bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒07‒26
23 papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Nat Genet. 2020 Jul 20.
    Pomerantz MM, Qiu X, Zhu Y, Takeda DY, Pan W, Baca SC, Gusev A, Korthauer KD, Severson TM, Ha G, Viswanathan SR, Seo JH, Nguyen HM, Zhang B, Pasaniuc B, Giambartolomei C, Alaiwi SA, Bell CA, O'Connor EP, Chabot MS, Stillman DR, Lis R, Font-Tello A, Li L, Cejas P, Bergman AM, Sanders J, van der Poel HG, Gayther SA, Lawrenson K, Fonseca MAS, Reddy J, Corona RI, Martovetsky G, Egan B, Choueiri T, Ellis L, Garraway IP, Lee GM, Corey E, Long HW, Zwart W, Freedman ML.
      Epigenetic processes govern prostate cancer (PCa) biology, as evidenced by the dependency of PCa cells on the androgen receptor (AR), a prostate master transcription factor. We generated 268 epigenomic datasets spanning two state transitions-from normal prostate epithelium to localized PCa to metastases-in specimens derived from human tissue. We discovered that reprogrammed AR sites in metastatic PCa are not created de novo; rather, they are prepopulated by the transcription factors FOXA1 and HOXB13 in normal prostate epithelium. Reprogrammed regulatory elements commissioned in metastatic disease hijack latent developmental programs, accessing sites that are implicated in prostate organogenesis. Analysis of reactivated regulatory elements enabled the identification and functional validation of previously unknown metastasis-specific enhancers at HOXB13, FOXA1 and NKX3-1. Finally, we observed that prostate lineage-specific regulatory elements were strongly associated with PCa risk heritability and somatic mutation density. Examining prostate biology through an epigenomic lens is fundamental for understanding the mechanisms underlying tumor progression.
  2. EMBO Mol Med. 2020 Jul 20. e11416
    Schito L, Rey S, Xu P, Man S, Cruz-Muñoz W, Kerbel RS.
      Conventional maximum-tolerated dose (MTD) chemotherapy relies on periodic, massive cancer cell ablation events followed by treatment-free intermissions, stereotypically resulting in resistance, relapse, and mortality. Furthermore, MTD chemotherapy can promote metastatic dissemination via activation of a transcriptional program dependent on hypoxia-inducible factor (HIF)-1α and (HIF)-2α (hereafter referred to as HIFα). Instead, frequent low-dose metronomic (LDM) chemotherapy displays less adverse effects while preserving significant pre-clinical anticancer activity. Consequently, we hereby compared the effect of MTD or LDM chemotherapy upon HIFα in models of advanced, metastatic colon and breast cancer. Our results revealed that LDM chemotherapy could offset paralog-specific, MTD-dependent HIFα induction in colon cancers disseminating to the liver and lungs, while limiting HIFα and hypoxia in breast cancer lung metastases. Moreover, we assessed the translational significance of HIFα activity in colorectal and breast TCGA/microarray data, by developing two compact, 11-gene transcriptomic signatures allowing the stratification/identification of patients likely to benefit from LDM and/or HIFα-targeting therapies. Altogether, these results suggest LDM chemotherapy as a potential maintenance strategy to stave off HIFα induction within the intra-metastatic tumor microenvironment.
    Keywords:  HIF-1; breast cancer; colon cancer; hypoxia; low-dose metronomic
  3. Cancer Cell. 2020 Jul 08. pii: S1535-6108(20)30316-0. [Epub ahead of print]
    Marjanovic ND, Hofree M, Chan JE, Canner D, Wu K, Trakala M, Hartmann GG, Smith O, Kim J, Evans KV, Hudson A, Ashenberg O, Porter CBM, Bejnood A, Subramanian A, Pitter K, Yan Y, Delroy T, Phillips DR, Shah N, Chaudhary O, Tsankov A, Hollmann T, Rekhtman N, Massion PP, Poirier JT, Mazutis L, Li R, Lee JH, Amon A, Rudin CM, Jacks T, Regev A, Tammela T.
      Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profile single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from pre-neoplastic hyperplasia to adenocarcinoma. The diversity of transcriptional states increases over time and is reproducible across tumors and mice. Cancer cells progressively adopt alternate lineage identities, computationally predicted to be mediated through a common transitional, high-plasticity cell state (HPCS). Accordingly, HPCS cells prospectively isolated from mouse tumors and human patient-derived xenografts display high capacity for differentiation and proliferation. The HPCS program is associated with poor survival across human cancers and demonstrates chemoresistance in mice. Our study reveals a central principle underpinning intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS.
