Article
Multidisciplinary Sciences
Nicholas H. Juul, Jung-Ki Yoon, Marina C. Martinez, Neha Rishi, Yana I. Kazadaeva, Maurizio Morri, Norma F. Neff, Winston L. Trope, Joseph B. Shrager, Rahul Sinha, Tushar J. Desai
Summary: This study identifies a new cell of origin for lung adenocarcinoma, the AT1 cell, which can be reprogrammed into AT2 stem cells after expressing KRAS(G12D) and subsequently form indolent tumors. These tumor cells spread slowly along alveolar walls in a non-destructive manner and have low ERK activity, resembling human lepidic adenocarcinoma.
Article
Biochemistry & Molecular Biology
Rebecca M. M. Peter, Md. Shahid Sarwar, Sarah Z. Z. Mostafa, Yujue Wang, Xiaoyang Su, Ah-Ng Kong
Summary: This study investigates the treatment effect of HDAC inhibitor belinostat on KRAS-mutant lung cancer. Metabolomic analysis reveals that belinostat regulates metabolites related to redox homeostasis and inhibits the growth of lung cancer cells through the Nrf2 pathway.
MOLECULAR CARCINOGENESIS
(2023)
Review
Medicine, General & Internal
Xuqing Shen, Ningning Niu, Jing Xue
Summary: KRAS activation is a key driver of PDAC initiation and progression, and PDAC cells undergo extensive metabolic reprogramming to meet their extreme energy and biomass demands.
JOURNAL OF TRANSLATIONAL INTERNAL MEDICINE
(2022)
Article
Oncology
Rama Krishna Nimmakayala, Sanchita Rauth, Ramakanth Chirravuri Venkata, Saravanakumar Marimuthu, Palanisamy Nallasamy, Raghupathy Vengoji, Subodh M. Lele, Satyanarayana Rachagani, Kavita Mallya, Mokenge P. Malafa, Moorthy P. Ponnusamy, Surinder K. Batra
Summary: Metabolic reprogramming and cancer stem cells play a crucial role in driving the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). This study found that pancreatic precursor lesions (PPL) and intraductal papillary mucinous neoplasms (IPMN) exhibit specific stemness signatures with unique metabolisms. Inhibition of PGC1 alpha can diminish the specific stemness features of PPLs and repress the growth of IPMN organoids.
CLINICAL CANCER RESEARCH
(2021)
Review
Medicine, Research & Experimental
Hong Xiang, Runjuan Yang, Jiaxin Tu, Yan Xi, Shilei Yang, Linlin Lv, Xiaohan Zhai, Yanna Zhu, Deshi Dong, Xufeng Tao
Summary: Abnormal intracellular metabolism in pancreatic cancer not only provides nutrition for tumor development, but also affects the function of immune cells in the immune microenvironment, promoting immune escape. This review discusses the emerging role of immune cells in pancreatic cancer, focusing on metabolic reprogramming and key metabolic pathways. The hotspots of immune cell metabolic reprogramming in pancreatic cancer mainly involve glucose metabolism, lipid metabolism, tricarboxylic acid cycle, and amino acid metabolism, which impact the function of anti-tumor immune cells and immunosuppressive cells through key metabolic signaling pathways. The review also elaborates on drugs targeting tumor metabolism pathways for clinical treatment of pancreatic cancer.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Editorial Material
Genetics & Heredity
Sanne Bootsma, Sanne M. van Neerven, Louis Vermeulen
Summary: Half of colorectal cancers have KRAS-activating mutations, which affect cancer cells' metabolic dependencies and lead to resistance to common drugs. A new study reveals the metabolic rewiring driven by KRAS and identifies a new therapeutic target for KRAS-mutant cancers.
Article
Food Science & Technology
Lujing Wang, Ahmad Abdel Fat Shannar, Renyi Wu, Pochung Chou, Md Shahid Sarwar, Hsiao-chen Kuo, Rebecca Mary Peter, Yujue Wang, Xiaoyang Su, Ah-Ng Kong
Summary: Butyrate regulates the expression of cancer markers through modulating CpG methylation, activates the mitochondrial TCA cycle, and inhibits methionine metabolism, thereby exerting cancer-preventive/anticancer effects in colorectal cancer cell model.
MOLECULAR NUTRITION & FOOD RESEARCH
(2022)
Editorial Material
Medicine, General & Internal
Cornelis J. M. Melief
Summary: Pancreatic ductal adenocarcinoma is the deadliest of all common cancers. The study reported remarkable deep and durable tumor shrinkage in a heavily pretreated patient who received an infusion of autologous T cells transduced.
