bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2022‒05‒08
thirty-two papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology
  1. Feed-forward loops between metastatic cancer cells and their microenvironment-the stage of escalation.
  2. A Patient-Derived Organoid Screen Identified the Bispecific Antibody MCLA-158.
  3. Be Easy and Chill: Melanoma Cells Tell Lymph Node Fibroblasts to Relax.
  4. Radiation Exposure Primes Neutrophil-Mediated Metastasis to the Lung.
  5. Role of p38 MAP kinase in cancer stem cells and metastasis.
  6. RIPK1 Promotes Intrinsic and Extrinsic Resistance to Immunotherapy.
  7. On-Target BTK Mutations Promote Resistance to Noncovalent BTK Inhibitors.
  8. Lineage tracing reveals the phylodynamics, plasticity, and paths of tumor evolution.
  9. Temozolomide treatment alters mismatch repair and boosts mutational burden in tumor and blood of colorectal cancer patients.
  10. Optimized protocol for stable isotope tracing and steady-state metabolomics in mouse HER2+ breast cancer brain metastasis.
  11. RUVBL1 promotes enzalutamide resistance of prostate tumors through the PLXNA1-CRAF-MAPK pathway.
  12. The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress.
  13. ISL2 is a putative tumor suppressor whose epigenetic silencing reprograms the metabolism of pancreatic cancer.
  14. The microbiome restrains melanoma bone growth by promoting intestinal NK and Th1 cells homing to bone.
  15. The immune checkpoint B7x expands tumor-infiltrating Tregs and promotes resistance to anti-CTLA-4 therapy.
  16. Screening for breast cancer brain metastases.
  17. Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer.
  18. Alterations in homologous recombination repair genes in prostate cancer brain metastases.
  19. Targeting Mitochondrial Apoptosis Improves NK cell-Based Immunotherapies.
  20. JNK Signaling Promotes Bladder Cancer Immune Escape by Regulating METTL3-Mediated m6A Modification of PD-L1 mRNA.
  21. MITF deficiency accelerates GNAQ-driven uveal melanoma.
  22. RNA bisulfite sequencing reveals NSUN2-mediated suppression of epithelial differentiation in pancreatic cancer.
  23. Targeting BCAT1 combined with α-ketoglutarate triggers metabolic synthetic lethality in glioblastoma.
  24. Insufficient ablation induces E3-ligase Nedd4 to promote hepatocellular carcinoma progression by tuning TGF-β signaling.
  25. Cancer Cells Induce Delayed DNA Breaks to Resist Radiation Therapy.
  26. METTL3 promotes homologous recombination repair and modulates chemotherapeutic response in breast cancer by regulating the EGF/Rad51 axis.
  27. Altered glycosylation in pancreatic cancer and beyond.
  28. A fluorogenic probe for granzyme B enables in-biopsy evaluation and screening of response to anticancer immunotherapies.
  29. A T cell resilience model associated with response to immunotherapy in multiple tumor types.
  30. Gender Equity in Science and Medicine: Breaking the Impasse.
  31. Loss of PRMT7 reprograms glycine metabolism to selectively eradicate leukemia stem cells in CML.
  32. Profiling the Landscape of Drug Resistance Mutations in Neosubstrates to Molecular Glue Degraders.
  1. EMBO Mol Med. 2022 May 04. e14283
    Feed-forward loops between metastatic cancer cells and their microenvironment-the stage of escalation.
    Zora Baumann, Priska Auf der Maur, Mohamed Bentires-Alj.
      Breast cancer is the most frequent cancer among women, and metastases in distant organs are the leading cause of the cancer-related deaths. While survival of early-stage breast cancer patients has increased dramatically, the 5-year survival rate of metastatic patients has barely improved in the last 20 years. Metastases can arise up to decades after primary tumor resection, hinting at microenvironmental factors influencing the sudden outgrowth of disseminated tumor cells (DTCs). This review summarizes how the environment of the most common metastatic sites (lung, liver, bone, brain) is influenced by the primary tumor and by the varying dormancy of DTCs, with a special focus on how established metastases persist and grow in distant organs due to feed-forward loops (FFLs). We discuss in detail the importance of FFL of cancer cells with their microenvironment including the secretome, interaction with specialized tissue-specific cells, nutrients/metabolites, and that novel therapies should target not only the cancer cells but also the tumor microenvironment, which are thick as thieves.
    Keywords:  breast cancer; feed-forward loops; interdependency; metastasis; tumor microenvironment
    DOI:  https://doi.org/10.15252/emmm.202114283
  2. Cancer Discov. 2022 May 06. OF1
    A Patient-Derived Organoid Screen Identified the Bispecific Antibody MCLA-158.
      MCLA-158, an LGR5 × EGFR bispecific antibody, inhibits growth and metastasis of colorectal cancer.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-082
  3. Cancer Res. 2022 May 03. 82(9): 1692-1694
    Be Easy and Chill: Melanoma Cells Tell Lymph Node Fibroblasts to Relax.
    Amanda W Lund.
      Melanomas coopt tumor-draining lymph nodes to support metastatic potential and install immunosuppression. The specific mechanisms that mediate lymph node education, however, remain incompletely understood. In this issue, Rovera and colleagues describe the deactivation of contractile lymph node fibroblasts by dedifferentiated melanoma cells, leading to lymph node expansion and enhanced melanoma invasive potential. Fibroblastic reticular cell relaxation depended upon inhibition of constitutive JAK1/STAT3 and YAP/TAZ signaling, which was mediated in part by tumor secretion of the inflammatory cytokine, IL1. These data support an emerging hypothesis that intrinsic melanoma heterogeneity feeds forward to drive microenvironmental adaptations that mediate invasion and progression. See related article by Rovera et al., p. 1774.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0940
  4. Cancer Discov. 2022 May 02. 12(5): OF5
    Radiation Exposure Primes Neutrophil-Mediated Metastasis to the Lung.
