bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2022‒04‒03
twenty papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology
  1. Suppression of endothelial cell FAK expression reduces pancreatic ductal adenocarcinoma metastasis after gemcitabine treatment.
  2. Altered propionate metabolism contributes to tumour progression and aggressiveness.
  3. Bone-Specific Enhancement of Antibody Therapy for Breast Cancer Metastasis to Bone.
  4. HSP90 inhibition overcomes resistance to molecular targeted therapy in BRAFV600E mutant high-grade glioma.
  5. Hypoxia-induced circWSB1 promotes breast cancer progression through destabilizing p53 by interacting with USP10.
  6. Identification of Functional Heterogeneity of Carcinoma-Associated Fibroblasts with Distinct IL-6 Mediated Therapy Resistance in Pancreatic Cancer.
  7. An SCD1-dependent mechanoresponsive pathway promotes HCC invasion and metastasis through lipid metabolic reprogramming.
  8. KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis.
  9. GIPC2 interacts with Fzd7 to promote prostate cancer metastasis by activating WNT signaling.
  10. Comprehensive proteomic profiling of serum extracellular vesicles in patients with colorectal liver metastases identifies a signature for non-invasive risk stratification and early-response evaluation.
  11. Cell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors.
  12. An acid trip activates protumoral macrophages to promote hepatocellular carcinoma malignancy.
  13. Exosomal DEK removes chemoradiotherapy resistance by triggering quiescence exit of breast cancer stem cells.
  14. Small-molecule targeted therapies induce dependence on DNA double-strand break repair in residual tumor cells.
  15. NFκB activation by hypoxic small extracellular vesicles drives oncogenic reprogramming in a breast cancer microenvironment.
  16. Selective histone methyltransferase G9a inhibition reduces metastatic development of Ewing sarcoma through the epigenetic regulation of NEU1.
  17. PRMT7 ablation stimulates anti-tumor immunity and sensitizes melanoma to immune checkpoint blockade.
  18. Radiotherapy plus immune checkpoint blockade in PD(L)-1-resistant metastatic NSCLC.
  19. Clinical significance of FBXW7 loss of function in human cancers.
  20. Precision medicine in pancreatic cancer: Patient derived organoid pharmacotyping is a predictive biomarker of clinical treatment response.
  1. Cancer Res. 2022 Mar 29. pii: canres.3807.2020. [Epub ahead of print]
    Suppression of endothelial cell FAK expression reduces pancreatic ductal adenocarcinoma metastasis after gemcitabine treatment.
    Marina Roy-Luzarraga, Louise E Reynolds, Beatriz de Lux N-Delgado, Oscar Maiques, Laura Wisniewski, Emma Newport, Vinothini Rajeeve, Rebecca J G Drake, Jes S G Mez-Escudero, Frances M Richards, C Line Weller, Christof Dormann, Ya-Ming Meng, Peter B Vermeulen, Dieter Saur, Victoria Sanz-Moreno, Ping-Pui Wong, Cyrill G Raud, Pedro R Cutillas, Kairbaan M Hodivala-Dilke.
      Despite substantial advances in the treatment of solid cancers, resistance to therapy remains a major obstacle to prolonged progression-free survival. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, with a high level of liver metastasis. Primary PDAC is highly hypoxic, and metastases are resistant to first-line treatment, including gemcitabine. Recent studies have indicated that endothelial cell (EC) focal adhesion kinase (FAK) regulates DNA damaging therapy-induced angiocrine factors and chemosensitivity in primary tumor models. Here, we show that inducible loss of EC-FAK in both orthotopic and spontaneous mouse models of PDAC is not sufficient to affect primary tumor growth but reduces liver and lung metastasis load and improves survival rates in gemcitabine-treated, but not untreated, mice. EC-FAK loss did not affect primary tumor angiogenesis, tumor blood vessel leakage, or early events in metastasis, including the numbers of circulating tumor cells, tumor cell homing or metastatic seeding. Phosphoproteomics analysis showed a downregulation of the MAPK, RAF, and PAK signaling pathways in gemcitabine-treated FAK-depleted ECs compared to gemcitabine-treated wild-type ECs. Moreover, low levels of EC-FAK correlated with increased survival and reduced relapse in gemcitabine-treated PDAC patients, supporting the clinical relevance of these findings. Altogether, we have identified a new role of EC-FAK in regulating PDAC metastasis upon gemcitabine treatment that impacts outcome.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-3807
  2. Nat Metab. 2022 Mar 31.
    Altered propionate metabolism contributes to tumour progression and aggressiveness.
    Ana P Gomes, Didem Ilter, Vivien Low, Stanislav Drapela, Tanya Schild, Edouard Mullarky, Julie Han, Ilaria Elia, Dorien Broekaert, Adam Rosenzweig, Michal Nagiec, Joana B Nunes, Bethany E Schaffer, Anders P Mutvei, John M Asara, Lewis C Cantley, Sarah-Maria Fendt, John Blenis.
