Oncology
Abstract
MRE11, a breast tumor suppressor and component of the MRE11-RAD50-NBS1 (MRN) complex, plays a critical role in DNA end resection and initiation of ATM-dependent DNA damage signaling. However, the precise mechanisms governing MRE11 function in the DNA damage response (DDR) remain incompletely understood. Here, we found that MRE11 is deacetylated by the SIRT2 sirtuin deacetylase and breast tumor suppressor, which promotes DNA binding to facilitate DNA end resection and ATM-dependent signaling. SIRT2 deacetylase activity promoted DNA end resection. SIRT2 further complexed with and deacetylated MRE11 at conserved lysine (K) 393 in response to DNA double-strand breaks (DSBs), which promoted MRE11 localization and DNA binding at DSBs but not interaction with RAD50, NBS1, or CtIP. Moreover, MRE11 K393 deacetylation by SIRT2 promoted ATM-dependent signaling. Our findings define a mechanism regulating MRE11 binding to DNA through SIRT2 deacetylation, elucidating a critical upstream signaling event directing MRE11 function in the DDR and providing insight into how SIRT2 dysregulation leads to genomic instability and tumorigenesis.
Authors
Fatmata Sesay, Hui Zhang, Priya Kapoor-Vazirani, Andrew T. Jung, Mark E. Essien, Amanda J. Bastien, Nho C. Luong, Xu Liu, PamelaSara E. Head, Duc M. Duong, Xiaofeng Yang, Zachary S. Buchwald, Xingming Deng, Nicholas T. Seyfried, David S. Yu
Abstract
Neutrophil extracellular traps (NETs) are associated with cancer progression; however, the functional role and clinical importance of NET-DNA in therapeutic resistance remain unclear. Here, we show that chemotherapy and radiotherapy provoke NET-DNA formation in primary tumor and metastatic organs in breast cancer patients and mouse models, and the level of NET-DNA correlates with treatment resistance. Mechanistically, the cathepsin C in tumor debris generated by anticancer therapy is phagocytosed by macrophages and drives CXCL1/2 and complement factor B production via activating the TLR4/NF-κB signaling pathway, subsequently promoting NETosis and impairing therapeutic efficacy. Importantly, we demonstrate that NET-DNA sensor CCDC25 is indispensable in NET-mediated treatment resistance by inducing cancer cell epithelial-mesenchymal transition via pyruvate kinase isoform M2–mediated STAT3 phosphorylation. Clinically, tumoral CCDC25 abundance is closely associated with poor prognosis in patients who underwent chemotherapy. Overall, our data reveal the mechanism of NET formation and elucidate the interaction of NET-CCDC25 in therapy resistance, highlighting CCDC25 as an appealing target for anticancer interventions.
Authors
Heliang Li, Yetong Zhang, Jianghua Lin, Jiayi Zeng, Xinyan Liang, Linxi Xu, Jiang Li, Xiaoming Zhong, Xu Liu, Zhou Liu, Xinyu Yang, Yunyi Zhang, Shun Wang, Erwei Song, Man Nie, Linbin Yang
Abstract
Pancreatic ductal adenocarcinoma (PDAC) occurs as a complex, multifaceted event driven by the interplay of tumor-permissive genetic mutations, the nature of the cellular origin, and microenvironmental stress. In this study, using primary human pancreatic acinar 3D organoids, we performed a CRISPR-KO screen targeting 199 potential tumor suppressors curated from clinical PDAC samples. Our data revealed significant enrichment of a list of candidate genes, with neurofibromatosis type 2 associated gene (NF2) emerging as the top target. Functional validation confirmed that loss of NF2 promoted the transition of PDAC to an invasive state, potentially through extracellular matrix modulation. NF2 inactivation was found to enhance PDAC cell fitness under nutrient starvation. This adaptation not only reinforced the oncogenic state but also conferred therapeutic resistance. Additionally, we found that NF2 loss was associated with fibroblast heterogeneity and cancer-stroma communication in tumor evolution. These findings establish NF2 as a critical tumor suppressor in PDAC and uncover its role in mediating nutrient adaptation and drug resistance. Importantly, this study provides additional insights into drug resistance mechanisms and potential therapeutic targets in PDAC.