      Radiation primes a neutrophil-mediated injury response in the lungs to promote lung metastasis.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-038
  5. Oncogene. 2022 Apr 30.
    Role of p38 MAP kinase in cancer stem cells and metastasis.
    Sriya Kudaravalli, Petra den Hollander, Sendurai A Mani.
      Therapeutic resistance and metastatic progression are responsible for the majority of cancer mortalities. In particular, the development of resistance is a significant barrier to the efficacy of cancer treatments such as chemotherapy, radiotherapy, targeted therapies, and immunotherapies. Cancer stem cells (CSCs) underlie treatment resistance and metastasis. p38 mitogen-activated protein kinase (p38 MAPK) is downstream of several CSC-specific signaling pathways, and it plays an important role in CSC development and maintenance and contributes to metastasis and chemoresistance. Therefore, the development of therapeutic approaches targeting p38 can sensitize tumors to chemotherapy and prevent metastatic progression.
    DOI:  https://doi.org/10.1038/s41388-022-02329-3
  6. Cancer Discov. 2022 May 06. OF1
    RIPK1 Promotes Intrinsic and Extrinsic Resistance to Immunotherapy.
      RIPK1 loss enhances immunotherapy by reshaping immune populations and poising tumor cells for killing.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-077
  7. Cancer Discov. 2022 May 02. 12(5): 1179
    On-Target BTK Mutations Promote Resistance to Noncovalent BTK Inhibitors.
      Resistance to noncovalent BTK inhibitors is mediated by non-C481 BTK and PLCγ2 mutations.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-041
  8. Cell. 2022 Apr 28. pii: S0092-8674(22)00462-7. [Epub ahead of print]
    Lineage tracing reveals the phylodynamics, plasticity, and paths of tumor evolution.
    Dian Yang, Matthew G Jones, Santiago Naranjo, William M Rideout, Kyung Hoi Joseph Min, Raymond Ho, Wei Wu, Joseph M Replogle, Jennifer L Page, Jeffrey J Quinn, Felix Horns, Xiaojie Qiu, Michael Z Chen, William A Freed-Pastor, Christopher S McGinnis, David M Patterson, Zev J Gartner, Eric D Chow, Trever G Bivona, Michelle M Chan, Nir Yosef, Tyler Jacks, Jonathan S Weissman.
      Tumor evolution is driven by the progressive acquisition of genetic and epigenetic alterations that enable uncontrolled growth and expansion to neighboring and distal tissues. The study of phylogenetic relationships between cancer cells provides key insights into these processes. Here, we introduced an evolving lineage-tracing system with a single-cell RNA-seq readout into a mouse model of Kras;Trp53(KP)-driven lung adenocarcinoma and tracked tumor evolution from single-transformed cells to metastatic tumors at unprecedented resolution. We found that the loss of the initial, stable alveolar-type2-like state was accompanied by a transient increase in plasticity. This was followed by the adoption of distinct transcriptional programs that enable rapid expansion and, ultimately, clonal sweep of stable subclones capable of metastasizing. Finally, tumors develop through stereotypical evolutionary trajectories, and perturbing additional tumor suppressors accelerates progression by creating novel trajectories. Our study elucidates the hierarchical nature of tumor evolution and, more broadly, enables in-depth studies of tumor progression.
    Keywords:  fitness; genetically engineered mouse model; lineage tracing; lung cancer; phylogenetics; plasticity; single cell; transcriptome heterogeneity; tumor evolution
    DOI:  https://doi.org/10.1016/j.cell.2022.04.015
  9. Cancer Discov. 2022 May 06. pii: candisc.1434.2021. [Epub ahead of print]
    Temozolomide treatment alters mismatch repair and boosts mutational burden in tumor and blood of colorectal cancer patients.
    Giovanni Crisafulli, Andrea Sartore-Bianchi, Luca Lazzari, Filippo Pietrantonio, Alessio Amatu, Marco Macagno, Ludovic Barault, Andrea Cassingena, Alice Bartolini, Paolo Luraghi, Gianluca Mauri, Paolo Battuello, Nicola Personeni, Maria Giulia Zampino, Valeria Pessei, Pietro Paolo Vitiello, Federica Tosi, Laura Idotta, Federica Morano, Emanuele Valtorta, Emanuela Bonoldi, Giovanni Germano, Federica Di Nicolantonio, Silvia Marsoni, Salvatore Siena, Alberto Bardelli.
      The majority of metastatic colorectal cancers (mCRC) are mismatch repair (MMR) proficient and unresponsive to immunotherapy, while MMR-deficient (MMRd) tumors often respond to immune-checkpoint-blockade. We previously reported that treatment of CRC preclinical models with temozolomide (TMZ) leads to MMR-deficiency, increased tumor mutational burden (TMB) and sensitization to immunotherapy. To clinically translate these findings, we designed the ARETHUSA clinical trial whereby O6-Methylguanine-DNA-methyltransferase (MGMT) deficient, MMR-proficient, RAS mutant mCRC patients received priming therapy with TMZ. Analysis of tissue biopsies and circulating tumor DNA (ctDNA) revealed the emergence of a distinct mutational signature and increased TMB after TMZ treatment. Multiple alterations in the nucleotide context favored by the TMZ signature emerged in MMR genes and the p.T1219I MSH6 variant was detected in ctDNA and tissue of 94% (16/17) of the cases. A patient's subset whose tumors displayed the MSH6 mutation, the TMZ mutational signature and increased TMB, achieved disease stabilization upon pembrolizumab treatment.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-1434
  10. STAR Protoc. 2022 Jun 17. 3(2): 101345
    Optimized protocol for stable isotope tracing and steady-state metabolomics in mouse HER2+ breast cancer brain metastasis.