      The alteration of metabolic pathways is a critical strategy for cancer cells to attain the traits necessary for metastasis in disease progression. Here, we find that dysregulation of propionate metabolism produces a pro-aggressive signature in breast and lung cancer cells, increasing their metastatic potential. This occurs through the downregulation of methylmalonyl coenzyme A epimerase (MCEE), mediated by an extracellular signal-regulated kinase 2-driven transcription factor Sp1/early growth response protein 1 transcriptional switch driven by metastatic signalling at its promoter level. The loss of MCEE results in reduced propionate-driven anaplerotic flux and intracellular and intratumoral accumulation of methylmalonic acid, a by-product of propionate metabolism that promotes cancer cell invasiveness. Altogether, we present a previously uncharacterized dysregulation of propionate metabolism as an important contributor to cancer and a valuable potential target in the therapeutic treatment of metastatic carcinomas.
    DOI:  https://doi.org/10.1038/s42255-022-00553-5
  3. ACS Cent Sci. 2022 Mar 23. 8(3): 312-321
    Bone-Specific Enhancement of Antibody Therapy for Breast Cancer Metastasis to Bone.
    Zeru Tian, Chenfei Yu, Weijie Zhang, Kuan-Lin Wu, Chenhang Wang, Ruchi Gupta, Zhan Xu, Ling Wu, Yuda Chen, Xiang H-F Zhang, Han Xiao.
      Despite the rapid evolution of therapeutic antibodies, their clinical efficacy in the treatment of bone tumors is hampered due to the inadequate pharmacokinetics and poor bone tissue accessibility of these large macromolecules. Here, we show that engineering therapeutic antibodies with bone-homing peptide sequences dramatically enhances their concentrations in the bone metastatic niche, resulting in significantly reduced survival and progression of breast cancer bone metastases. To enhance the bone tumor-targeting ability of engineered antibodies, we introduced varying numbers of bone-homing peptides into permissive sites of the anti-HER2 antibody, trastuzumab. Compared to the unmodified antibody, the engineered antibodies have similar pharmacokinetics and in vitro cytotoxic activity, but exhibit improved bone tumor distribution in vivo. Accordingly, in xenograft models of breast cancer metastasis to bone sites, engineered antibodies with enhanced bone specificity exhibit increased inhibition of both initial bone metastases and secondary multiorgan metastases. Furthermore, this engineering strategy is also applied to prepare bone-targeting antibody-drug conjugates with enhanced therapeutic efficacy. These results demonstrate that adding bone-specific targeting to antibody therapy results in robust bone tumor delivery efficacy. This provides a powerful strategy to overcome the poor accessibility of antibodies to the bone tumors and the consequential resistance to the therapy.
    DOI:  https://doi.org/10.1021/acscentsci.1c01024
  4. Clin Cancer Res. 2022 Mar 28. pii: clincanres.3622.2021. [Epub ahead of print]
    HSP90 inhibition overcomes resistance to molecular targeted therapy in BRAFV600E mutant high-grade glioma.
    Jo Sasame, Naoki Ikegaya, Masahito Kawazu, Manabu Natsumeda, Takahiro Hayashi, Masataka Isoda, Kaishi Satomi, Arata Tomiyama, Akito Oshima, Hirokuni Honma, Yohei Miyake, Katsuhiro Takabayashi, Taishi Nakamura, Toshihide Ueno, Yuko Matsushita, Hiromichi Iwashita, Yu Kanemaru, Hidetoshi Murata, Akihide Ryo, Keita Terashima, Shoji Yamanaka, Yukihiko Fujii, Hiroyuki Mano, Takashi Komori, Koichi Ichimura, Daniel P Cahill, Hiroaki Wakimoto, Tetsuya Yamamoto, Kensuke Tateishi.
      PURPOSE: Molecular targeted therapy using BRAF and/or MEK inhibitors has been applied to BRAFV600E mutant high-grade gliomas (HGGs); however, the therapeutic effect is limited by the emergence of drug resistance.EXPERIMENTAL DESIGN: We established multiple paired BRAFV600E mutant HGG patient-derived xenograft (PDX) models based on tissues collected prior to and at relapse after molecular targeted therapy. Using these models, we dissected treatment resistant mechanisms for molecular targeted therapy and explored therapeutic targets to overcome resistance in BRAFV600E HGG models in vitro and in vivo.
    RESULTS: We found that, despite causing no major genetic and epigenetic changes, BRAF and/or MEK inhibitor treatment deregulated multiple negative feedback mechanisms, which led to the re-activation of the MAPK pathway through c-Raf and AKT signaling. This altered oncogenic signaling primarily mediated resistance to molecular targeted therapy in BRAFV600E mutant HGG. To overcome this resistance mechanism, we performed a high-throughput drug screening to identify therapeutic agents that potently induce additive cytotoxicity with BRAF and MEK inhibitors. We discovered that HSP90 inhibition combined with BRAF/MEK inhibition coordinately deactivated the MAPK and AKT/mTOR pathways, and subsequently induced apoptosis via dephosphorylation of GSK3β (Ser9) and inhibition of Bcl-2 family proteins. This mediated potent cytotoxicity in vitro and in vivo in refractory models with acquired resistance to molecular-targeted therapy.