NEW ENGLAND JOURNAL OF MEDICINE
(2022)
Article
Immunology
Erika Machado de Salles, Paulo Lisboa Raeder, Claudia Blanes Angeli, Veronica Feijoli Santiago, Cristiane Naffah de Souza, Theresa Ramalho, Niels Olsen Saraiva Camara, Giuseppe Palmisano, Jose Maria alvarez, Maria Regina D'Imperio Lima
Summary: This study provides evidence that P2RX7 modulates the metabolism of Th1 cells through induction of T-bet expression and aerobic glycolysis. P2RX7 signaling leads to bioenergetic mitochondrial stress and sustains the glycolytic pathway in activated CD4+ T cells responding to malaria. Inhibition of ATP synthase and subsequent reduction in oxidative phosphorylation is sufficient to promote Th1 differentiation in the absence of P2RX7.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Shashi Anand, Mohammad Aslam Khan, Haseeb Zubair, Sarabjeet Kour Sudan, Kunwar Somesh Vikramdeo, Sachin Kumar Deshmukh, Shafquat Azim, Sanjeev Kumar Srivastava, Seema Singh, Ajay Pratap Singh
Summary: Extensive desmoplasia and poor vasculature contribute to the aggressiveness and therapy resistance of pancreatic tumors by causing severe hypoxia. In this study, we identify the HuR/MYB/HIF1 alpha axis as a critical regulator of the metabolic plasticity and hypoxic survival of pancreatic cancer cells. HuR translocates from the nuclear to the cytoplasm under hypoxia and stabilizes MYB transcripts, which in turn upregulates HIF1 alpha transcriptionally. MYB promotes the transcription of multiple HIF1 alpha-regulated glycolytic genes by binding directly to their promoters, thus enhancing HIF1 alpha recruitment to hypoxia-responsive elements through interaction with p300-dependent histone acetylation. Depletion of MYB significantly reduces tumorigenic ability, glucose uptake, and metabolism in orthotopic mouse models of pancreatic cancer, even after the restoration of HIF1 alpha. These findings highlight the essential role of MYB in the metabolic reprogramming that supports the survival of pancreatic cancer cells under hypoxia.
Article
Biochemistry & Molecular Biology
Huashan Liu, Zhenxing Liang, Chi Zhou, Ziwei Zeng, Fengwei Wang, Tuo Hu, Xiaowen He, Xiaojian Wu, Xianrui Wu, Ping Lan
Summary: This study reveals a cell-extrinsic role of KRAS in modulating the tumor microenvironment by reprogramming tumor-associated macrophages, promoting tumor progression and inducing resistance to cetuximab therapy. Mechanistically, mutant KRAS stabilizes HIF-1 alpha to drive the production of CSF2 and lactate in tumor cells, enhancing HIF-1 alpha stabilization and contributing to a permissive microenvironment for tumor malignancy.
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2021)
Article
Gastroenterology & Hepatology
Ashley Velez-Delgado, Katelyn L. Donahue, Kristee L. Brown, Wenting Du, Valerie Irizarry-Negron, Rosa E. Menjivar, Emily L. Lasse Opsahl, Nina G. Steele, Stephanie The, Jenny Lazarus, Veerin R. Sirihorachai, Wei Yan, Samantha B. Kemp, Samuel A. Kerk, Murali Bollampally, Sion Yang, Michael K. Scales, Faith R. Avritt, Fatima Lima, Costas A. Lyssiotis, Arvind Rao, Howard C. Crawford, Filip Bednar, Timothy L. Frankel, Benjamin L. Allen, Yaqing Zhang, Marina Pasca di Magliano
Summary: This study reveals that non-cell autonomous oncogenic KRAS signaling can reprogram pancreatic fibroblasts, leading to an inflammatory response and affecting the tumor microenvironment, thereby promoting tumor development.
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
(2022)
Article
Multidisciplinary Sciences
Irene Ischenko, Stephen D'Amico, Manisha Rao, Jinyu Li, Michael J. Hayman, Scott Powers, Oleksi Petrenko, Nancy C. Reich
Summary: In established KRAS-driven pancreatic cancer, KRAS ablation does not impact intrinsic tumorigenic capacity but triggers an antitumor immune response, highlighting the significance of KRAS-driven immune suppression in tumor maintenance.
