a murine model of KRAS(G12D)-driven lung adenocarcinoma (LUAD). The study found that SOS1 plays a critical role in the development and survival of KRAS(G12D)-driven LUAD, and its ablation can significantly increase the lifespan of mice and reduce tumor burden and populations of cancer-associated cells in the tumor microenvironment.
NATURE COMMUNICATIONS
(2023)
Review
Oncology
Wenkai Jiang, Xin Li, Caifei Xiang, Wence Zhou
Summary: Neutrophils play a significant role in the development and progression of pancreatic cancer, affecting angiogenesis, tumor progression, and immunosuppression. Neutrophils may also be a novel therapeutic target for pancreatic cancer.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Christophe Glorieux, Xiaojun Xia, Yong-Qiao He, Yumin Hu, Kelly Cremer, Annie Robert, Junchen Liu, Fen Wang, Jianhua Ling, Paul J. Chiao, Peng Huang
Summary: K-ras mutations enhance PD-L1 expression through a redox-mediated mechanism, while inhibition of the FGFR1 pathway reduces PD-L1 expression and enhances T cell-mediated tumor suppression.
Review
Chemistry, Medicinal
Huan Xiao, Guan Wang, Min Zhao, Wen Shuai, Liang Ouyang, Qiu Sun
Summary: This review mainly summarizes the important role of GAPs in human tumors by introducing their classification, function, and regulatory mechanism. The relationship between dysregulated GAPs and a certain type of tumor is comprehensively described. In addition, the current status, research progress, and clinical value of GAPs as therapeutic targets, as well as the challenges and future direction in cancer therapy, are discussed.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Rintaro Mikata, Shin Yasui, Takashi Kishimoto, Yusuke Kouchi, Ayako Shingyoji, Junichi Senoo, Koji Takahashi, Hiroki Nagashima, Yuko Kusakabe, Hiroshi Ohyama, Izumi Ohno, Harutoshi Sugiyama, Tetsuhiro Chiba, Jun Kato, Naoya Kato
Summary: The study aimed to evaluate the utility of IMP3 and p53 immunohistochemical staining in EUS-FNA samples for pancreatic solid masses. Results showed that using IMP3 and/or p53 immunostaining in PDAC and benign tumors can increase the sensitivity of cytohistological analysis.
SCIENTIFIC REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Andrew M. Kidger, Mark K. Saville, Linda K. Rushworth, Jane Davidson, Julia Stellzig, Motoharu Ono, Ludwig A. Kuebelsbeck, Klaus-Peter Janssen, Bernhard Holzmann, Jennifer P. Morton, Owen J. Sansom, Christopher J. Caunt, Stephen M. Keyse
Summary: DUSP5 and DUSP6 are negative regulators of RAS/ERK signaling pathway. Deletion of either Dusp5 or Dusp6 promotes pancreatic hyperplasia, acinar to ductal metaplasia, and pre-neoplastic pancreatic intraepithelial neoplasia in a mouse model of KRAS-driven pancreatic cancer. However, as time progresses, pancreatic hyperplasia is reversed with atrophy of pancreatic tissue and weight loss observed in animals lacking either DUSP5 or DUSP6. These findings suggest that DUSP5 and DUSP6 have partially non-redundant roles in suppressing oncogenic KRAS signaling, thereby retarding tumor progression.
Review
Cell Biology
Isha Godwin, Nikhil Ponnoor Anto, Smitha Bava, Mani Shankar Babu, Goodwin G. Jinesh
Summary: Cellular transformation plays a crucial role in evading apoptosis, genomic instability, and immune surveillance, ultimately promoting cancer stem cell expansion and tumor progression. Defects in key apoptotic regulators lead to cellular transformation, stemness, tumorigenesis, and metastasis.
CELL DEATH DISCOVERY
(2021)
Article
Multidisciplinary Sciences
Roland Beckmann, Kristian Jensen, Sebastian Fenn, Janina Speck, Katrin Krause, Anastasia Meier, Melanie Roeth, Sascha Fauser, Raymond Kimbung, Derek T. Logan, Martin Steegmaier, Hubert Kettenberger
Summary: The study introduces a platform of dual targeting Fab molecules with two independent binding sites, allowing simultaneous binding of two target molecules. These molecules exhibit high affinity, physico-chemical stability, solubility, and superior efficacy compared to anti-VEGF monotherapy in vivo.