    CONCLUSIONS: The combination of an HSP90 inhibitor with BRAF or MEK inhibitors can overcome the limitations of the current therapeutic strategies for BRAFV600E mutant HGG.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-3622
  5. Mol Cancer. 2022 Mar 29. 21(1): 88
    Hypoxia-induced circWSB1 promotes breast cancer progression through destabilizing p53 by interacting with USP10.
    Rui Yang, Hang Chen, Lei Xing, Bin Wang, Mengting Hu, Xiaoqiang Ou, Hong Chen, Yumei Deng, Dawei Liu, Rong Jiang, Junxia Chen.
      BACKGROUND: Hypoxia has long been considered as a hallmark of solid tumors and is closely associated with tumor progression. Circular RNAs (circRNAs) have been identified as a critical modulator in various cancers. However, the connections between hypoxia and circRNAs are largely unknown.METHODS: Here, we investigated the expression profile of circRNAs in breast cancer (BC) MCF-7 cells under hypoxia and normoxia using microarray. We identified a novel hypoxia-responsive circRNA named circWSB1, whose expression pattern, potential diagnostic value and prognostic significance were assessed by qRT-PCR and in situ hybridization. Loss- and gain-of-function investigations in vivo and in vitro were performed to determine the biological functions of circWSB1. Mechanistically, chromatin immunoprecipitation and dual luciferase reporter assays were carried out to analyze the biogenesis of circWSB1. Furthermore, biotin-labeled RNA pull-down, mass spectrometry, RNA immunoprecipitation, fluorescent in situ hybridization, RNA electrophoretic mobility shift, deletion-mapping, co-immunoprecipitation assays and rescue experiments were applied to investigate the interaction between circWSB1 and Ubiquitin-specific peptidase 10 (USP10) as well as the relationship between USP10 and p53.
    RESULTS: We found that the expression of circWSB1 was significantly upregulated in BC tissues and correlated with poor clinical outcomes, which might serve as an independent prognostic factor for BC patients. Ectopic expression of circWSB1 promoted the proliferation of BC cell in vitro and in vivo. Mechanistically, circWSB1 was transcriptionally upregulated by HIF1α in response to hypoxia and could competitively bind to deubiquitinase USP10 to prevent the access of p53 to USP10 in BC cells, leading to degradation of p53 and tumor progression of BC.
    CONCLUSIONS: Taken together, our findings disclose a novel mechanism that hypoxia-inducible circWSB1 could interact with USP10 to attenuate USP10 mediated p53 stabilization and promote the progression of BC, providing an alternative prognostic biomarker and therapeutic target for BC.
    Keywords:  Breast cancer; Hypoxia; USP10; circWSB1; p53
    DOI:  https://doi.org/10.1186/s12943-022-01567-z
  6. Cancer Discov. 2022 Mar 29. pii: candisc.1484.2020. [Epub ahead of print]
    Identification of Functional Heterogeneity of Carcinoma-Associated Fibroblasts with Distinct IL-6 Mediated Therapy Resistance in Pancreatic Cancer.
    Kathleen M McAndrews, Yang Chen, J Kebbeh Darpolor, Xiaofeng Zheng, Sujuan Yang, Julienne L Carstens, Bingrui Li, Huamin Wang, Toru Miyake, Pedro Correa de Sampaio, Michelle L Kirtley, Mariangela Natale, Chia-Chin Wu, Hikaru Sugimoto, Valerie S LeBleu, Raghu Kalluri.
      The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of fibroblasts as part of the host response to cancer. Employing single-cell RNA-sequencing, multiplex immunostaining, and several genetic mouse models, we identify carcinoma-associated fibroblasts (CAFs) with opposing functions in PDAC progression. Depletion of fibroblast activation protein (FAP)+ CAFs results in increased survival, in contrast to depletion of alpha smooth muscle actin (aSMA)+ CAFs that leads to decreased survival. Tumor-promoting FAP+ CAFs (TP-CAFs) and tumor-restraining aSMA+ CAFs (TR-CAFs) differentially regulate cancer-associated pathways and accumulation of Tregs. Improved efficacy of gemcitabine is observed when IL-6 is deleted from aSMA+ CAFs but not from FAP+ CAFs employing dual-recombinase genetic PDAC models. Improved gemcitabine efficacy due to lack of IL-6 synergizes with anti-PD1 immunotherapy to significantly improve survival of PDAC mice. Our study identifies functional heterogeneity of CAFs in PDAC progression and their different roles in therapy response.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1484
  7. Mol Ther. 2022 Mar 28. pii: S1525-0016(22)00175-7. [Epub ahead of print]
    An SCD1-dependent mechanoresponsive pathway promotes HCC invasion and metastasis through lipid metabolic reprogramming.