    Pravat Kumar Parida, Mauricio Marquez-Palencia, Akash K Kaushik, Kangsan Kim, Vidhya Nair, Jessica Sudderth, Hieu Vu, Lauren Zacharias, Ralph DeBerardinis, Srinivas Malladi.
      Analyzing the metabolic dependencies of tumor cells is vital for cancer diagnosis and treatment. Here, we describe a protocol for 13C-stable glucose and glutamine isotope tracing in mice HER2+ breast cancer brain metastatic lesions. We describe how to inject cancer cells intracardially to generate brain metastatic lesions in mice. We then detail how to perform 13C-stable isotope infusion in mice with established brain metastasis. Finally, we outline steps for sample collection, processing for metabolite extraction, and analyzing mass spectrometry data. For complete details on the use and execution of this protocol, please refer to Parida et al. (2022).
    Keywords:  Cancer; Cell Biology; Cell culture; Mass Spectrometry; Metabolism; Metabolomics
    DOI:  https://doi.org/10.1016/j.xpro.2022.101345
  11. Oncogene. 2022 May 04.
    RUVBL1 promotes enzalutamide resistance of prostate tumors through the PLXNA1-CRAF-MAPK pathway.
    Feifei Sun, Xinpei Wang, Jing Hu, Junmei Liu, Xin Wang, Wenqiao Jia, Zeyuan Yu, Lin Gao, Baokai Dou, Ru Zhao, Tingting Feng, Xueli Wang, Wenbo Zhang, Hui Liu, Kaihua Liu, Yang Shao, Xuesen Dong, Bo Han.
      Although enzalutamide improves the overall survival of patients with metastatic prostate cancers, enzalutamide resistance (ENZR) will be inevitably developed. Emerging evidence support that alternative oncogenic pathways may bypass the androgen receptor (AR) signaling to promote ENZR progression, however, the underpinning mechanisms remain poorly defined. Here, we report that the expression of RuvB like AAA ATPase 1 (RUVBL1) is upregulated in ENZR cells and xenograft models and prostate tumors in patients. Enzalutamide increases RUVBL1 accumulation in the cytoplasm, which in turn enhances the recruitment of CRAF proto-oncogene serine/threonine kinase protein to plexin A1 (PLXNA1) and the subsequent activation of the downstream MAPK pathway. Co-overexpression of RUVBL1 and PLXNA1 defines a subgroup of prostate cancer (PCa) patients with a poor prognosis. Furthermore, pharmacological inhibition of RUVBL1 by CB-6644 suppresses ENZR cell proliferation and xenograft growth and allows re-sensitization of ENZR cells and xenografts to enzalutamide, indicating that RUVBL1 may act to substitute the AR signaling to promote cancer cell survival and ENZR development. Together, these findings may lead to the identification of RUVBL1 as a potential therapeutic target for ENZR tumors.
    DOI:  https://doi.org/10.1038/s41388-022-02332-8
  12. Elife. 2022 05 03. pii: e69255. [Epub ahead of print]11
    The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress.
    Yanan Liu, Juanjuan Feng, Kun Yuan, Zhengzhen Wu, Longmiao Hu, Yue Lu, Kun Li, Jiawei Guo, Jing Chen, Chengbin Ma, Xiufeng Pang.
      Genotoxic agents remain the mainstay of cancer treatment. Unfortunately, the clinical benefits are often countered by a rapid tumor adaptive response. Here, we report that the oncoprotein B cell lymphoma 6 (BCL6) is a core component that confers solid tumor adaptive resistance to genotoxic stress. Multiple genotoxic agents promoted BCL6 transactivation, which was positively correlated with a weakened therapeutic efficacy and a worse clinical outcome. Mechanistically, we discovered that treatment with the genotoxic agent etoposide led to the transcriptional reprogramming of multiple pro-inflammatory cytokines, among which the interferon-α and interferon-γ responses were substantially enriched in resistant cells. Our results further revealed that the activation of interferon/signal transducer and activator of transcription 1 axis directly upregulated BCL6 expression. The increased expression of BCL6 further repressed the tumor suppressor PTEN and consequently enabled resistant cancer cell survival. Accordingly, targeted inhibition of BCL6 remarkably enhanced etoposide-triggered DNA damage and apoptosis both in vitro and in vivo. Our findings highlight the importance of BCL6 signaling in conquering solid tumor tolerance to genotoxic stress, further establishing a rationale for a combined approach with genotoxic agents and BCL6-targeted therapy.
    Keywords:  BCL6; adaptive resistance; cancer biology; combination chemotherapy; genotoxic agents; immunology; inflammation; interferon responses; mouse
    DOI:  https://doi.org/10.7554/eLife.69255
  13. Dev Cell. 2022 Apr 22. pii: S1534-5807(22)00254-4. [Epub ahead of print]
    ISL2 is a putative tumor suppressor whose epigenetic silencing reprograms the metabolism of pancreatic cancer.
    Harun Ozturk, Harun Cingoz, Turan Tufan, Jiekun Yang, Sara J Adair, Krishna Seshu Tummala, Cem Kuscu, Meric Kinali, Gamze Comertpay, Sarbajeet Nagdas, Bernadette J Goudreau, Husnu Umit Luleyap, Yagmur Bingul, Timothy B Ware, Wiliam L Hwang, Ku-Lung Hsu, David F Kashatus, David T Ting, Navdeep S Chandel, Nabeel Bardeesy, Todd W Bauer, Mazhar Adli.
