bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2022–02–20
twenty papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. Metabolic Features of Tumor Dormancy: Possible Therapeutic Strategies.
  2. Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance.
  3. A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis.
  4. Remodeling of the tumor/tumor microenvironment ecosystem during KRAS G12C inhibitor clinical resistance in lung cancer.
  5. Blockade of the pro-fibrotic reaction mediated by the miR-143/-145 cluster enhances the responses to targeted therapy in melanoma.
  6. Ghost mitochondria drive metastasis through adaptive GCN2/Akt therapeutic vulnerability.
  7. Ferroptosis in cancer therapy: a novel approach to reversing drug resistance.
  8. AXL Receptor Tyrosine Kinase as a Promising Therapeutic Target Directing Multiple Aspects of Cancer Progression and Metastasis.
  9. Downregulation of LNMAS orchestrates partial EMT and immune escape from macrophage phagocytosis to promote lymph node metastasis of cervical cancer.
  10. Substrate rigidity dictates colorectal tumorigenic cell stemness and metastasis via CRAD-dependent mechanotransduction.
  11. Overexpression of BACH1 mediated by IGF2 facilitates hepatocellular carcinoma growth and metastasis via IGF1R and PTK2.
  12. EMT-mediated regulation of CXCL1/5 for resistance to anti-EGFR therapy in colorectal cancer.
  13. Lin28B-high breast cancer cells promote immune suppression in the lung pre-metastatic niche via exosomes and support cancer progression.
  14. Treatment-driven tumour heterogeneity and drug resistance: Lessons from solid tumours.
  15. NCAPG promotes the oncogenesis and progression of non-small cell lung cancer cells through upregulating LGALS1 expression.
  16. Antifibrotic drugs as therapeutic tools in resistant melanoma.
  17. A non-catalytic scaffolding activity of hexokinase 2 contributes to EMT and metastasis.
  18. TET2 suppresses VHL deficiency-driven clear cell renal cell carcinoma by inhibiting HIF signaling.
  19. USP13 promotes development and metastasis of high-grade serous ovarian carcinoma in a novel mouse model.
  20. The histone demethylase PHF8 regulates TGFβ signaling and promotes melanoma metastasis.
  1. Cancers (Basel). 2022 Jan 21. pii: 547. [Epub ahead of print]14(3):
    Metabolic Features of Tumor Dormancy: Possible Therapeutic Strategies.
    Erica Pranzini, Giovanni Raugei, Maria Letizia Taddei.
      Tumor relapse represents one of the main obstacles to cancer treatment. Many patients experience cancer relapse even decades from the primary tumor eradication, developing more aggressive and metastatic disease. This phenomenon is associated with the emergence of dormant cancer cells, characterized by cell cycle arrest and largely insensitive to conventional anti-cancer therapies. These rare and elusive cells may regain proliferative abilities upon the induction of cell-intrinsic and extrinsic factors, thus fueling tumor re-growth and metastasis formation. The molecular mechanisms underlying the maintenance of resistant dormant cells and their awakening are intriguing but, currently, still largely unknown. However, increasing evidence recently underlined a strong dependency of cell cycle progression to metabolic adaptations of cancer cells. Even if dormant cells are frequently characterized by a general metabolic slowdown and an increased ability to cope with oxidative stress, different factors, such as extracellular matrix composition, stromal cells influence, and nutrient availability, may dictate specific changes in dormant cells, finally resulting in tumor relapse. The main topic of this review is deciphering the role of the metabolic pathways involved in tumor cells dormancy to provide new strategies for selectively targeting these cells to prevent fatal recurrence and maximize therapeutic benefit.
    Keywords:  cancer stem cells; circulating tumor cells; dormancy; metabolism; tumor recurrence
    DOI:  https://doi.org/10.3390/cancers14030547
  2. Nat Cell Biol. 2022 Feb;24(2): 168-180
    Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance.
    Patrizia Romani, Nunzia Nirchio, Mattia Arboit, Vito Barbieri, Anna Tosi, Federica Michielin, Soichi Shibuya, Thomas Benoist, Danchen Wu, Charles Colin Thomas Hindmarch, Monica Giomo, Anna Urciuolo, Flavia Giamogante, Antonella Roveri, Probir Chakravarty, Marco Montagner, Tito Calì, Nicola Elvassore, Stephen L Archer, Paolo De Coppi, Antonio Rosato, Graziano Martello, Sirio Dupont.