    Hua-Hua Liu, Yang Xu, Cao-Jie Li, Shu-Jung Hsu, Xia-Hui Lin, Rui Zhang, Jie Chen, Jun Chen, Dong-Mei Gao, Jie-Feng Cui, Xin-Rong Yang, Zheng-Gang Ren, Rong-Xin Chen.
      Matrix stiffness promotes hepatocellular carcinoma (HCC) metastasis. This study examined the contribution of lipid metabolic reprogramming to matrix stiffness-induced HCC metastasis. HCC cells were cultured on mechanically tunable polyacrylamide gels and subjected to lipidomic analysis. The key enzyme that responded to matrix stiffness and regulated lipid metabolism was identified. The comparative lipidomic screening revealed that stearoyl-CoA desaturase 1 (SCD1) is a mechanoresponsive enzyme that reprogrammed HCC cell lipid metabolism. The genetic and pharmacological inhibition of SCD1 expression/activity altered the cellular lipid composition, which in turn impaired plasma membrane fluidity and inhibited in vitro invasive motility of HCC cells in response to high matrix stiffness. Knockdown of SCD1 suppressed HCC invasion and metastasis in vivo. Conversely, the overexpression of SCD1 or exogenous administration of its product oleic acid augmented plasma membrane fluidity and rescued in vitro invasive migration in HCC cells cultured on soft substrates, mimicking the effects imposed by high matrix stiffness. In human HCC tissues, collagen content, a marker of increasing matrix stiffness, and increased expression of SCD1 together predicted poor survival of HCC patients. An SCD1-dependent mechanoresponsive pathway that responds to increasing matrix stiffness in the tumor microenvironment promotes HCC invasion and metastasis through lipid metabolic reprogramming.
    DOI:  https://doi.org/10.1016/j.ymthe.2022.03.015
  8. Mol Cancer. 2022 Mar 30. 21(1): 89
    KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis.
    Tanja Limberger, Michaela Schlederer, Karolina Trachtová, Ines Garces de Los Fayos Alonso, Jiaye Yang, Sandra Högler, Christina Sternberg, Vojtech Bystry, Jan Oppelt, Boris Tichý, Margit Schmeidl, Petra Kodajova, Anton Jäger, Heidi A Neubauer, Monika Oberhuber, Belinda S Schmalzbauer, Sarka Pospisilova, Helmut Dolznig, Wolfgang Wadsak, Zoran Culig, Suzanne D Turner, Gerda Egger, Sabine Lagger, Lukas Kenner.
      BACKGROUND: Frequent truncation mutations of the histone lysine N-methyltransferase KMT2C have been detected by whole exome sequencing studies in various cancers, including malignancies of the prostate. However, the biological consequences of these alterations in prostate cancer have not yet been elucidated.METHODS: To investigate the functional effects of these mutations, we deleted the C-terminal catalytic core motif of Kmt2c specifically in mouse prostate epithelium. We analysed the effect of Kmt2c SET domain deletion in a Pten-deficient PCa mouse model in vivo and of truncation mutations of KMT2C in a large number of prostate cancer patients.
    RESULTS: We show here for the first time that impaired KMT2C methyltransferase activity drives proliferation and PIN formation and, when combined with loss of the tumour suppressor PTEN, triggers loss of senescence, metastatic dissemination and dramatically reduces life expectancy. In Kmt2c-mutated tumours we show enrichment of proliferative MYC gene signatures and loss of expression of the cell cycle repressor p16INK4A. In addition, we observe a striking reduction in disease-free survival of patients with KMT2C-mutated prostate cancer.
    CONCLUSIONS: We identified truncating events of KMT2C as drivers of proliferation and PIN formation. Loss of PTEN and KMT2C in prostate cancer results in loss of senescence, metastatic dissemination and reduced life expectancy. Our data demonstrate the prognostic significance of KMT2C mutation status in prostate cancer patients. Inhibition of the MYC signalling axis may be a viable treatment option for patients with KMT2C truncations and therefore poor prognosis.
    Keywords:  KMT2C; MYC; Metastasis; Prostate cancer; Senescence; p16INK4A
    DOI:  https://doi.org/10.1186/s12943-022-01542-8
  9. Oncogene. 2022 Mar 28.
    GIPC2 interacts with Fzd7 to promote prostate cancer metastasis by activating WNT signaling.
    Liang Wang, Jiayi Wang, Xiaolin Yin, Xin Guan, Ying Li, Chenqi Xin, Jing Liu.