    Keywords:  cell state transition; lung cancer; plasticity; single-cell transcriptomics; tumor evolution; tumor heterogeneity
  4. Cancer Res. 2020 Jul 22. pii: canres.1738.2019. [Epub ahead of print]
    Wang L, Jia Z, Xie D, Zhao T, Tan Z, Zhang S, Kong F, Wei D, Xie K.
      Pancreatic cancer is a lethal disease owing to its intrinsic and acquired resistance to therapeutic modalities. The altered balance between pro- and anti-apoptosis signals within cancer cells is critical to therapeutic resistance. However, the molecular mechanisms underlying increased anti-apoptosis signals remain poorly understood. In this study, we report that PRMT1 expression is increased in pancreatic cancer tissues and associated with higher tumor grade, increased aggressiveness and worse prognosis. PRMT1 overexpression increased arginine methylation of HSP70; this methylation enhanced HSP70 binding and stabilization of BCL-2 mRNA through AU-rich elements in 3'-UTR and consequentially increased BCL-2 protein expression and protected cancer cells from apoptosis induced by cellular stresses and therapeutics. RNA binding and regulation function of HSP70 was involved in pancreatic cancer drug resistance and was dependent on protein arginine methylation. These findings not only reveal a novel PRMT1-HSP70-BCL-2 signaling axis that is crucial to pancreatic cancer cell survival and therapeutic resistance, but they also provide a proof of concept that targeted inhibition of this axis may represent a new therapeutic strategy.
  5. Nat Commun. 2020 Jul 24. 11(1): 3726
    Kim H, Xu H, George E, Hallberg D, Kumar S, Jagannathan V, Medvedev S, Kinose Y, Devins K, Verma P, Ly K, Wang Y, Greenberg RA, Schwartz L, Johnson N, Scharpf RB, Mills GB, Zhang R, Velculescu VE, Brown EJ, Simpkins F.
      Ovarian cancer (OVCA) inevitably acquires resistance to platinum chemotherapy and PARP inhibitors (PARPi). We show that acquisition of PARPi-resistance is accompanied by increased ATR-CHK1 activity and sensitivity to ATR inhibition (ATRi). However, PARPi-resistant cells are remarkably more sensitive to ATRi when combined with PARPi (PARPi-ATRi). Sensitivity to PARPi-ATRi in diverse PARPi and platinum-resistant models, including BRCA1/2 reversion and CCNE1-amplified models, correlate with synergistic increases in replication fork stalling, double-strand breaks, and apoptosis. Surprisingly, BRCA reversion mutations and an ability to form RAD51 foci are frequently not observed in models of acquired PARPi-resistance, suggesting the existence of alternative resistance mechanisms. However, regardless of the mechanisms of resistance, complete and durable therapeutic responses to PARPi-ATRi that significantly increase survival are observed in clinically relevant platinum and acquired PARPi-resistant patient-derived xenografts (PDXs) models. These findings indicate that PARPi-ATRi is a highly promising strategy for OVCAs that acquire resistance to PARPi and platinum.
  6. Nat Metab. 2020 Apr;2(4): 318-334
    Fox DB, Garcia NMG, McKinney BJ, Lupo R, Noteware LC, Newcomb R, Liu J, Locasale JW, Hirschey MD, Alvarez JV.
      The survival and recurrence of dormant tumour cells following therapy is a leading cause of death in cancer patients. The metabolic properties of these cells are likely distinct from those of rapidly growing tumours. Here we show that Her2 down-regulation in breast cancer cells promotes changes in cellular metabolism, culminating in oxidative stress and compensatory upregulation of the antioxidant transcription factor, NRF2. NRF2 is activated during dormancy and in recurrent tumours in animal models and breast cancer patients with poor prognosis. Constitutive activation of NRF2 accelerates recurrence, while suppression of NRF2 impairs it. In recurrent tumours, NRF2 signalling induces a transcriptional metabolic reprogramming to re-establish redox homeostasis and upregulate de novo nucleotide synthesis. The NRF2-driven metabolic state renders recurrent tumour cells sensitive to glutaminase inhibition, which prevents reactivation of dormant tumour cells in vitro, suggesting that NRF2-high dormant and recurrent tumours may be targeted. These data provide evidence that NRF2-driven metabolic reprogramming promotes the recurrence of dormant breast cancer.
    Keywords:  Breast cancer recurrence; Her2; NRF2; ROS; Residual disease; Tumor metabolism
  7. Nat Rev Clin Oncol. 2020 Jul 22.
    Gatenby RA, Brown JS.