      Metastatic breast cancer cells disseminate to organs with a soft microenvironment. Whether and how the mechanical properties of the local tissue influence their response to treatment remains unclear. Here we found that a soft extracellular matrix empowers redox homeostasis. Cells cultured on a soft extracellular matrix display increased peri-mitochondrial F-actin, promoted by Spire1C and Arp2/3 nucleation factors, and increased DRP1- and MIEF1/2-dependent mitochondrial fission. Changes in mitochondrial dynamics lead to increased production of mitochondrial reactive oxygen species and activate the NRF2 antioxidant transcriptional response, including increased cystine uptake and glutathione metabolism. This retrograde response endows cells with resistance to oxidative stress and reactive oxygen species-dependent chemotherapy drugs. This is relevant in a mouse model of metastatic breast cancer cells dormant in the lung soft tissue, where inhibition of DRP1 and NRF2 restored cisplatin sensitivity and prevented disseminated cancer-cell awakening. We propose that targeting this mitochondrial dynamics- and redox-based mechanotransduction pathway could open avenues to prevent metastatic relapse.
    DOI:  https://doi.org/10.1038/s41556-022-00843-w
  3. EMBO Mol Med. 2022 Feb 17. e14552
    A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis.
    RENACER
      We report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere.
    Keywords:  drug-screen; metastasis; organotypic cultures; patient-derived; resistance
    DOI:  https://doi.org/10.15252/emmm.202114552
  4. J Clin Invest. 2022 02 15. pii: e156891. [Epub ahead of print]132(4):
    Remodeling of the tumor/tumor microenvironment ecosystem during KRAS G12C inhibitor clinical resistance in lung cancer.
    Tadashi Manabe, Trever G Bivona.
      KRAS G12C inhibitors such as sotorasib and adagrasib are often effective in KRAS G12C-driven non-small cell lung cancer (NSCLC) patients. However, acquired resistance limits long-term patient survival. In this issue of the JCI, Tsai et al. present a comprehensive genetic analysis of multiple tumors with acquired sotorasib resistance obtained through an autopsy of a patient with KRAS G12C-mutant NSCLC. This analysis of pre- and posttreatment tumors uncovered cancer cell-intrinsic and -extrinsic features of resistance, including reactivation of KRAS-mediated signaling, reprogramming of metabolism, epithelial-mesenchymal transition, and tumor microenvironment changes. This elegant study demonstrates the multifaceted nature of KRAS G12C inhibitor clinical resistance and potential avenues to overcome resistance.
    DOI:  https://doi.org/10.1172/JCI156891
  5. EMBO Mol Med. 2022 Feb 14. e15295
    Blockade of the pro-fibrotic reaction mediated by the miR-143/-145 cluster enhances the responses to targeted therapy in melanoma.
    Serena Diazzi, Alberto Baeri, Julien Fassy, Margaux Lecacheur, Oskar Marin-Bejar, Christophe A Girard, Lauren Lefevre, Caroline Lacoux, Marie Irondelle, Carine Mounier, Marin Truchi, Marie Couralet, Mickael Ohanna, Alexandrine Carminati, Ilona Berestjuk, Frederic Larbret, David Gilot, Georges Vassaux, Jean-Christophe Marine, Marcel Deckert, Bernard Mari, Sophie Tartare-Deckert.
      Lineage dedifferentiation toward a mesenchymal-like state displaying myofibroblast and fibrotic features is a common mechanism of adaptive and acquired resistance to targeted therapy in melanoma. Here, we show that the anti-fibrotic drug nintedanib is active to normalize the fibrous ECM network, enhance the efficacy of MAPK-targeted therapy, and delay tumor relapse in a preclinical model of melanoma. Acquisition of this resistant phenotype and its reversion by nintedanib pointed to miR-143/-145 pro-fibrotic cluster as a driver of this mesenchymal-like phenotype. Upregulation of the miR-143/-145 cluster under BRAFi/MAPKi therapy was observed in melanoma cells in vitro and in vivo and was associated with an invasive/undifferentiated profile. The 2 mature miRNAs generated from this cluster, miR-143-3p and miR-145-5p, collaborated to mediate transition toward a drug-resistant undifferentiated mesenchymal-like state by targeting Fascin actin-bundling protein 1 (FSCN1), modulating the dynamic crosstalk between the actin cytoskeleton and the ECM through the regulation of focal adhesion dynamics and mechanotransduction pathways. Our study brings insights into a novel miRNA-mediated regulatory network that contributes to non-genetic adaptive drug resistance and provides proof of principle that preventing MAPKi-induced pro-fibrotic stromal response is a viable therapeutic opportunity for patients on targeted therapy.