      Prostate cancer (PCa) causes significant mortality and morbidity, with advanced metastasis. WNT signaling is a promising therapeutic target for metastatic PCa. GIPC2 is a GIPC1 paralog involved in WNT signaling pathways associated with tumor progression, but its role in PCa metastasis remains unclear. Herein, we demonstrated that high GIPC2 expression in PCa tissues was significantly associated with distant metastasis and poor prognosis. Functional studies demonstrated that high GIPC2 expression due to CpG-island demethylation promoted increased metastatic capabilities of PCa cells. Conversely, silencing GIPC2 expression significantly inhibited PCa metastasis in vitro and in vivo. Furthermore, GIPC2 directly bound the WNT co-receptor Fzd7 through its PDZ domain, which enabled activation of WNT-β-catenin cascades, thereby stimulating PCa metastasis. Interestingly, GIPC2 protein was also identified as a component of exosomes and that it robustly stimulated PCa adhesion, invasion, and migration. The presence of GIPC2 in tumor-derived exosomes and ability to impact the behavior of tumor cells suggest that GIPC2 is a novel epigenetic oncogene involved in PCa metastasis. Our findings identified GIPC2 as a novel exosomal molecule associated with WNT signaling and may represent a potential therapeutic target and biomarker for metastatic PCa.
    DOI:  https://doi.org/10.1038/s41388-022-02255-4
  10. Mol Cancer. 2022 Apr 01. 21(1): 91
    Comprehensive proteomic profiling of serum extracellular vesicles in patients with colorectal liver metastases identifies a signature for non-invasive risk stratification and early-response evaluation.
    Kuailu Lin, Franziska Baenke, Xixi Lai, Martin Schneider, Dominic Helm, Heike Polster, Venkatesh S Rao, Nicole Ganig, Fang Cheng Wong, Lena Seifert, Adrian M Seifert, Beatrix Jahnke, Nicole Kretschmann, Tjalf Ziemssen, Fee Klupp, Thomas Schmidt, Martin Schneider, Yi Han, Tim F Weber, Verena Plodeck, Heiner Nebelung, Nathalie Schmitt, Felix Korell, Bruno C Köhler, Carina Riediger, Jürgen Weitz, Nuh N Rahbari, Christoph Kahlert.
      
    Keywords:  Colorectal liver metastases; Early response prediction; Extracellular vesicles; Molecular risk stratification; Protein signature
    DOI:  https://doi.org/10.1186/s12943-022-01562-4
  11. Nat Commun. 2022 Mar 28. 13(1): 1487
    Cell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors.
    Fotis Nikolos, Kazukuni Hayashi, Xen Ping Hoi, Mark Ellie Alonzo, Qianxing Mo, Armine Kasabyan, Hideki Furuya, Jane Trepel, Dolores Di Vizio, Jlenia Guarnerio, Dan Theodorescu, Charles Rosser, Andrea Apolo, Matthew Galsky, Keith Syson Chan.
      Chemoimmunotherapy has recently failed to demonstrate significant clinical benefit in advanced bladder cancer patients; and the mechanism(s) underlying such suboptimal response remain elusive. To date, most studies have focused on tumor-intrinsic properties that render them "immune-excluded". Here, we explore an alternative, drug-induced mechanism that impedes therapeutic response via disrupting the onset of immunogenic cell death. Using two immune-excluded syngeneic mouse models of muscle-invasive bladder cancer (MIBC), we show that platinum-based chemotherapy diminishes CD8+ T cell tumor infiltration and constraines their antitumoral activity, despite expression of activation markers IFNγ and granzyme B. Mechanistically, chemotherapy induces the release of prostaglandin E2 (PGE2) from dying cancer cells, which is an inhibitory damage-associated molecular pattern (iDAMP) that hinderes dendritic cell maturation. Upon pharmaceutical blockade of PGE2 release, CD8+ T cells become tumoricidal and display an intraepithelial-infiltrating (or inflamed) pattern. This "iDAMP blockade" approach synergizes with chemotherapy and sensitizes bladder tumors towards anti-PD1 immune checkpoint inhibitor therapy. These findings provide a compelling rationale to evaluate this drug combination in future clinical trials.
    DOI:  https://doi.org/10.1038/s41467-022-29026-9
  12. J Clin Invest. 2022 Apr 01. pii: e158562. [Epub ahead of print]132(7):
    An acid trip activates protumoral macrophages to promote hepatocellular carcinoma malignancy.
    Nicola Graham, Jeffrey W Pollard.
      Tumor-associated macrophages (TAMs) promote metastasis and tumor cell extravasation, survival, and growth. In hepatocellular carcinoma (HCC), the presence of TAM subpopulations correlates with poor outcome. In this issue of the JCI, Ning et al. report on their use of cell culture, mouse models, and human data sets to investigate the interactions between aerobic glycolysis and carbonic anhydrase XII (CA12) expression in HCC. Aerobic glycolysis promoted CA12 upregulation in TAMs, which induced a protumoral phenotype to promote tumor growth and metastasis. Tumor cell factors derived from HCC samples induced CA12 upregulation in tumor-infiltrating TAMs via the HIF1α pathway. In preclinical models of HCC, CA12 inhibition reduced tumor growth and lung metastasis and reduced TAM infiltrate. Notably, dual treatment with anti-PD1 and CA12 inhibitors synergistically attenuated tumor growth and metastasis and enhanced survival compared with either treatment alone. These findings suggest that targeting CA12 in combination with immune-checkpoint blockade may provide treatment options for HCC.