NATURE COMMUNICATIONS
(2021)
Article
Oncology
Maria Teresa Blasco, Carolina Navas, Guillermo Martin-Serrano, Osvaldo Grana-Castro, Carmen G. Lechuga, Laura Martin-Diaz, Magdolna Djurec, Jing Li, Lucia Morales-Cacho, Laura Esteban-Burgos, Javier Perales-Paton, Emilie Bousquet-Mur, Eva Castellano, Harrys K. C. Jacob, Lavinia Cabras, Monica Musteanu, Matthias Drosten, Sagrario Ortega, Francisca Mulero, Bruno Sainz Jr, Nelson Dusetti, Juan Iovanna, Francisco Sanchez-Bueno, Manuel Hidalgo, Hossein Khiabanian, Raul Rabadan, Fatima Al-Shahrour, Carmen Guerra, Mariano Barbacid
Article
Multidisciplinary Sciences
Jessica Vitos-Faleato, Sebastian M. Real, Nuria Gutierrez-Prat, Alberto Villanueva, Elisabet Llonch, Matthias Drosten, Mariano Barbacid, Angel R. Nebreda
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2020)
Review
Oncology
Matthias Drosten, Mariano Barbacid
Article
Multidisciplinary Sciences
Laura Esteban-Burgos, Haiyun Wang, Patricia Nieto, Jie Zheng, Carmen Blanco-Aparicio, Carmen Varela, Gonzalo Gomez-Lopez, Fernando Fernandez-Garcia, Manuel Sanclemente, Carmen Guerra, Matthias Drosten, Javier Galan, Eduardo Caleiras, Jorge Martinez-Torrecuadrada, Lluis Fajas, Sheng-Bin Peng, David Santamaria, Monica Musteanu, Mariano Barbacid
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2020)
Letter
Oncology
Manuel Sanclemente, Patricia Nieto, Sara Garcia-Alonso, Fernando Fernandez-Garcia, Laura Esteban-Burgos, Carmen Guerra, Matthias Drosten, Eduardo Caleiras, Jorge Martinez-Torrecuadrada, David Santamaria, Monica Musteanu, Mariano Barbacid
Article
Oncology
Mohamad Assi, Younes Achouri, Axelle Loriot, Nicolas Dauguet, Hajar Dahou, Jonathan Baldan, Maxime Libert, Jean S. Fain, Carmen Guerra, Luc Bouwens, Mariano Barbacid, Frederic P. Lemaigre, Patrick Jacquemin
Summary: The study demonstrates that pancreatic acinar cells become less sensitive to tumorigenesis induced by oncogenic Kras mutations after birth, due to low expression of KRAS and its effectors. Pancreatitis induces the expression of KRAS and its effectors, requiring the activity of EGFR. Expression of C-RAF in adult pancreas is essential for pancreatic tumorigenesis.
Article
Multidisciplinary Sciences
Marina Salmon, Guillem Paniagua, Carmen G. Lechuga, Fernando Fernandez-Garcia, Eduardo Zarzuela, Ruth Alvarez-Diaz, Monica Musteanu, Carmen Guerra, Eduardo Caleiras, Javier Munoz, Sagrario Ortega, Matthias Drosten, Mariano Barbacid
Summary: In mice, the KRAS locus encodes two protein isoforms, KRAS4A and KRAS4B, differing only in their C terminus via alternative splicing of distinct fourth exons. By generating a mouse strain with a terminator codon in exon 4B, researchers created a bona fide Kras4B-null allele, leading to perinatal death due to heart defects. Lack of KRAS4B expression in mice resulted in reduced proliferation of fibroblasts but could be compensated for by ectopic expression of KRAS4A.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Oncology
Matthias Drosten, Mariano Barbacid
Summary: This article discusses the challenges of personalized medicine in treating KRAS mutant lung adenocarcinomas and highlights the recent breakthrough in developing selective KRAS(G12C) inhibitors. The mechanisms of resistance to these inhibitors and alternative therapeutic strategies to target KRAS oncogenic signaling are also explored. The article also examines the failure of MEK and ERK inhibitors in clinical trials and the potential of targeting RAF1 as a MAPK-independent activity. These developments are likely to provide new avenues for effectively treating KRAS mutant lung adenocarcinomas.
MOLECULAR ONCOLOGY
(2022)
Article
Oncology
Guillem Paniagua, Harrys K. C. Jacob, Oksana Brehey, Sara Garcia-Alonso, Carmen G. Lechuga, Tirso Pons, Monica Musteanu, Carmen Guerra, Matthias Drosten, Mariano Barbacid
Summary: KSR1 and KSR2 play important roles in the MAPK pathway, and overexpression of KSR1 or KSR2 can independently activate the pathway and induce cell proliferation. KSR1 requires dimerization with members of the RAF family to stimulate cell proliferation and decreases dependence on KRAS oncogenic signaling.
MOLECULAR ONCOLOGY
(2022)
Editorial Material
Oncology
Matthias Drosten, Mariano Barbacid
Summary: This study identified a potent inhibitor for KRAS(G12D) and demonstrated its strong antitumor activity in preclinical models of pancreatic and colorectal cancer, especially when combined with other treatments.
MOLECULAR ONCOLOGY
(2022)
Article
Medicine, Research & Experimental
Marina Salmon, Ruth Alvarez-Diaz, Coral Fustero-Torre, Oksana Brehey, Carmen G. Lechuga, Manuel Sanclemente, Fernando Fernandez-Garcia, Alejandra Lopez-Garcia, Maria Carmen Martin-Guijarro, Sandra Rodriguez-Perales, Emily Bousquet-Mur, Lucia Morales-Cacho, Francisca Mulero, Fatima Al-Shahrour, Lola Martinez, Orlando Dominguez, Eduardo Caleiras, Sagrario Ortega, Carmen Guerra, Monica Musteanu, Matthias Drosten, Mariano Barbacid
Summary: KRASG12C inhibitors have greatly improved the clinical management of KRASG12C-mutant lung adenocarcinoma patients, but resistance develops rapidly. In this study, genetically engineered mice were used to compare the efficacy and resistance between genetic ablation and pharmacological inhibition of mutant Kras. Results showed that Kras ablation effectively regressed tumors and prevented resistant cells, while treatment with sotorasib, a selective KRASG12C inhibitor, led to limited antitumor response and rapid onset of resistance. Unlike human tumors, resistance in mice was not due to mutations in RAS signaling pathways, but rather amplification of mutant Kras allele and activation of xenobiotic metabolism pathways.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Article
Gastroenterology & Hepatology
Evans Quilichini, Melanie Fabre, Thassadite Dirami, Aline Stedma, Matias De Vas, Ozge Ozguc, Raymond C. Pasek, Silvia Cereghini, Lucie Morillon, Carmen Guerra, Anne Couvelard, Maureen Gannon, Cecile Haumaitre
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
(2019)