    Keywords:  MAPK inhibitors; fibrosis; melanoma; microRNA; nintedanib
    DOI:  https://doi.org/10.15252/emmm.202115295
  6. Proc Natl Acad Sci U S A. 2022 Feb 22. pii: e2115624119. [Epub ahead of print]119(8):
    Ghost mitochondria drive metastasis through adaptive GCN2/Akt therapeutic vulnerability.
    Jagadish C Ghosh, Michela Perego, Ekta Agarwal, Irene Bertolini, Yuan Wang, Aaron R Goldman, Hsin-Yao Tang, Andrew V Kossenkov, Catherine J Libby, Lucia R Languino, Edward F Plow, Annamaria Morotti, Luisa Ottobrini, Marco Locatelli, David W Speicher, M Cecilia Caino, Joel Cassel, Joseph M Salvino, Marie E Robert, Valentina Vaira, Dario C Altieri.
      Cancer metabolism, including in mitochondria, is a disease hallmark and therapeutic target, but its regulation is poorly understood. Here, we show that many human tumors have heterogeneous and often reduced levels of Mic60, or Mitofilin, an essential scaffold of mitochondrial structure. Despite a catastrophic collapse of mitochondrial integrity, loss of bioenergetics, and oxidative damage, tumors with Mic60 depletion slow down cell proliferation, evade cell death, and activate a nuclear gene expression program of innate immunity and cytokine/chemokine signaling. In turn, this induces epithelial-mesenchymal transition (EMT), activates tumor cell movements through exaggerated mitochondrial dynamics, and promotes metastatic dissemination in vivo. In a small-molecule drug screen, compensatory activation of stress response (GCN2) and survival (Akt) signaling maintains the viability of Mic60-low tumors and provides a selective therapeutic vulnerability. These data demonstrate that acutely damaged, "ghost" mitochondria drive tumor progression and expose an actionable therapeutic target in metastasis-prone cancers.
    Keywords:  cell motility; metastasis; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2115624119
  7. Mol Cancer. 2022 02 12. 21(1): 47
    Ferroptosis in cancer therapy: a novel approach to reversing drug resistance.
    Chen Zhang, Xinyin Liu, Shidai Jin, Yi Chen, Renhua Guo.
      Ferroptosis is an intracellular iron-dependent form of cell death that is distinct from apoptosis, necrosis, and autophagy. Extensive studies suggest that ferroptosis plays a pivotal role in tumor suppression, thus providing new opportunities for cancer therapy. The development of resistance to cancer therapy remains a major challenge. A number of preclinical and clinical studies have focused on overcoming drug resistance. Intriguingly, ferroptosis has been correlated with cancer therapy resistance, and inducing ferroptosis has been demonstrated to reverse drug resistance. Herein, we provide a detailed description of the mechanisms of ferroptosis and the therapeutic role of regulating ferroptosis in reversing the resistance of cancer to common therapies, such as chemotherapy, targeted therapy and immunotherapy. We discuss the prospect and challenge of regulating ferroptosis as a therapeutic strategy for reversing cancer therapy resistance and expect that our review could provide some references for further studies.
    Keywords:  Chemotherapy; Drug resistance; Ferroptosis; Immunotherapy; Targeted therapy
    DOI:  https://doi.org/10.1186/s12943-022-01530-y
  8. Cancers (Basel). 2022 Jan 18. pii: 466. [Epub ahead of print]14(3):
    AXL Receptor Tyrosine Kinase as a Promising Therapeutic Target Directing Multiple Aspects of Cancer Progression and Metastasis.
    Marie-Anne Goyette, Jean-François Côté.
      The receptor tyrosine kinase AXL is emerging as a key player in tumor progression and metastasis and its expression correlates with poor survival in a plethora of cancers. While studies have shown the benefits of AXL inhibition for the treatment of metastatic cancers, additional roles for AXL in cancer progression are still being explored. This review discusses recent advances in understanding AXL's functions in different tumor compartments including cancer, vascular, and immune cells. AXL is required at multiple steps of the metastatic cascade where its activation in cancer cells leads to EMT, invasion, survival, proliferation and therapy resistance. AXL activation in cancer cells and various stromal cells also results in tumor microenvironment deregulation, leading to modulation of angiogenesis, fibrosis, immune response and hypoxia. A better understanding of AXL's role in these processes could lead to new therapeutic approaches that would benefit patients suffering from metastatic diseases.