    DOI:  https://doi.org/10.1172/JCI158562
  13. Oncogene. 2022 Mar 29.
    Exosomal DEK removes chemoradiotherapy resistance by triggering quiescence exit of breast cancer stem cells.
    Yao-Shun Yang, Xi-Zheng Jia, Qian-Yun Lu, Sun-Li Cai, Xue-Ting Huang, Shu-Hua Yang, Chris Wood, Yue-Hong Wang, Jiao-Jiao Zhou, Yi-Ding Chen, Jin-Shu Yang, Wei-Jun Yang.
      Tumor therapeutics often target the primary tumor bulk but fail to eradicate therapy-resistant cancer stem cells (CSCs) in quiescent state. These can then become activated to initiate recurrence and/or metastasis beyond therapy. Here, we identified and isolated chemoradiotherapy-resistant CSCs in quiescent state with high capacity of tumor-initiation and tumorsphere formation from three types of breast tumors in mice. Experiments of knockdown and rescue revealed DEK, a nuclear protein, as essential for CSC activation. Exogenous DEK was then used to trigger quiescence exit of CSCs. ChIP-seq and ATAC-seq showed that DEK directly binds to chromatin, facilitating its genome-wide accessibility. The resulting epigenetic events upregulate the expression of cellular activation-related genes including MYC targets, whereas cellular quiescence-related genes including the p53 signaling pathway are silenced. However, twinned with DEK-induced activation, formerly resistant CSCs were then destroyed by chemotherapy in vitro. In mice, traditional chemoradiotherapy concurrent with the injection of DEK-containing exosomes resulted in eradication of primary tumors together with formerly resistant CSCs without recurrence or metastasis. Our findings advance knowledge of the mechanism of quiescent CSC activation and may provide novel clinical opportunities for removal of quiescence-linked therapy resistance.
    DOI:  https://doi.org/10.1038/s41388-022-02278-x
  14. Sci Transl Med. 2022 Mar 30. 14(638): eabc7480
    Small-molecule targeted therapies induce dependence on DNA double-strand break repair in residual tumor cells.
    Moiez Ali, Min Lu, Hazel Xiaohui Ang, Ryan S Soderquist, Christine E Eyler, Haley M Hutchinson, Carolyn Glass, Christopher F Bassil, Omar M Lopez, D Lucas Kerr, Christina J Falcon, Helena A Yu, Aaron N Hata, Collin M Blakely, Caroline E McCoach, Trever G Bivona, Kris C Wood.
      Residual cancer cells that survive drug treatments with targeted therapies act as a reservoir from which eventual resistant disease emerges. Although there is great interest in therapeutically targeting residual cells, efforts are hampered by our limited knowledge of the vulnerabilities existing in this cell state. Here, we report that diverse oncogene-targeted therapies, including inhibitors of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), KRAS, and BRAF, induce DNA double-strand breaks and, consequently, ataxia-telangiectasia mutated (ATM)-dependent DNA repair in oncogene-matched residual tumor cells. This DNA damage response, observed in cell lines, mouse xenograft models, and human patients, is driven by a pathway involving the activation of caspases 3 and 7 and the downstream caspase-activated deoxyribonuclease (CAD). CAD is, in turn, activated through caspase-mediated degradation of its endogenous inhibitor, ICAD. In models of EGFR mutant non-small cell lung cancer (NSCLC), tumor cells that survive treatment with small-molecule EGFR-targeted therapies are thus synthetically dependent on ATM, and combined treatment with an ATM kinase inhibitor eradicates these cells in vivo. This led to more penetrant and durable responses in EGFR mutant NSCLC mouse xenograft models, including those derived from both established cell lines and patient tumors. Last, we found that rare patients with EGFR mutant NSCLC harboring co-occurring, loss-of-function mutations in ATM exhibit extended progression-free survival on first generation EGFR inhibitor therapy relative to patients with EGFR mutant NSCLC lacking deleterious ATM mutations. Together, these findings establish a rationale for the mechanism-based integration of ATM inhibitors alongside existing targeted therapies.
    DOI:  https://doi.org/10.1126/scitranslmed.abc7480
  15. Oncogene. 2022 Mar 30.
    NFκB activation by hypoxic small extracellular vesicles drives oncogenic reprogramming in a breast cancer microenvironment.
    Irene Bertolini, Michela Perego, Jagadish C Ghosh, Andrew V Kossenkov, Dario C Altieri.