Authors
Yi Xu, Michael H. Nipper, Angel A. Dominguez, Chenhui He, Francis E. Sharkey, Sajid Khan, Han Xu, Daohong Zhou, Lei Zheng, Yu Luan, Jun Liu, Pei Wang
Abstract
Cuproptosis involves accumulation of intracellular copper that triggers mitochondrial lipoylated protein aggregation and destabilization of iron–sulfur cluster proteins, leading to cell death. Pharmacologic induction of cuproptosis has been proposed as a cancer therapy. Here, we find that glioblastoma (GBM) stem cells (GSCs) displayed relative resistance to cuproptosis with circadian variation of intracellular copper levels. CRISPR screening of copper regulators under concurrent treatment with copper ionophore or clock disruption revealed dependency on ATPase copper transporting alpha (ATP7A). Circadian control of copper homeostasis was mediated by the core clock transcription factor, brain and muscle ARNT-like 1 (BMAL1). In turn, ATP7A promoted tumor cell growth through regulation of fatty acid desaturation. Copper levels negatively fed back into the circadian circuitry through sequestosome 1/p62–mediated lysosomal degradation of BMAL1. Targeting the circadian clock or fatty acid desaturation augmented cuproptosis antitumor effects. Crosstalk between the core circadian clock and copper sustains GSCs, reshaping fatty acid metabolism and promoting drug resistance, which may inform development of combination therapies for GBM.
Authors
Fanen Yuan, Xujia Wu, Huairui Yuan, Donghai Wang, Tengfei Huang, Po Zhang, Hailong Mi, Weichi Wu, Suchet Taori, Priscilla Chan, Kenji Miki, Maged T. Ghoche, Linjie Zhao, Kalil G. Abdullah, Steve A. Kay, Qiulian Wu, Jeremy N. Rich
Abstract
Mutations in DNA mismatch repair (MMR) pathway genes (MSH2, MSH6, MLH1, and PMS2) are linked to acquired resistance to temozolomide (TMZ) and high tumor mutation burden (TMB) in high-grade gliomas (HGG), including glioblastoma (GBM). However, the specific roles of individual MMR genes in the initiation, progression, TMB, microsatellite instability (MSI), and resistance to TMZ in glioma remain unclear. Here, we developed de novo mouse models of germline and somatic MMR-deficient (MMRd) HGG. Surprisingly, loss of Msh2 or Msh6 does not lead to high TMB, MSI, nor confer response to anti-PD-1 in GBM. Similarly, human GBM shows discordance between MMR gene mutations and TMB/MSI.Germline MMRd leads to promoted progression from low-grade to HGG and reduced survival compared to MMR-proficient (MMRp) tumor-bearing mice. This effect is not tumor cell intrinsic but is associated with MMRd in the tumor immune microenvironment, driving immunosuppressive myeloid programs, reduced lymphoid infiltration, and CD8+ T cell exhaustion. Both MMR-reduced (MMRr) and MMRd GBM are resistant to temozolomide (TMZ), unlike MMRp tumors. Our study shows that KL-50, a imidazotetrazine-based DNA targeting agent inducing MMR-independent cross-link–mediated cytotoxicity, was effective against germline and somatic MMRr/MMRd GBM, offering a potential therapy for TMZ-resistant HGG with MMR alterations.