      Pancreatic ductal adenocarcinoma (PDA) cells reprogram their transcriptional and metabolic programs to survive the nutrient-poor tumor microenvironment. Through in vivo CRISPR screening, we discovered islet-2 (ISL2) as a candidate tumor suppressor that modulates aggressive PDA growth. Notably, ISL2, a nuclear and chromatin-associated transcription factor, is epigenetically silenced in PDA tumors and high promoter DNA methylation or its reduced expression correlates with poor patient survival. The exogenous ISL2 expression or CRISPR-mediated upregulation of the endogenous loci reduces cell proliferation. Mechanistically, ISL2 regulates the expression of metabolic genes, and its depletion increases oxidative phosphorylation (OXPHOS). As such, ISL2-depleted human PDA cells are sensitive to the inhibitors of mitochondrial complex I in vitro and in vivo. Spatial transcriptomic analysis shows heterogeneous intratumoral ISL2 expression, which correlates with the expression of critical metabolic genes. These findings nominate ISL2 as a putative tumor suppressor whose inactivation leads to increased mitochondrial metabolism that may be exploitable therapeutically.
    Keywords:  CRISPR; ISL2; pancreatic cancer; tumor suppressor
    DOI:  https://doi.org/10.1016/j.devcel.2022.04.014
  14. J Clin Invest. 2022 May 03. pii: e157340. [Epub ahead of print]
    The microbiome restrains melanoma bone growth by promoting intestinal NK and Th1 cells homing to bone.
    Subhashis Pal, Daniel S Perrien, Tetsuya Yumoto, Roberta Faccio, Andreea Stoica, Jonathan Adams, Craig M Coopersmith, Rheinallt M Jones, M Neale Weitzmann, Roberto Pacifici.
      Bone metastases are frequent complications of malignant melanoma leading to reduced quality of life and significant morbidity. Regulation of immune cells by the gut microbiome influences cancer progression, but the role of the microbiome in tumor growth in bone is unknown. Using intracardiac or intratibial injections of B16-F10 melanoma cells in mice we showed that gut microbiome depletion by broad-spectrum antibiotics accelerated intraosseous tumor growth and osteolysis. Microbiome depletion blunted melanoma-induced expansion of intestinal natural killer (NK) cells and T helper 1 (Th1) cells and their migration from the gut to tumor bearing bones. Demonstrating the functional relevance of immune cell trafficking from the gut to the bone marrow (BM) in bone metastasis, blockade of S1P-mediated NK and Th1 cells intestinal egress, or inhibition of their CXCR3/CXCL9-mediated influx into the BM prevented expansion of BM NK and Th1 cells and accelerated tumor growth and osteolysis. Using a mouse model, this study revealed mechanisms of microbiota-mediated gut-bone crosstalk that are relevant to the immunological restraint of melanoma metastasis and tumor growth in bone. Microbiome modifications induced by antibiotics might have negative clinical consequences in melanoma patients.
    Keywords:  Bone Biology; Melanoma
    DOI:  https://doi.org/10.1172/JCI157340
  15. Nat Commun. 2022 May 06. 13(1): 2506
    The immune checkpoint B7x expands tumor-infiltrating Tregs and promotes resistance to anti-CTLA-4 therapy.
    Peter John, Marc C Pulanco, Phillip M Galbo, Yao Wei, Kim C Ohaegbulam, Deyou Zheng, Xingxing Zang.
      Immune checkpoint molecules play critical roles in regulating the anti-tumor immune response, and tumor cells often exploit these pathways to inhibit and evade the immune system. The B7-family immune checkpoint B7x is widely expressed in a broad variety of cancer types, and is generally associated with advanced disease progression and poorer clinical outcomes, but the underlying mechanisms are unclear. Here, we show that transduction and stable expression of B7x in multiple syngeneic tumor models leads to the expansion of immunosuppressive regulatory T cells (Tregs). Mechanistically, B7x does not cause increased proliferation of Tregs in tumors, but instead promotes the conversion of conventional CD4+ T cells into Tregs. Further, we find that B7x induces global transcriptomic changes in Tregs, driving these cells to adopt an activated and suppressive phenotype. B7x increases the expression of the Treg-specific transcription factor Foxp3 in CD4+ T cells by modulating the Akt/Foxo pathway. B7x-mediated regulation of Tregs reduces the efficacy of anti-CTLA-4 treatment, a therapeutic that partially relies on Treg-depletion. However, combination treatment of anti-B7x and anti-CTLA-4 leads to synergistic therapeutic efficacy and overcomes the B7x-mediated resistance to anti-CTLA-4. Altogether, B7x mediates an immunosuppressive Treg-promoting pathway within tumors and is a promising candidate for combination immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-022-30143-8
  16. Lancet Oncol. 2022 May;pii: S1470-2045(22)00201-7. [Epub ahead of print]23(5): e200
    Screening for breast cancer brain metastases.
    Jonathan Knisely.
      
    DOI:  https://doi.org/10.1016/S1470-2045(22)00201-7
  17. J Exp Med. 2022 Jun 06. pii: e20210390. [Epub ahead of print]219(6):
    Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer.
    Renuka Raman, Jacques A Villefranc, Timothy M Ullmann, Jessica Thiesmeyer, Viviana Anelli, Jun Yao, James R Hurley, Chantal Pauli, Rohan Bareja, Kenneth Wha Eng, Princesca Dorsaint, David C Wilkes, Shaham Beg, Sarah Kudman, Reid Shaw, Michael Churchill, Adnan Ahmed, Laurel Keefer, Ian Misner, Donna Nichol, Naveen Gumpeni, Theresa Scognamiglio, Mark A Rubin, Carla Grandori, James Patrick Solomon, Wei Song, Juan Miguel Mosquera, Noah Dephoure, Andrea Sboner, Olivier Elemento, Yariv Houvras.