    Keywords:  AXL; EMT; angiogenesis; fibrosis; hypoxia; immune evasion; invasion; metastasis; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers14030466
  9. Oncogene. 2022 Feb 12.
    Downregulation of LNMAS orchestrates partial EMT and immune escape from macrophage phagocytosis to promote lymph node metastasis of cervical cancer.
    Yuandong Liao, Jiaming Huang, Pan Liu, Chunyu Zhang, Junxiu Liu, Meng Xia, Chunliang Shang, Shiyin Ooi, Yili Chen, Shuhang Qin, Qiqiao Du, Tianyu Liu, Manman Xu, Qiaojian Zou, Yijia Zhou, Hua Huang, Yuwen Pan, Wei Wang, Shuzhong Yao.
      Epithelial-mesenchymal transition (EMT) is an essential step to drive the metastatic cascade to lymph nodes (LNs) in cervical cancer cells. However, few of them metastasize successfully partially due to increased susceptibility to immunosurveillance conferred by EMT. The precise mechanisms of cancer cells orchestrate EMT and immune evasion remain largely unexplored. In this study, we identified a lncRNA termed lymph node metastasis associated suppressor (LNMAS), which was downregulated in LN-positive cervical cancer patients and correlated with LN metastasis and prognosis. Functionally, LNMAS suppressed cervical cancer cells metastasis in vitro and in vivo. Mechanistically, LNMAS exerts its metastasis suppressive activity by competitively interacting with HMGB1 and abrogating the chromatin accessibility of TWIST1 and STC1, inhibiting TWIST1-mediated partial EMT and STC1-dependent immune escape from macrophage phagocytosis. We further demonstrated that the CpG sites in the promoter region of LNMAS was hypermethylated and contributed to the downregulation of LNMAS. Taken together, our results reveal the essential role of LNMAS in the LN metastasis of cervical cancer and provide mechanistic insights into the regulation of LNMAS in EMT and immune evasion.
    DOI:  https://doi.org/10.1038/s41388-022-02202-3
  10. Cell Rep. 2022 02 15. pii: S2211-1247(22)00111-5. [Epub ahead of print]38(7): 110390
    Substrate rigidity dictates colorectal tumorigenic cell stemness and metastasis via CRAD-dependent mechanotransduction.
    Yuhan Chang, Juan Zhang, Xinying Huo, Xinliang Qu, Chunlei Xia, Kaizong Huang, Fuyang Xie, Nuofan Wang, Xiaowei Wei, Qiong Jia.
      Tumor physical microenvironment contributes greatly to the response of tumor cells. However, the mechanism of how extracellular substrate rigidity remodels colorectal cancer (CRC) cell fate and affects CRC progression remains elusive. Here, we show that F-actin regulator KIAA1211, also known as Capping protein inhibiting regulator of actin dynamics (CRAD), negatively correlates with CRC progression, stemness, and metastasis. Mechanistically, decreased CRAD in soft substrates induces Yes-associated protein (YAP) retention in the cytoplasm, restoring the repression effect on stemness markers NANOG and OCT4, thereby promoting CRC stemness and metastasis. Furthermore, CRAD deficiency promotes colorectal tumor cell softening and regulates epithelial-mesenchymal transition (EMT) states, contributing to its metastasis potential. Clinically, CRAD expression is correlated with malignant degrees and metastasis in CRC patients. Our work uncovers a role of CRAD in anticancer and mechanical signal transduction of the extracellular matrix in CRC.
    Keywords:  CRAD; CRC; F-actin; YAP; cancer stemness; mechanotransduction; metastasis
    DOI:  https://doi.org/10.1016/j.celrep.2022.110390
  11. Theranostics. 2022 ;12(3): 1097-1116
    Overexpression of BACH1 mediated by IGF2 facilitates hepatocellular carcinoma growth and metastasis via IGF1R and PTK2.
    Meng Xie, Mengyu Sun, Xiaoyu Ji, Dongxiao Li, Xiaoping Chen, Bixiang Zhang, Wenjie Huang, Tongyue Zhang, Yijun Wang, Dean Tian, Limin Xia.