Authors
Montserrat Puigdelloses Vallcorba, Nishant Soni, Seung-Won Choi, Kavita Rawat, Tanvi Joshi, Sam Friedman, Alice Buonfiglioli, Angelo Angione, Zhihong Chen, Gonzalo Piñero, Gabrielle Price, Mehek Dedhia, Raina Roche, Emir Radkevich, Anne M. Bowcock, Deepti Bhatt, Winfried Edelmann, Robert M. Samstein, Timothy E. Richardson, Nadejda M. Tsankova, Alexander M. Tsankov, Ranjit S. Bindra, Raul Rabadan, Juan C. Vasquez, Dolores Hambardzumyan
Abstract
Non-small cell lung cancer (NSCLC) exhibits the highest rates of brain metastases (BM) among all solid tumors and presents a significant clinical challenge. The development of novel therapeutic strategies targeting BM is clearly needed. We identified a significant enrichment of MET amplification in lung adenocarcinoma (LUAD) BM compared to primary LUAD and extracranial metastases in oncogene driver-negative patients. Of note, MET amplified BM were responsive to MET inhibitors in vivo including models with acquired MET amplification at the time of metastasis. MET alterations (amplifications and/or mutations) were also more frequently detected in circulating tumor DNA from LUAD BM patients than in those without BM. MET altered BM also demonstrated unique genomic features compared to non-MET altered BM. Transcriptomic analyses revealed that in contrast to MET wildtype BM, MET amplified BM exhibited a more inflamed tumor microenvironment and displayed evidence of metabolic adaptation, particularly a reliance on glycolysis in contrast to oxidative phosphorylation in MET wildtype BM. Further, MET amplified BM demonstrated evidence of epithelial-mesenchymal transition signaling including increased expression of TWIST1. Patients with MET amplified BM had significantly shorter overall survival. These findings highlight MET amplification as a critical driver of LUAD BM, emphasizing its potential as a therapeutic target.
Authors
Timothy F. Burns, Sanja Dacic, Anish Chakka, Ethan Miller, Maria A. Velez, Ashwin Somasundaram, Saveri Bhattacharya, Autumn Gaither-Davis, Princey Devadassan, Jingxiao Jin, Vinod Kumar, Arjun Pennathur, Joanne Xiu, Matthew Oberley, Michael J. Glantz, Sonikpreet Aulakh, Uma R. Chandran, Riyue Bao, Curtis Tatsuoka, Laura P. Stabile
Abstract
Fanconi anemia (FA) confers a high risk (~700-fold increase) of solid tumor formation, most often head and neck squamous cell carcinoma (HNSCC). FA germline DNA repair defects preclude administration of most chemotherapies and prior hematopoietic stem cell transplantation limits use of immunotherapy. Thus, surgery and judicious delivery of radiation offer the only treatment options, with most patients succumbing to their cancers. A paucity of preclinical models has limited the development of new treatments. Here, we report, to our knowledge, the first patient-derived xenografts (PDXs) of FA-HNSCC and highlight the efficacy of FDA-approved EGFR targeted therapies in tumors with high EGFR/p-EGFR levels and the activity of the FDA-approved Bcl-2 inhibitor venetoclax in a FA-HNSCC PDX overexpressing Bcl-2. These findings support the development of precision medicine approaches for FA-HNSCC.
Authors
Jennifer Grandis, Hua Li, Benjamin A. Harrison, Andrew L.H. Webster, Joanna Pucilowska, Austin Nguyen, Jinho Lee, Gordon B. Mills, Jovanka Gencel-Augusto, Yan Zeng, Steven R. Long, Mi-Ok Kim, Rex H. Lee, David I. Kutler, Theresa Scognamiglio, Margaret Brandwein-Weber, Mark Urken, Inna Khodos, Elisa de Stanchina, Yu-Chien Lin, Frank X. Donovan, Settara C. Chandrasekharappa, Moonjung Jung, Mathijs A. Sanders, Agata Smogorzewska, Daniel E. Johnson
Abstract
Mechanistic target of rapamycin complex 1 (mTORC1) is a master controller of cell growth and its dysregulation is associated with cancer. KICSTOR, a complex comprising KPTN, ITFG2, C12orf66, and SZT2, functions as a critical negative regulator of amino acid-induced mTORC1 activation. However, the regulatory mechanisms governing KICSTOR remain largely unclear. In this study, we identify FBXO2 as a key modulator of amino acid-dependent mTORC1 signaling. Mechanistically, FBXO2 colocalizes and directly interacts with KPTN via its F-box-associated domain, promoting K48- and K63-linked polyubiquitination of KPTN at lysine residues 49, 67, 262, and 265. FBXO2-mediated KPTN ubiquitination disrupts its interaction with ITFG2 and SZT2, while enhancing its interaction with C12orf66, thereby impairing the ability of KICSTOR to recruit the GATOR1 complex to the lysosomal surface. Notably, FBXO2 protein levels are substantially upregulated in liver cancer patients and FBXO2-mediated KPTN ubiquitination facilitates the progression of hepatocellular carcinoma (HCC). These results reveal a key regulatory mechanism of the mTORC1 signaling and highlight FBXO2 and KPTN ubiquitination as therapeutic targets for HCC treatment.