      Genetic alterations in RET lead to activation of ERK and AKT signaling and are associated with hereditary and sporadic thyroid cancer and lung cancer. Highly selective RET inhibitors have recently entered clinical use after demonstrating efficacy in treating patients with diverse tumor types harboring RET gene rearrangements or activating mutations. In order to understand resistance mechanisms arising after treatment with RET inhibitors, we performed a comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer. Using a combination of drug screening and proteomic and biochemical profiling, we identified an adaptive resistance to RET inhibitors that reactivates ERK signaling within hours of drug exposure. We found that activation of FGFR signaling is a mechanism of adaptive resistance to RET inhibitors that activates ERK signaling. Combined inhibition of FGFR and RET prevented the development of adaptive resistance to RET inhibitors, reduced cell viability, and decreased tumor growth in cellular and animal models of CCDC6-RET-rearranged thyroid cancer.
    DOI:  https://doi.org/10.1084/jem.20210390
  18. Nat Commun. 2022 May 03. 13(1): 2400
    Alterations in homologous recombination repair genes in prostate cancer brain metastases.
    Antonio Rodriguez-Calero, John Gallon, Dilara Akhoundova, Sina Maletti, Alison Ferguson, Joanna Cyrta, Ursula Amstutz, Andrea Garofoli, Viola Paradiso, Scott A Tomlins, Ekkehard Hewer, Vera Genitsch, Achim Fleischmann, Erik Vassella, Elisabeth J Rushing, Rainer Grobholz, Ingeborg Fischer, Wolfram Jochum, Gieri Cathomas, Adeboye O Osunkoya, Lukas Bubendorf, Holger Moch, George Thalmann, Charlotte K Y Ng, Silke Gillessen, Salvatore Piscuoglio, Mark A Rubin.
      Improved survival rates for prostate cancer through more effective therapies have also led to an increase in the diagnosis of metastases to infrequent locations such as the brain. Here we investigate the repertoire of somatic genetic alterations present in brain metastases from 51 patients with prostate cancer brain metastases (PCBM). We highlight the clonal evolution occurring in PCBM and demonstrate an increased mutational burden, concomitant with an enrichment of the homologous recombination deficiency mutational signature in PCBM compared to non-brain metastases. Focusing on known pathogenic alterations within homologous recombination repair genes, we find 10 patients (19.6%) fulfilling the inclusion criteria used in the PROfound clinical trial, which assessed the efficacy of PARP inhibitors (PARPi) in homologous recombination deficient prostate cancer. Eight (15.7%) patients show biallelic loss of one of the 15 genes included in the trial, while 5 patients (9.8%) harbor pathogenic alterations in BRCA1/2 specifically. Uncovering these molecular features of PCBM may have therapeutic implications, suggesting the need of clinical trial enrollment of PCBM patients when evaluating potential benefit from PARPi.
    DOI:  https://doi.org/10.1038/s41467-022-30003-5
  19. Cancer Discov. 2022 May 06. OF1
    Targeting Mitochondrial Apoptosis Improves NK cell-Based Immunotherapies.
      Mitochondrial apoptosis is essential for efficient NK-mediated killing in multiple cancer cell types.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-078
  20. Cancer Res. 2022 May 03. 82(9): 1789-1802
    JNK Signaling Promotes Bladder Cancer Immune Escape by Regulating METTL3-Mediated m6A Modification of PD-L1 mRNA.
    Zegui Ni, Pengli Sun, Jin Zheng, Mingqing Wu, Congcong Yang, Maosheng Cheng, Mingwei Yin, Chengying Cui, Guangxian Wang, Lin Yuan, Qian Gao, Yang Li.
      The RNA N6-methyladenosine (m6A) writer methyltransferase-like 3 (METTL3) is upregulated in many types of cancer and promotes cancer progression by increasing expression of several oncogenes. Therefore, a better understanding of the mechanisms regulating METTL3 expression and the key targets of METTL3 in cancer cells could provide new therapeutic targets. In this study, we found that activated JNK signaling is associated with increased METTL3 expression in bladder cancer. Knockdown of JNK1 or administration of a JNK inhibitor impaired the binding of c-Jun with the METTL3 promoter, thereby decreasing the expression of METTL3 and global RNA m6A levels. Moreover, RNA m6A sequencing indicated enrichment of m6A in the 3'-UTR of immune checkpoint PD-L1 mRNA, which could be recognized by the m6A reader IGF2BP1 to mediate RNA stability and expression levels of PD-L1. Inhibition of JNK signaling suppressed m6A abundance in PD-L1 mRNA, leading to decreased PD-L1 expression. Functionally, METTL3 was essential for bladder cancer cells to resist the cytotoxicity of CD8+ T cells by regulating PD-L1 expression. Additionally, JNK signaling contributed to tumor immune escape in a METTL3-dependent manner both in vitro and in vivo. These data reveal the JNK/METTL3 axis as a mechanism of aberrant m6A modification and immune regulation in bladder cancer.SIGNIFICANCE: The identification of a novel m6A-dependent mechanism underlying immune system evasion by bladder cancer cells reveals JNK signaling as a potential target for bladder cancer immunotherapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-1323
  21. Proc Natl Acad Sci U S A. 2022 May 10. 119(19): e2107006119
    MITF deficiency accelerates GNAQ-driven uveal melanoma.
    Grace B Phelps, Hannah R Hagen, Adam Amsterdam, Jacqueline A Lees.
      SignificanceUveal melanoma (UM) is a cancer of eye melanocytes. Although relatively rare, UM is extremely deadly, as approximately half of all patients develop liver metastases for which there are no approved therapies. Even therapies that succeed in cutaneous melanoma (CM) treatment have proven ineffectual for UM, highlighting both the distinct nature of these two melanomas and the need to understand the differences between them. Here, we show that autochthonous UM tumors are rapidly induced by activated YAP and can lack hyperactive ERK, highlighting YAP as a promising therapeutic target. We further show that MITF functions as a tumor suppressor in UM in contrast to its essential role in CM, establishing that MITF inhibition should not be entertained for UM treatment.
    Keywords:  melanoma; mitf; uveal; zebrafish
    DOI:  https://doi.org/10.1073/pnas.2107006119
  22. Oncogene. 2022 May 02.
    RNA bisulfite sequencing reveals NSUN2-mediated suppression of epithelial differentiation in pancreatic cancer.