      Background: Accumulating studies manifest that BTB and CNC homology 1 (BACH1) facilitates multiple malignancies progression and metastasis, and targeting the BACH1 pathway enhances antitumor efficacy. Nevertheless, the exact mechanism of BACH1 promoting growth and metastasis and its therapeutic significance in hepatocellular carcinoma (HCC) remain unclear. Methods: The expression of BACH1 in human HCC specimens and HCC cell lines was analyzed by quantitative RT-PCR (RT-qPCR), western blot, and immunohistochemistry (IHC). The invasiveness and metastasis of HCC cells in vitro and in vivo were evaluated using transwell assays and orthotopic xenograft models. The luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays were performed to explore the transcriptional regulation of insulin-like growth factor 1 receptor (IGF1R) and protein tyrosine kinase 2 (PTK2) by BACH1. Results: BACH1 was prominently upregulated in human HCC samples and elevated BACH1 expression was associated with poor overall survival (OS) and high recurrence rates of HCC patients. BACH1 facilitated growth and metastasis of HCC by upregulating cell motility-related genes IGF1R and PTK2. Notably, insulin-like growth factor 2 (IGF2), the ligand of IGF1R, in turn upregulated BACH1 expression through the IGF1R-ERK1/2-ETS1 cascades, thus forming a positive feedback loop to provoke HCC growth and metastasis. Moreover, combining IGF1R inhibitor linsitinib with PTK2 inhibitor defactinib prominently suppressed BACH1-mediated HCC growth and metastasis. Conclusions: These results demonstrated the tumorigenic and pro-metastatic role of BACH1 in HCC, which could be a promising biomarker for predicting poor prognosis and selecting patients who could benefit from combination therapy of IGF1R-targeted and PTK2-directed.
    Keywords:  BTB and CNC homology 1; Defactinib; Insulin-like growth factor 1 receptor; Linsitinib; Protein tyrosine kinase 2
    DOI:  https://doi.org/10.7150/thno.65775
  12. Oncogene. 2022 Feb 16.
    EMT-mediated regulation of CXCL1/5 for resistance to anti-EGFR therapy in colorectal cancer.
    Ye-Lim Park, Hwang-Phill Kim, Chan-Young Ock, Dong-Wook Min, Jun Kyu Kang, Yoo Joo Lim, Sang-Hyun Song, Sae-Won Han, Tae-You Kim.
      The emergence of RAS/RAF mutant clone is the main feature of EGFR inhibitor resistance in KRAS wild-type colon cancer. However, its molecular mechanism is thought to be multifactorial, mainly due to cellular heterogeneity. In order to better understand the resistance mechanism in a single clone level, we successfully isolated nine cells with cetuximab-resistant (CR) clonality from in vitro system. All CR cells harbored either KRAS or BRAF mutations. Characteristically, these cells showed a higher EMT (Epithelial to mesenchymal transition) signature, showing increased EMT markers such as SNAI2. Moreover, the expression level of CXCL1/5, a secreted protein, was significantly higher in CR cells compared to the parental cells. In these CR cells, CXCL1/5 expression was coordinately regulated by SNAI2/NFKB and transactivated EGFR through CXCR/MMPI/EGF axis via autocrine singling. We also observed that combined cetuximab/MEK inhibitor not only showed growth inhibition but also reduced the secreted amounts of CXCL1/5. We further found that serum CXCL1/5 level was positively correlated with the presence of RAS/RAF mutation in colon cancer patients during cetuximab therapy, suggesting its role as a biomarker. These data indicated that the application of serum CXCL1/5 could be a potential serologic biomarker for predicting resistance to EGFR therapy in colorectal cancer.
    DOI:  https://doi.org/10.1038/s41388-021-01920-4
  13. Nat Commun. 2022 Feb 16. 13(1): 897
    Lin28B-high breast cancer cells promote immune suppression in the lung pre-metastatic niche via exosomes and support cancer progression.
    Meiyan Qi, Yun Xia, Yanjun Wu, Zhuo Zhang, Xinyu Wang, Liying Lu, Cheng Dai, Yanan Song, Keying Xu, Weiwei Ji, Lixing Zhan.