NATURE COMMUNICATIONS
(2021)
Review
Oncology
Noah C. Cheng, Robert H. Vonderheide
Summary: The long-held desire to target the mutant KRAS gene therapeutically is being fulfilled with the development of small-molecule inhibitors. In addition to its role as a therapeutic target, KRAS also plays a crucial role in shaping the immunosuppressive nature of the tumor microenvironment. This opens up new possibilities for combination immunotherapy using mKRAS inhibitors.
Article
Chemistry, Multidisciplinary
Huashan Liu, Zhenxing Liang, Sijing Cheng, Liang Huang, Wenxin Li, Chi Zhou, Xiaobin Zheng, Shujuan Li, Ziwei Zeng, Liang Kang
Summary: The study reveals that mutant KRAS plays a crucial role in tumor immune evasion in colorectal cancer. Reduced infiltration of cytotoxic CD8(+) T cells is observed in colorectal cancer specimens with mutant KRAS compared to wild type KRAS. Preclinical models confirm this finding and show poor response to anti-PD-1 and adoptive T-cell therapies in KRAS mutant tumors. Mechanistic analysis reveals that lactic acid derived from mutant KRAS-expressing tumor cells sensitizes tumor-specific cytotoxic CD8(+) T cells to activation-induced cell death through NF-kappa B inactivation, explaining the inverse association between intratumoral cytotoxic CD8(+) T cells and KRAS mutation. Importantly, KRAS mutated tumor resistance to immunotherapies can be overcome by targeting KRAS or inhibiting lactic acid production. This study suggests the potential of targeting the KRAS-mediated immune program for the treatment of patients with KRAS mutant colorectal cancer.
Article
Gastroenterology & Hepatology
Kazuma Sekiba, Motoyuki Otsuka, Kazuyoshi Funato, Yu Miyakawa, Eri Tanaka, Takahiro Seimiya, Mari Yamagami, Takeya Tsutsumi, Kazuya Okushin, Kei Miyakawa, Akihide Ryo, Kazuhiko Koike
Summary: The HBV X protein degrades the Smc5/6 complex, impairing DNA double-strand break repair and promoting cellular transformation. Nitazoxanide (NTZ) restores the function of the Smc5/6 complex, repairing HR in HBx-expressing cells and promoting colony formation.
JOURNAL OF HEPATOLOGY
(2022)
Article
Gastroenterology & Hepatology
Hiroyuki Kato, Keisuke Tateishi, Hiroaki Fujiwara, Takuma Nakatsuka, Keisuke Yamamoto, Yotaro Kudo, Yoku Hayakawa, Hayato Nakagawa, Yasuo Tanaka, Hideaki Ijichi, Motoyuki Otsuka, Dosuke Iwadate, Hiroki Oyama, Sachiko Kanai, Kensaku Noguchi, Tatsunori Suzuki, Tatsuya Sato, Ryunosuke Hakuta, Kazunaga Ishigaki, Kei Saito, Tomotaka Saito, Naminatsu Takahara, Takahiro Kishikawa, Tsuyoshi Hamada, Ryota Takahashi, Koji Miyabayashi, Suguru Mizuno, Hirofumi Kogure, Yousuke Nakai, Yoshihiro Hirata, Atsushi Toyoda, Kazuki Ichikawa, Wei Qu, Shinichi Morishita, Junichi Arita, Mariko Tanaka, Tetsuo Ushiku, Kiyoshi Hasegawa, Mitsuhiro Fujishiro, Kazuhiko Koike
Summary: Our study identified the MNX1-HNF1B axis to be biologically significant in IPMN lineages, and this axis is crucial for the regulation of genes such as MYC, SOX9, and OLFM4.