    Szu-Ying Chen, Kuan-Lin Chen, Li-Yun Ding, Chien-Hung Yu, Hsin-Yi Wu, Ya-Yi Chou, Chia-Jung Chang, Chih-Han Chang, Ya-Na Wu, Shang-Rung Wu, Ya-Chin Hou, Chung-Ta Lee, Peng-Chieh Chen, Yan-Shen Shan, Po-Hsien Huang.
      Posttranscriptional modifications in RNA have been considered to contribute to disease pathogenesis and tumor progression. NOL1/NOP2/Sun domain family member 2 (NSUN2) is an RNA methyltransferase that promotes tumor progression in several cancers. Pancreatic cancer relapse inevitably occurs even in cases where primary tumors have been successfully treated. Associations of cancer progression due to reprogramming of the cancer methyl-metabolome and the cancer genome have been noted, but the effect of base modifications, namely 5-methylcytosine (m5C), in the transcriptome remains unclear. Aberrant regulation of 5-methylcytosine turnover in cancer may affect posttranscriptional modifications in coding and noncoding RNAs in disease pathogenesis. Mutations in NSUN2 have been reported as drivers of neurodevelopmental disorders in mice, and upregulated expression of NSUN2 in tumors of the breast, bladder, and pancreas has been reported. In this study, we conducted mRNA whole transcriptomic bisulfite sequencing to categorize NSUN2 target sites in the mRNA of human pancreatic cancer cells. We identified a total of 2829 frequent m5C sites in mRNA from pancreatic cancer cells. A total of 90.9% (2572/2829) of these m5C sites were mapped to annotated genes in autosomes and sex chromosomes X and Y. Immunohistochemistry staining confirmed that the NSUN2 expression was significantly upregulated in cancer lesions in the LSL-KrasG12D/+;Trp53fl/fl;Pdx1-Cre (KPC) spontaneous pancreatic cancer mouse model induced by Pdx1-driven Cre/lox system expressing mutant KrasG12D and p53 deletion. The in vitro phenotypic analysis of NSUN2 knockdown showed mild effects on pancreatic cancer cell 2D/3D growth, morphology and gemcitabine sensitivity in the early phase of tumorigenesis, but cumulative changes after multiple cell doubling passages over time were required for these mutations to accumulate. Syngeneic transplantation of NSUN2-knockdown KPC cells via subcutaneous injection showed decreased stromal fibrosis and restored differentiation of ductal epithelium in vivo. SIGNIFICANCE: Transcriptome-wide mRNA bisulfite sequencing identified candidate m5C sites of mRNAs in human pancreatic cancer cells. NSUN2-mediated m5C mRNA metabolism was observed in a mouse model of pancreatic cancer. NSUN2 regulates cancer progression and epithelial differentiation via mRNA methylation.
    DOI:  https://doi.org/10.1038/s41388-022-02325-7
  23. Cancer Res. 2022 May 02. pii: canres.3868.2021. [Epub ahead of print]
    Targeting BCAT1 combined with α-ketoglutarate triggers metabolic synthetic lethality in glioblastoma.
    Bo Zhang, Hui Peng, Mi Zhou, Lei Bao, Chenliang Wang, Feng Cai, Hongxia Zhang, Jennifer E Wang, Yanling Niu, Yan Chen, Yijie Wang, Kimmo Hatanpaa, John A Copland, Ralph J DeBerardinis, Yingfei Wang, Weibo Luo.
      Branched-chain amino acid transaminase 1 (BCAT1) is upregulated selectively in human isocitrate dehydrogenase (IDH) wildtype (WT) but not mutant glioblastoma multiforme (GBM) and promotes IDHWT GBM growth. Through a metabolic synthetic lethal screen, we report here that α-ketoglutarate (AKG) kills IDHWT GBM cells when BCAT1 protein is lost, which is reversed by re-expression of BCAT1 or supplementation with branched-chain α-ketoacids (BCKAs), downstream metabolic products of BCAT1. In patient-derived IDHWT GBM tumors in vitro and in vivo, co-treatment of BCAT1 inhibitor gabapentin and AKG resulted in synthetic lethality. However, AKG failed to evoke a synthetic lethal effect with loss of BCAT2, BCKDHA, or GPT2 in IDHWT GBM cells. Mechanistically, loss of BCAT1 increased the NAD+/NADH ratio but impaired oxidative phosphorylation, mTORC1 activity, and nucleotide biosynthesis. These metabolic alterations were synergistically augmented by AKG treatment, thereby causing mitochondrial dysfunction and depletion of cellular building blocks, including ATP, nucleotides, and proteins. Partial restoration of ATP, nucleotides, proteins, and mTORC1 activity by BCKA supplementation prevented IDHWT GBM cell death conferred by the combination of BCAT1 loss and AKG. These findings define a targetable metabolic vulnerability in the most common subset of GBM that is currently incurable.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3868
  24. Oncogene. 2022 Apr 30.
    Insufficient ablation induces E3-ligase Nedd4 to promote hepatocellular carcinoma progression by tuning TGF-β signaling.
    Kai Li, Yi Niu, Yichuan Yuan, Jiliang Qiu, Yunxing Shi, Chengrui Zhong, Zhiyu Qiu, Keren Li, Zhu Lin, Zhenkun Huang, Chao Zhang, Dinglan Zuo, Wei He, Yunfei Yuan, Binkui Li.