      The formation of pre-metastatic niche is a key step in the metastatic burden. The pluripotent factor Lin28B is frequently expressed in breast tumors and is particularly upregulated in the triple negative breast cancer subtype. Here, we demonstrate that Lin28B promotes lung metastasis of breast cancer by building an immune-suppressive pre-metastatic niche. Lin28B enables neutrophil recruitment and N2 conversion. The N2 neutrophils are then essential for immune suppression in pre-metastatic lung by PD-L2 up-regulation and a dysregulated cytokine milieu. We also identify that breast cancer-released exosomes with low let-7s are a prerequisite for Lin28B-induced immune suppression. Moreover, Lin28B-induced breast cancer stem cells are the main sources of low-let-7s exosomes. Clinical data further verify that high Lin28B and low let-7s in tumors are both indicators for poor prognosis and lung metastasis in breast cancer patients. Together, these data reveal a mechanism by which Lin28B directs the formation of an immune-suppressive pre-metastatic niche.
    DOI:  https://doi.org/10.1038/s41467-022-28438-x
  14. Cancer Treat Rev. 2022 Feb 01. pii: S0305-7372(22)00003-2. [Epub ahead of print]104 102340
    Treatment-driven tumour heterogeneity and drug resistance: Lessons from solid tumours.
    Stefania Crucitta, Federico Cucchiara, Ron Mathijssen, Joaquin Mateo, Agnes Jager, Arjen Joosse, Antonio Passaro, Ilaria Attili, Iacopo Petrini, Ron van Schaik, Romano Danesi, Marzia Del Re.
      Molecular heterogeneity characterizes tumours' evolution and adaptation and, because of its dynamics and continuous changes under external pressure, it is one of the major causes of drug resistance, contributing to therapy failure. Several studies reported evidence of molecular events occuring in individual tumours, including monoclonal or polyclonal resistance, and primary or secondary resistance mechanisms. While primary resistance is a phenomenon already present at the diagnosis of a tumor, the acquired one is strongly related to the selective pressure of treatments administered. Therefore, the pharmacological characteristics of a drug, including its potency, binding affinity and structure, largely influence the mechanism of resistance that will arise at the progression of the disease. As an example, the lung cancer experience clearly demonstrated that the highest is the potency of a drug on its target, the more are the possibilities that the mechanism of resistance will arise independently of the target itself. The present review is focused on tumour heterogeneity and its relation to resistance to targeted-therapy, based on treatment selective pressure across different tumour types, including lung, colorectal, prostate, breast cancer and melanoma. The mechanisms of resistance based on the drug potency and the selective pressure of treatments are discussed, leading to new drug developments or new therapeutic combinations.
    Keywords:  CRC; CRPC; Melanoma; NSCLC; Resistance to treatment; Tumour heterogeneity; mBC
    DOI:  https://doi.org/10.1016/j.ctrv.2022.102340
  15. Mol Cancer. 2022 Feb 18. 21(1): 55
    NCAPG promotes the oncogenesis and progression of non-small cell lung cancer cells through upregulating LGALS1 expression.
    Huanhuan Sun, Hong Zhang, Yan Yan, Yushi Li, Gang Che, Cuiling Zhou, Christophe Nicot, Haiqing Ma.
       BACKGROUND: Numerous common oncogenic driver events have been confirmed in non-small cell lung cancer (NSCLC). Although targeted therapy has revolutionized NSCLC treatment, some patients still do not respond. NCAPG, also known as non-SMC condensin I complex subunit G, was positively associated with proliferation and migration in several tumor types.
    METHODS: We used transcriptional sequencing and TCGA database analysis to identify NCAPG as a new therapeutic target for NSCLC. The oncogenic roles of NCAPG in NSCLC tumor growth and metastasis were detected in vitro and in vivo. Ncapg+/+ or Ncapg+/- mice with urethane treatment were analyzed for oncogenesis of NSCLC.
    RESULTS: We investigated NCAPG as a new oncogenic driver which promoted NSCLC tumorigenesis and progression. We used transcriptome sequencing and the Cancer Genome Atlas (TCGA) database analysis to screen and found that NCAPG was negatively correlated with NSCLC survival. Using immunohistochemistry, we demonstrated that NCAPG overexpression was an independent risk factor for NSCLC survival. Functionally, NCAPG knockdown inhibited proliferation, migration, and invasion of NSCLC cells in vitro and in vivo. We exposed wildtype or Ncapg+/- mice to urethane and discovered that urethane-induced lung tumors were reduced in Ncapg+/- mice. Mechanistically, the function of NCAPG in promoting initiation and progression of NSCLC was closely related to LGALS1, which was also upregulated in NSCLC and might interact directly with NCAPG.
    CONCLUSIONS: This study indicates that NCAPG is one of the essential factors for NSCLC oncogenesis and progression, providing a new target for prognosis prediction and treatment of NSCLC.