      Small extracellular vesicles (sEV) contribute to the crosstalk between tumor cells and stroma, but the underlying signals are elusive. Here, we show that sEV generated by breast cancer cells in hypoxic (sEVHYP), but not normoxic (sEVNORM) conditions activate NFκB in recipient normal mammary epithelial cells. This increases the production and release of inflammatory cytokines, promotes mitochondrial dynamics leading to heightened cell motility and disrupts 3D mammary acini architecture with aberrant cell proliferation, reduced apoptosis and EMT. Mechanistically, Integrin-Linked Kinase packaged in sEVHYP via HIF1α is sufficient to activate NFκB in the normal mammary epithelium, in vivo. Therefore, sEVHYP activation of NFκB drives multiple oncogenic steps of inflammation, mitochondrial dynamics, and mammary gland morphogenesis in a breast cancer microenvironment.
    DOI:  https://doi.org/10.1038/s41388-022-02280-3
  16. Oncogene. 2022 Mar 30.
    Selective histone methyltransferase G9a inhibition reduces metastatic development of Ewing sarcoma through the epigenetic regulation of NEU1.
    Daniel J García-Domínguez, Nabil Hajji, Roser López-Alemany, Sara Sánchez-Molina, Elisabet Figuerola-Bou, Francisco J Morón Civanto, Santiago Rello-Varona, Eduardo Andrés-León, Adrián Benito, Hector C Keun, Jaume Mora, Óscar M Tirado, Enrique de Álava, Lourdes Hontecillas-Prieto.
      Ewing sarcoma (EWS) is an aggressive bone and soft tissue tumor with high susceptibility to metastasize. The underlying molecular mechanisms leading to EWS metastases remain poorly understood. Epigenetic changes have been implicated in EWS tumor growth and progression. Linking epigenetics and metastases may provide insight into novel molecular targets in EWS and improve its treatment. Here, we evaluated the effects of a selective G9a histone methyltransferase inhibitor (BIX01294) on EWS metastatic process. Our results showed that overexpression of G9a in tumors from EWS patients correlates with poor prognosis. Moreover, we observe a significantly higher expression of G9a in metastatic EWS tumor as compared to either primary or recurrent tumor. Using functional assays, we demonstrate that pharmacological G9a inhibition using BIX01294 disrupts several metastatic steps in vitro, such as migration, invasion, adhesion, colony formation and vasculogenic mimicry. Moreover, BIX01294 reduces tumor growth and metastases in two spontaneous metastases mouse models. We further identified the sialidase NEU1 as a direct target and effector of G9a in the metastatic process in EWS. NEU1 overexpression impairs migration, invasion and clonogenic capacity of EWS cell lines. Overall, G9a inhibition impairs metastases in vitro and in vivo through the overexpression of NEU1. G9a has strong potential as a prognostic marker and may be a promising therapeutic target for EWS patients.
    DOI:  https://doi.org/10.1038/s41388-022-02279-w
  17. Cell Rep. 2022 Mar 29. pii: S2211-1247(22)00326-6. [Epub ahead of print]38(13): 110582
    PRMT7 ablation stimulates anti-tumor immunity and sensitizes melanoma to immune checkpoint blockade.
    Nivine Srour, Oscar D Villarreal, Swanand Hardikar, Zhenbao Yu, Samuel Preston, Wilson H Miller, Magdelena M Szewczyk, Dalia Barsyte-Lovejoy, Han Xu, Taiping Chen, Sonia V Del Rincón, Stéphane Richard.
      Despite the success of immune checkpoint inhibitor (ICI) therapy for cancer, resistance and relapse are frequent. Combination therapies are expected to enhance response rates and overcome this resistance. Herein, we report that combining PRMT7 inhibition with ICI therapy induces a strong anti-tumor T cell immunity and restrains tumor growth in vivo by increasing immune cell infiltration. PRMT7-deficient B16.F10 melanoma exhibits increased expression of genes in the interferon pathway, antigen presentation, and chemokine signaling. PRMT7 deficiency or inhibition with SGC3027 in B16.F10 melanoma results in reduced DNMT expression, loss of DNA methylation in the regulatory regions of endogenous retroviral elements (ERVs) causing their increased expression. PRMT7-deficient cells increase RIG-I and MDA5 expression with a reduction in the H4R3me2s repressive histone mark at their gene promoters. Our findings identify PRMT7 as a regulatory checkpoint for RIG-I, MDA5, and their ERV-double-stranded RNA (dsRNA) ligands, facilitating immune escape and anti-tumor T cell immunity to restrain tumor growth.
    Keywords:  CP: Cancer; CP: Immunology; DNMTs; PRMT7; RLR pathway; arginine methylation; cytotoxic T cells; dsRNA; immune checkpoint inhibitors; melanoma
    DOI:  https://doi.org/10.1016/j.celrep.2022.110582
  18. Lancet Oncol. 2022 Apr;pii: S1470-2045(22)00154-1. [Epub ahead of print]23(4): e157
    Radiotherapy plus immune checkpoint blockade in PD(L)-1-resistant metastatic NSCLC.