      Thermal ablation is a main curative therapy for early-stage hepatocellular carcinoma (HCC). However, insufficient ablation has been shown to promote HCC progression. E3 ligases have been approved to play important roles in malignant tumors. Whether E3 ligases are involved in HCC progression caused by insufficient ablation remains unclear. Herein, using RNA-sequencing coupled with an in vitro loss-of-function screen, we found that the E3 ligase Neuronal Precursor cell-expressed Developmentally Downregulated 4 (Nedd4) was upregulated in HCC insufficient ablation tissues and promoted HCC cells migration. The upregulation of Nedd4 was induced by METTL14-mediated N6-methyladenosine modification after sublethal heat treatment. Knockdown of Nedd4 inhibited HCC metastasis and growth in vitro and in vivo. Mechanistically, Nedd4 enhanced TGF-β signal transduction mediated tumor progression by directly binding to TGF-β type I receptor (TGFBR1) and forming K27-linked ubiquitin at Lysine 391. Additionally, the adverse effect on HCC of sublethal heat treatment was mediated by Nedd4. Clinically, high Nedd4 expression was positively correlated with aggressive tumor phenotypes and poor prognosis in HCC patients. Patient-derived xenograft (PDX) model confirmed this conclusion. Collectively, this study demonstrated that Nedd4 induced by insufficient ablation plays a crucial role in promoting HCC progression and provides a novel therapeutic target for HCC.
    DOI:  https://doi.org/10.1038/s41388-022-02334-6
  25. Cancer Discov. 2022 May 06. OF1
    Cancer Cells Induce Delayed DNA Breaks to Resist Radiation Therapy.
      Cancer cells resist irradiation by inducing regulated DNA breaks to prevent premature mitotic entry.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-081
  26. Elife. 2022 May 03. pii: e75231. [Epub ahead of print]11
    METTL3 promotes homologous recombination repair and modulates chemotherapeutic response in breast cancer by regulating the EGF/Rad51 axis.
    Enjie Li, Mingyue Xia, Yu Du, Kaili Long, Feng Ji, Feiyan Pan, Lingfeng He, Zhigang Hu, Zhigang Guo.
      METTL3 and N6-methyladenosine (m6A) are involved in many types of biological and pathological processes, including DNA repair. However, the function and mechanism of METTL3 in DNA repair and chemotherapeutic response remain largely unknown. In present study, we identified that METTL3 participates in the regulation of homologous recombination repair (HR), which further influences chemotherapeutic response in both MCF-7 and MDA-MB-231 breast cancer (BC) cells. Knockdown of METTL3 sensitized these BC cells to Adriamycin (ADR; also named as doxorubicin) treatment and increased accumulation of DNA damage. Mechanically, we demonstrated that inhibition of METTL3 impaired HR efficiency and increased ADR-induced DNA damage by regulating m6A modification of EGF/RAD51 axis. METTL3 promoted EGF expression through m6A modification, which further upregulated RAD51 expression, resulting in enhanced HR activity. We further demonstrated that the m6A 'reader', YTHDC1, bound to the m6A modified EGF transcript and promoted EGF synthesis, which enhanced HR and cell survival during ADR treatment in breast cancer cells. Our findings reveal a pivotal mechanism of METTL3-mediated HR and chemotherapeutic drug response, which may contribute to cancer therapy.
    Keywords:  biochemistry; cell biology; chemical biology; mouse
    DOI:  https://doi.org/10.7554/eLife.75231
  27. J Exp Med. 2022 Jun 06. pii: e20211505. [Epub ahead of print]219(6):
    Altered glycosylation in pancreatic cancer and beyond.
    Jan C Lumibao, Jacob R Tremblay, Jasper Hsu, Dannielle D Engle.
      Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest cancers and is projected to soon be the second leading cause of cancer death. Median survival of PDA patients is 6-10 mo, with the majority of diagnoses occurring at later, metastatic stages that are refractory to treatment and accompanied by worsening prognoses. Glycosylation is one of the most common types of post-translational modifications. The complex landscape of glycosylation produces an extensive repertoire of glycan moieties, glycoproteins, and glycolipids, thus adding a dynamic and tunable level of intra- and intercellular signaling regulation. Aberrant glycosylation is a feature of cancer progression and influences a broad range of signaling pathways to promote disease onset and progression. However, despite being so common, the functional consequences of altered glycosylation and their potential as therapeutic targets remain poorly understood and vastly understudied in the context of PDA. In this review, the functionality of glycans as they contribute to hallmarks of PDA are highlighted as active regulators of disease onset, tumor progression, metastatic capability, therapeutic resistance, and remodeling of the tumor immune microenvironment. A deeper understanding of the functional consequences of altered glycosylation will facilitate future hypothesis-driven studies and identify novel therapeutic strategies in PDA.
    DOI:  https://doi.org/10.1084/jem.20211505
  28. Nat Commun. 2022 May 02. 13(1): 2366
    A fluorogenic probe for granzyme B enables in-biopsy evaluation and screening of response to anticancer immunotherapies.
    Jamie I Scott, Lorena Mendive-Tapia, Doireann Gordon, Nicole D Barth, Emily J Thompson, Zhiming Cheng, David Taggart, Takanori Kitamura, Alberto Bravo-Blas, Edward W Roberts, Jordi Juarez-Jimenez, Julien Michel, Berber Piet, I Jolanda de Vries, Martijn Verdoes, John Dawson, Neil O Carragher, Richard A O' Connor, Ahsan R Akram, Margaret Frame, Alan Serrels, Marc Vendrell.
      Immunotherapy promotes the attack of cancer cells by the immune system; however, it is difficult to detect early responses before changes in tumor size occur. Here, we report the rational design of a fluorogenic peptide able to detect picomolar concentrations of active granzyme B as a biomarker of immune-mediated anticancer action. Through a series of chemical iterations and molecular dynamics simulations, we synthesize a library of FRET peptides and identify probe H5 with an optimal fit into granzyme B. We demonstrate that probe H5 enables the real-time detection of T cell-mediated anticancer activity in mouse tumors and in tumors from lung cancer patients. Furthermore, we show image-based phenotypic screens, which reveal that the AKT kinase inhibitor AZD5363 shows immune-mediated anticancer activity. The reactivity of probe H5 may enable the monitoring of early responses to anticancer treatments using tissue biopsies.