    Keywords:  LGALS1; NCAPG; NSCLC; Oncogenesis; Progression
    DOI:  https://doi.org/10.1186/s12943-022-01533-9
  16. EMBO Mol Med. 2022 Feb 14. e15449
    Antifibrotic drugs as therapeutic tools in resistant melanoma.
    Berta Sanchez-Laorden, M Angela Nieto.
      Melanoma is the most aggressive form of skin cancer. Together with the recent advances in immunotherapy, targeted therapy with inhibitors of the Mitogen Activated Protein Kinase (MAPKi) pathway including BRAF and MEK inhibitors has greatly improved the clinical outcome of these patients. Unfortunately, due to genetic and non-genetic events, many patients develop resistance to MAPKi. Melanoma phenotypic plasticity, understood as the ability of melanoma cells to dynamically transition between different states with varying levels of differentiation/dedifferentiation, is key for melanoma progression. Lineage plasticity has also emerged as an important mechanism of non-genetic adaptive melanoma drug resistance in the clinic (Arozarena & Wellbrock, 2019), highlighting the need for a deeper characterization of the mechanisms that control this process. In this issue of EMBO Molecular Medicine, Diazzi et al (2022) identify a mechanism regulating MAPKi-induced phenotypic plasticity and resistance, providing evidence to support the use of an anti-fibrotic drug as a potential novel combinatorial therapeutic approach.
    DOI:  https://doi.org/10.15252/emmm.202115449
  17. Nat Commun. 2022 Feb 16. 13(1): 899
    A non-catalytic scaffolding activity of hexokinase 2 contributes to EMT and metastasis.
    Catherine S Blaha, Gopalakrishnan Ramakrishnan, Sang-Min Jeon, Veronique Nogueira, Hyunsoo Rho, Soeun Kang, Prashanth Bhaskar, Alexander R Terry, Alexandre F Aissa, Maxim V Frolov, Krushna C Patra, R Brooks Robey, Nissim Hay.
      Hexokinase 2 (HK2), which catalyzes the first committed step in glucose metabolism, is induced in cancer cells. HK2's role in tumorigenesis has been attributed to its glucose kinase activity. Here, we describe a kinase independent HK2 activity, which contributes to metastasis. HK2 binds and sequesters glycogen synthase kinase 3 (GSK3) and acts as a scaffold forming a ternary complex with the regulatory subunit of protein kinase A (PRKAR1a) and GSK3β to facilitate GSK3β phosphorylation and inhibition by PKA. Thus, HK2 functions as an A-kinase anchoring protein (AKAP). Phosphorylation by GSK3β targets proteins for degradation. Consistently, HK2 increases the level and stability of GSK3 targets, MCL1, NRF2, and particularly SNAIL. In addition to GSK3 inhibition, HK2 kinase activity mediates SNAIL glycosylation, which prohibits its phosphorylation by GSK3. Finally, in mouse models of breast cancer metastasis, HK2 deficiency decreases SNAIL protein levels and inhibits SNAIL-mediated epithelial mesenchymal transition and metastasis.
    DOI:  https://doi.org/10.1038/s41467-022-28440-3
  18. Cancer Res. 2022 Feb 17. pii: canres.3013.2021. [Epub ahead of print]
    TET2 suppresses VHL deficiency-driven clear cell renal cell carcinoma by inhibiting HIF signaling.
    Xinchao Zhang, Shuyan Li, Jing He, Yun-Jie Jin, Ruonan Zhang, Wenjing Dong, Mingen Lin, Yajing Yang, Tongguan Tian, Yuefan Zhou, Yixin Xu, Qun-Ying Lei, Jing Zhang, Qing Zhang, Yanping Xu, Lei Lv.