    Maria Ochoa-de-Olza, Jean Bourhis, George Coukos, Fernanda G Herrera.
      
    DOI:  https://doi.org/10.1016/S1470-2045(22)00154-1
  19. Mol Cancer. 2022 Mar 26. 21(1): 87
    Clinical significance of FBXW7 loss of function in human cancers.
    Jingyi Fan, Marcia Bellon, Mingyi Ju, Lin Zhao, Minjie Wei, Liwu Fu, Christophe Nicot.
      FBXW7 (F-Box and WD Repeat Domain Containing 7) (also referred to as FBW7 or hCDC4) is a component of the Skp1-Cdc53 / Cullin-F-box-protein complex (SCF/β-TrCP). As a member of the F-box protein family, FBXW7 serves a role in phosphorylation-dependent ubiquitination and proteasome degradation of oncoproteins that play critical role(s) in oncogenesis. FBXW7 affects many regulatory functions involved in cell survival, cell proliferation, tumor invasion, DNA damage repair, genomic instability and telomere biology. This thorough review of current literature details how FBXW7 expression and functions are regulated through multiple mechanisms and how that ultimately drives tumorigenesis in a wide array of cell types. The clinical significance of FBXW7 is highlighted by the fact that FBXW7 is frequently inactivated in human lung, colon, and hematopoietic cancers. The loss of FBXW7 can serve as an independent prognostic marker and is significantly correlated with the resistance of tumor cells to chemotherapeutic agents and poorer disease outcomes. Recent evidence shows that genetic mutation of FBXW7 differentially affects the degradation of specific cellular targets resulting in a distinct and specific pattern of activation/inactivation of cell signaling pathways. The clinical significance of FBXW7 mutations in the context of tumor development, progression, and resistance to therapies as well as opportunities for targeted therapies is discussed.
    Keywords:  Aneuploidy; Apoptosis; CDC4; Cancer; Cell cycle; Centrosome; Chromosome instability; Cyclin E; DNA repair; Drug resistance; Epigenetic; FBW7; FBXW7; Immunotherapy; LncRNA; MCL-1; MYC; Mutation; NOTCH; Non-coding RNA; Tumor suppressor; circRNA; miRNA
    DOI:  https://doi.org/10.1186/s12943-022-01548-2
  20. Clin Cancer Res. 2022 Apr 01. pii: clincanres.4165.2021. [Epub ahead of print]
    Precision medicine in pancreatic cancer: Patient derived organoid pharmacotyping is a predictive biomarker of clinical treatment response.
    Toni T Seppälä, Jacquelyn W Zimmerman, Reecha Suri, Haley Zlomke, Gabriel D Ivey, Annamaria Szabolcs, Christopher R Shubert, John L Cameron, William R Burns, Kelly J Lafaro, Jin He, Christopher L Wolfgang, Ying S Zou, Lei Zheng, David A Tuveson, James R Eshlemann, David P Ryan, Alec C Kimmelman, Theodore S Hong, David T Ting, Elizabeth M Jaffee, Richard A Burkhart.
      RATIONALE: Patient-derived organoids (PDOs) are a promising technology to support precision medicine initiatives for patients with pancreatic ductal adenocarcinoma (PDAC). PDOs may improve clinical next-generation sequencing (NGS) and enable rapid ex vivo chemotherapeutic screening (pharmacotyping).METHODS: PDOs were derived from tissues obtained during surgical resection and endoscopic biopsies and studied with NGS and pharmacotyping. PDO-specific pharmacotype is assessed prospectively as a predictive biomarker of clinical therapeutic response by leveraging data from a randomized-controlled clinical trial.
    RESULTS: Clinical sequencing pipelines often fail to detect PDAC-associated somatic mutations in surgical specimens that demonstrate a good pathological response to previously administered chemotherapy. Sequencing the PDOs derived from these surgical specimens, after biomass expansion, improves the detection of somatic mutations and enables quantification of copy number variants. The detection of clinically relevant mutations and structural variants is improved following PDO biomass expansion. On clinical trial, PDOs were derived from biopsies of treatment naïve patients prior to treatment with FOLFIRINOX (FFX). Ex vivo PDO pharmacotyping with FFX components predicted clinical therapeutic response in these patients with borderline resectable or locally advanced PDAC treated in a neoadjuvant or induction paradigm. PDO pharmacotypes suggesting sensitivity to FFX components were associated with longitudinal declines of tumor marker, CA-19-9 and favorable RECIST imaging response.
    CONCLUSION: PDOs establishment from tissues obtained from patients previously receiving cytotoxic chemotherapies can be accomplished in a clinically-certified laboratory. Sequencing PDOs following biomass expansion improves clinical sequencing quality. High in-vitro sensitivity to standard-of-care chemotherapeutics predicts good clinical response to systemic chemotherapy in PDAC.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-4165
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