    DOI:  https://doi.org/10.1038/s41467-022-29691-w
  29. Nat Med. 2022 May 02.
    A T cell resilience model associated with response to immunotherapy in multiple tumor types.
    Yu Zhang, Vu Trang, Douglas C Palmer, Rigel J Kishton, Lanqi Gong, Jiao Huang, Thanh Nguyen, Zuojia Chen, Cari Smith, Ferenc Livák, Rohit Paul, Chi-Ping Day, Chuan Wu, Glenn Merlino, Kenneth Aldape, Xin-Yuan Guan, Peng Jiang.
      Despite breakthroughs in cancer immunotherapy, most tumor-reactive T cells cannot persist in solid tumors due to an immunosuppressive environment. We developed Tres (tumor-resilient T cell), a computational model utilizing single-cell transcriptomic data to identify signatures of T cells that are resilient to immunosuppressive signals, such as transforming growth factor-β1, tumor necrosis factor-related apoptosis-inducing ligand and prostaglandin E2. Tres reliably predicts clinical responses to immunotherapy in melanoma, lung cancer, triple-negative breast cancer and B cell malignancies using bulk T cell transcriptomic data from pre-treatment tumors from patients who received immune-checkpoint inhibitors (n = 38), infusion products for chimeric antigen receptor T cell therapies (n = 34) and pre-manufacture samples for chimeric antigen receptor T cell or tumor-infiltrating lymphocyte therapies (n = 84). Further, Tres identified FIBP, whose functions are largely unknown, as the top negative marker of tumor-resilient T cells across many solid tumor types. FIBP knockouts in murine and human donor CD8+ T cells significantly enhanced T cell-mediated cancer killing in in vitro co-cultures. Further, Fibp knockout in murine T cells potentiated the in vivo efficacy of adoptive cell transfer in the B16 tumor model. Fibp knockout T cells exhibit reduced cholesterol metabolism, which inhibits effector T cell function. These results demonstrate the utility of Tres in identifying biomarkers of T cell effectiveness and potential therapeutic targets for immunotherapies in solid tumors.
    DOI:  https://doi.org/10.1038/s41591-022-01799-y
  30. Cancer Discov. 2022 May 02. 12(5): 1191-1194
    Gender Equity in Science and Medicine: Breaking the Impasse.
    Jennifer R Grandis.
      Women comprise half of the scientific and medical workforce, yet still hold a minority of leadership positions. Here I discuss the barriers to gender equity and offer a new approach to address the problem.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0253
  31. Cell Metab. 2022 Apr 26. pii: S1550-4131(22)00131-0. [Epub ahead of print]
    Loss of PRMT7 reprograms glycine metabolism to selectively eradicate leukemia stem cells in CML.
    Chang Liu, Waiyi Zou, Danian Nie, Shuyi Li, Chen Duan, Min Zhou, Peilong Lai, Shengyong Yang, Sen Ji, Yangqiu Li, Mei Mei, Shilai Bao, Yanli Jin, Jingxuan Pan.
      Our group has reported previously on the role of various members of the protein arginine methyltransferase (PRMT) family, which are involved in epigenetic regulation, in the progression of leukemia. Here, we explored the role of PRMT7, given its unique function within the PRMT family, in the maintenance of leukemia stem cells (LSCs) in chronic myeloid leukemia (CML). Genetic loss of Prmt7, and the development and testing of a small-molecule specific inhibitor of PRMT7, showed that targeting PRMT7 delayed leukemia development and impaired self-renewal of LSCs in a CML mouse model and in primary CML CD34+ cells from humans without affecting normal hematopoiesis. Mechanistically, loss of PRMT7 resulted in reduced expressions of glycine decarboxylase, leading to the reprograming of glycine metabolism to generate methylglyoxal, which is detrimental to LSCs. These findings link histone arginine methylation with glycine metabolism, while suggesting PRMT7 as a potential therapeutic target for the eradication of LSCs in CML.
    Keywords:  GLDC; JS1310; PRMT7; chronic myelogenous leukemia; epigenetic; glycine metabolism; leukemia stem cells; self-renewal; survival
    DOI:  https://doi.org/10.1016/j.cmet.2022.04.004
  32. ACS Cent Sci. 2022 Apr 27. 8(4): 417-429
    Profiling the Landscape of Drug Resistance Mutations in Neosubstrates to Molecular Glue Degraders.
    Pallavi M Gosavi, Kevin C Ngan, Megan J R Yeo, Cindy Su, Jiaming Li, Nicholas Z Lue, Samuel M Hoenig, Brian B Liau.
      Targeted protein degradation (TPD) holds immense promise for drug discovery, but mechanisms of acquired resistance to degraders remain to be fully identified. Here, we used clustered regularly interspaced short palindromic repeats (CRISPR)-suppressor scanning to identify mechanistic classes of drug resistance mutations to molecular glue degraders in GSPT1 and RBM39, neosubstrates targeted by E3 ligase substrate receptors cereblon and DCAF15, respectively. While many mutations directly alter the ternary complex heterodimerization surface, distal resistance sites were also identified. Several distal mutations in RBM39 led to modest decreases in degradation, yet can enable cell survival, underscoring how small differences in degradation can lead to resistance. Integrative analysis of resistance sites across GSPT1 and RBM39 revealed varying levels of sequence conservation and mutational constraint that control the emergence of different resistance mechanisms, highlighting that many regions co-opted by TPD are nonessential. Altogether, our study identifies common resistance mechanisms for molecular glue degraders and outlines a general approach to survey neosubstrate requirements necessary for effective degradation.
    DOI:  https://doi.org/10.1021/acscentsci.1c01603
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