Article
Biochemistry & Molecular Biology
Kazuyoshi Funato, Motoyuki Otsuka, Kazuma Sekiba, Yu Miyakawa, Takahiro Seimiya, Chikako Shibata, Takahiro Kishikawa, Mitsuhiro Fujishiro
Summary: DNA repair processes are potential therapeutic targets for cancer treatment. This study reveals that HBV-associated HCC with a deficiency in the Smc5/6 complex is more susceptible to PARP inhibitors due to impaired homologous recombination. The findings suggest a potential treatment strategy for HBV-related HCC.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Hiroaki Kanzaki, Tetsuhiro Chiba, Tatsuya Kaneko, Junjie Ao, Motoyasu Kan, Ryosuke Muroyama, Shingo Nakamoto, Tatsuo Kanda, Hitoshi Maruyama, Jun Kato, Yoh Zen, Ai Kotani, Kazuma Sekiba, Motoyuki Otsuka, Masayuki Ohtsuka, Naoya Kato
Summary: ELAVL1 protein is not only involved in the replication of hepatitis B virus, but also has an impact on the cell growth of hepatocellular carcinoma, making it a potential therapeutic target for HBV-related HCC treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Oncology
Chikako Shibata, Motoyuki Otsuka, Takahiro Seimiya, Takahiro Kishikawa, Kazunaga Ishigaki, Mitsuhiro Fujishiro
CLINICAL AND TRANSLATIONAL MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Chikako Shibata, Motoyuki Otsuka, Takahiro Seimiya, Kazunaga Ishigaki, Yu Miyakawa, Takahiro Kishikawa, Mitsuhiro Fujishiro
Summary: The size of EVs is influenced by different types of cancers, with EVs derived from pancreatic cancer cells being smaller than those from non-cancer cells. Low glucose conditions reduce EVs' size distribution and increase levels of unsaturated fatty acids in EVs. Increased uptake of smaller EVs by recipient cells may lead to enhanced functional outcomes.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Oncology
Hiroyuki Kato, Keisuke Tateishi, Dosuke Iwadate, Keisuke Yamamoto, Hiroaki Fujiwara, Takuma Nakatsuka, Yotaro Kudo, Yoku Hayakawa, Hideaki Ijichi, Motoyuki Otsuka, Takahiro Kishikawa, Ryota Takahashi, Koji Miyabayashi, Yousuke Nakai, Yoshihiro Hirata, Atsushi Toyoda, Shinichi Morishita, Mitsuhiro Fujishiro
Summary: This study discovered the correlation between 3D genome structures and molecular subtypes of pancreatic cancer (PC) through Hi-C analysis. They found that HNF1B regulates the expression of related genes by influencing the 3D structures. These findings are significant for a better understanding of the molecular features of PC.
Article
Multidisciplinary Sciences
Takahiro Seimiya, Tatsunori Suzuki, Takuma Iwata, Takahiro Kishikawa, Kazuma Sekiba, Chikako Shibata, Kazunaga Ishigaki, Hiroaki Fujiwara, Hiroki Oyama, Sachiko Kanai, Tatsuya Sato, Yousuke Nakai, Rei Ishibashi, Masaru Moriyama, Ryo Nakagawa, Hideaki Ijichi, Motoyuki Otsuka, Kazuhiko Koike
Summary: Pancreatic ductal adenocarcinoma (PDAC) is difficult to diagnose and has a poor prognosis. Human satellite II (HSATII) RNA, highly expressed in human PDAC, may serve as a biomarker for PDAC. We developed a convenient method, tandem repeat amplification by nuclease protection (TRAP) combined with droplet digital PCR (ddPCR), to measure serum HSATII RNA level with high sensitivity and reproducibility. By simultaneously measuring serum miR-21-5p level, we refined the method and constructed a PDAC-Index that accurately discriminates PDAC patients. The PDAC-Index was clinically validated as a supportive test in challenging diagnostic cases and showed satisfactory diagnostic performance for routine PDAC detection.
Letter
Medicine, General & Internal
Elif Hindie
NEW ENGLAND JOURNAL OF MEDICINE
(2022)
Letter
Medicine, General & Internal
Motoyuki Otsuka
NEW ENGLAND JOURNAL OF MEDICINE
(2022)
Article
Medicine, Research & Experimental
Satoshi Kawamura, Yuki Matsushita, Shigeyuki Kurosaki, Mizuki Tange, Naoto Fujiwara, Yuki Hayata, Yoku Hayakawa, Nobumi Suzuki, Masahiro Hata, Mayo Tsuboi, Takahiro Kishikawa, Hiroto Kinoshita, Takuma Nakatsuka, Masaya Sato, Yotaro Kudo, Yujin Hoshida, Atsushi Umemura, Akiko Eguchi, Tsuneo Ikenoue, Yoshihiro Hirata, Motonari Uesugi, Ryosuke Tateishi, Keisuke Tateishi, Mitsuhiro Fujishiro, Kazuhiko Koike, Hayato Nakagawa
Summary: Inhibition of sterol regulatory element-binding proteins (SREBPs) is not an effective approach for treating nonalcoholic steatohepatitis (NASH), as it exacerbates liver injury and liver cancer development despite reducing hepatic steatosis. Additionally, SREBP inhibition alters lipid composition, causes endoplasmic reticulum stress and hepatocyte injury, but these effects can be mitigated by supplementation with phosphatidylcholines.
JOURNAL OF CLINICAL INVESTIGATION
(2022)