      Inactivating mutations of von Hippel-Lindau (VHL) are highly prevalent in clear cell renal cell carcinoma (ccRCC). Improved understanding of the vulnerabilities of VHL-deficient ccRCC could lead to improved treatment strategies. The activity of DNA dioxygenase TET2 is significantly reduced in multiple cancers by different mechanisms, but its role in ccRCC progression remains unclear. Here, we report that increased expression of TET2, but not TET1 and TET3, is negatively associated with tumor metastasis and advanced tumor stage and positively associated with good prognosis uniquely in ccRCC among all 33 types of cancer in the TCGA datasets. TET2 restrained glycolysis and pentose phosphate pathway metabolism in a VHL deficiency-dependent manner, thereby suppressing ccRCC progression. Notably, TET2 and VHL mutations tended to co-occur in ccRCC, providing genetic evidence that they cooperate to inhibit the progression of ccRCC. Mechanistically, TET2 was recruited by transcription factor HNF4α to activate FBP1 expression, which antagonized the function of HIF1/2α in metabolic reprogramming to impede ccRCC growth. Stimulating the TET2-FBP1 axis with vitamin C repressed the growth of VHL-deficient ccRCC with wild-type TET2 and increased the sensitivity to glycolysis inhibitors. Moreover, combined expression levels of the HNF4α-TET2-FBP1 axis served as a biomarker of prognosis in ccRCC patients. This study reveals a unique function of TET2 in the suppression of tumor metabolism and HIF signaling, and it also provides therapeutic targets, potential drugs, and prognostic markers for the management of ccRCC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3013
  19. Oncogene. 2022 Feb 16.
    USP13 promotes development and metastasis of high-grade serous ovarian carcinoma in a novel mouse model.
    Juntae Kwon, Hyeongjwa Choi, Anna D Ware, Bernadette Cecilia Morillo, Haiyang Wang, Kerrie B Bouker, Xiongbin Lu, Todd Waldman, Cecil Han.
      Epithelial ovarian cancer is the most lethal gynecologic malignancy and one of the most common causes of cancer mortality among women worldwide. Ubiquitin-Specific Peptidase 13 (USP13) gene copy is strongly amplified in human epithelial ovarian cancer, and high USP13 expression is correlated with poor survival outcomes. Yet, its pathological contribution to ovarian tumorigenesis remains unknown. We crossed a conditional Usp13 overexpressing knock-in mouse with a conditional knockout of Trp53 and Pten mouse and generated a novel ovarian cancer genetically engineered mouse model (GEMM), which closely recapitulates the genetic changes driving ovarian cancer in humans. Overexpression of USP13 with deletion of Trp53 and Pten in murine ovarian surface epithelium accelerated ovarian tumorigenesis and led to decreased survival in mice. Notably, USP13 greatly enhanced peritoneal metastasis of ovarian tumors with frequent development of hemorrhagic ascites. The primary and metastatic tumors exhibited morphology and clinical behavior similar to human high-grade serous ovarian cancer. Co-inhibition of USP13 and AKT significantly decreased the viability of the primary murine ovarian cancer cells isolated from the GEMM. USP13 also increased the tumorigenic and metastatic abilities of primary murine ovarian cancer cells in a syngeneic mouse study. These findings suggest a critical role of USP13 in ovarian cancer development and reveal USP13 as a potential therapeutic target for ovarian cancer.
    DOI:  https://doi.org/10.1038/s41388-022-02224-x
  20. Sci Adv. 2022 Feb 18. 8(7): eabi7127
    The histone demethylase PHF8 regulates TGFβ signaling and promotes melanoma metastasis.
    Rana S Moubarak, Ana de Pablos-Aragoneses, Vanessa Ortiz-Barahona, Yixiao Gong, Michael Gowen, Igor Dolgalev, Sorin A A Shadaloey, Diana Argibay, Alcida Karz, Richard Von Itter, Eleazar Carmelo Vega-Sáenz de Miera, Elena Sokolova, Farbod Darvishian, Aristotelis Tsirigos, Iman Osman, Eva Hernando.
      The contribution of epigenetic dysregulation to metastasis remains understudied. Through a meta-analysis of gene expression datasets followed by a mini-screen, we identified Plant Homeodomain Finger protein 8 (PHF8), a histone demethylase of the Jumonji C protein family, as a previously unidentified prometastatic gene in melanoma. Loss- and gain-of-function approaches demonstrate that PHF8 promotes cell invasion without affecting proliferation in vitro and increases dissemination but not subcutaneous tumor growth in vivo, thus supporting its specific contribution to the acquisition of metastatic potential. PHF8 requires its histone demethylase activity to enhance melanoma cell invasion. Transcriptomic and epigenomic analyses revealed that PHF8 orchestrates a molecular program that directly controls the TGFβ signaling pathway and, as a consequence, melanoma invasion and metastasis. Our findings bring a mechanistic understanding of epigenetic regulation of metastatic fitness in cancer, which may pave the way for improved therapeutic interventions.
    DOI:  https://doi.org/10.1126/sciadv.abi7127
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