Authors
Jianfang Gao, Jina Qing, Xianglong Li, Yuxuan Luo, Lingwen Huang, Hongxia Li, Huan Zhang, Jiao Zhang, Pei Xiao, Jinsong Li, Tingting Li, Shanping He
Abstract
The metabolic microenvironment plays important roles in tumorigenesis, but how leukemia-initiating cells (LICs) response to the acidic BM niche remains largely unknown. Here, we show that acid-sensing ion channel 3 (ASIC3) dramatically delays leukemogenesis. Asic3 deletion results in a remarkably enhanced self-renewal, reduced differentiation, and 9-fold greater number of murine acute myeloid LICs. We developed an ultrasensitive, ratiometric, genetically encoded fluorescent pH sensor (pHluorin3) and demonstrated that LICs prefer localizing in the endosteal niche with a neutral pH range of 7.34–7.42, but not in the vascular niche with a lower pH range of 6.89–7.22. Unexpectedly, acid-ASIC3 signaling inhibits both murine and human LIC activities in a noncanonical manner by interacting with the N-terminal of STIM1 to reduce calcium-mediated CAMK1-CREB-MEIS1-LDHA levels, without inducing cation currents. This study reveals a pathway in suppression of leukemogenesis in the acidic BM niche and provides insight into targeting LICs or other cancer stem cells through pH-dependent ASICs.
Authors
Hao Gu, Lietao Weng, Chiqi Chen, Xiaoxin Hao, Rongkun Tao, Xin Qi, Xiaoyun Lai, Ligen Liu, Tinghua Zhang, Yiming Jiang, Jin Wang, Wei-Guang Li, Zhuo Yu, Li Xie, Yaping Zhang, Xiaoxiao He, Ye Yu, Yi Yang, Dehua Wu, Yuzheng Zhao, Tian-Le Xu, Guo-Qiang Chen, Junke Zheng
Abstract
Triple-negative breast cancer (TNBC), being both aggressive and highly lethal, poses a major clinical challenge in terms of treatment. Its heterogeneity and lack of hormone receptors or HER2 expression further restrict the availability of targeted therapy. Breast cancer stem cells (BCSCs), known to fuel TNBC malignancy, are now being exploited as a vulnerability for TNBC treatment. Here, we dissected the transcriptome of BCSCs and identified kinesin family member 20A (KIF20A) as a key regulator of BCSC survival and TNBC tumorigenesis. Genetic depletion or pharmacological inhibition of KIF20A impairs BCSC viability and tumor initiation and development in vitro and in vivo. Mechanistically, KIF20A supports BCSC stemness through modulation of mitochondrial oxidative phosphorylation, which is repressed by SMARCA4, a component of the SWI/SNF chromatin remodeling complex. Therapeutically, KIF20A inhibition sensitizes TNBC xenografts to standard-of-care chemotherapy. Our study highlights the importance of targeting KIF20A to exploit BCSC vulnerabilities in TNBC.
Authors
Yayoi Adachi, Weilong Chen, Cheng Zhang, Tao Wang, Nina Gildor, Rachel Shi, Haoyong Fu, Masashi Takeda, Qian Liang, Fangzhou Zhao, Hongyi Liu, Jun Fang, Jin Zhou, Hongwei Yao, Lianxin Hu, Shina Li, Lei Guo, Lin Xu, Ling Xie, Xian Chen, Chengheng Liao, Qing Zhang
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)