      Many effective drugs for metastatic and/or advanced-stage cancers have been developed over the past decade, although the evolution of resistance remains the major barrier to disease control or cure. In large, diverse populations such as the cells that compose metastatic cancers, the emergence of cells that are resistant or that can quickly develop resistance is virtually inevitable and most likely cannot be prevented. However, clinically significant resistance occurs only when the pre-existing resistant phenotypes are able to proliferate extensively, a process governed by eco-evolutionary dynamics. Attempts to disrupt the molecular mechanisms of resistance have generally been unsuccessful in clinical practice. In this Review, we focus on the Darwinian processes driving the eco-evolutionary dynamics of treatment-resistant cancer populations. We describe a variety of evolutionarily informed strategies designed to increase the probability of disease control or cure by anticipating and steering the evolutionary dynamics of acquired resistance.
  8. Cancer Discov. 2020 Jul 22. pii: CD-19-1485. [Epub ahead of print]
    Pettitt SJ, Frankum JR, Punta M, Lise S, Alexander J, Chen Y, Yap TA, Haider S, Tutt ANJ, Lord CJ.
      Reversion mutations in BRCA1 or BRCA2 are associated with resistance to PARP inhibitors and platinum. To better understand the nature of these mutations, we collated, codified and analysed over 300 reversions. This identified reversion "hotspots" and "deserts" in the N- and C-terminal regions (respectively) of BRCA2, suggesting that pathogenic mutations in these regions may be at higher or lower risk of reversion. Missense and splice-site pathogenic mutations in BRCA1/2 also appeared less likely to revert than truncating mutations. Most reversions were <100 bp deletions. Although many deletions exhibited microhomology, this was not universal, suggesting that multiple DNA repair processes cause reversion. Finally, we found that many reversions were predicted to encode immunogenic neopeptides, suggesting a route to the treatment of reverted disease. As well as providing a freely-available database for the collation of future reversion cases, these observations have implications for how drug resistance might be managed in BRCA-mutant cancers.
  9. Clin Cancer Res. 2020 Jul 24. pii: clincanres.3870.2020. [Epub ahead of print]
    Navarro P, Martínez-Bosch N, Blidner AG, Rabinovich GA.
      Galectins are an endogenous family of β-galactoside-binding proteins that play complex and multifaceted roles at various stages of cancer progression, including modulation of tumor cell proliferation, signaling, adhesion, migration, invasion, epithelial-mesenchymal transition, angiogenesis and immune escape. Recently, galectins have been implicated as major therapeutic determinants that confer sensitivity or resistance to a wide range of anticancer modalities including chemotherapy, radiotherapy, targeted therapies, antiangiogenic therapies and immunotherapies. Here, we present an integrated approach to the pleiotropic functions of galectins and discuss their emerging roles with respect to mechanisms of resistance or sensitivity to anticancer therapies. Taken together, these findings suggest that targeting galectins and/or their glycosylated ligands may help to overcome resistance and to increase the clinical efficacy of anticancer strategies.
  10. Theranostics. 2020 ;10(17): 7545-7560
    Ye G, Yang Q, Lei X, Zhu X, Li F, He J, Chen H, Ling R, Zhang H, Lin T, Liang Z, Liang Y, Huang H, Guo W, Deng H, Liu H, Hu Y, Yu J, Li G.
      Rationale: Peritoneal metastasis predicts poor prognosis of gastric cancer (GC) patients, and the underlying mechanisms are poorly understood. Methods: The 2-DIGE, MALDI-TOF/TOF MS and single-cell transcriptome were used to detect differentially expressed proteins among normal gastric mucosa, primary GC and peritoneal metastatic tissues. Lentiviruses carrying shRNA and transcription activator-like effector nuclease technology were used to knock down myosin heavy chain 9 (MYH9) expression in GC cell lines. Immunofluorescence, immune transmission electron microscopy, chromatin fractionation, co-immunoprecipitation, and assays for chromatin immunoprecipitation, dual luciferase reporter, agarose-oligonucleotide pull-down, flow cytometry and cell anoikis were performed to uncover nuclear MYH9-induced β-catenin (CTNNB1) transcription in vitro. Nude mice and conditional transgenic mice were used to investigate the findings in vivo. Results: We observed that MYH9 was upregulated in metastatic GC tissues and was associated with a poor prognosis of GC patients. Mechanistically, we confirmed that MYH9 was mainly localized in the GC cell nuclei by four potential nuclear localization signals. Nuclear MYH9 bound to the CTNNB1 promoter through its DNA-binding domain, and interacted with myosin light chain 9, β-actin and RNA polymerase II to promote CTNNB1 transcription, which conferred resistance to anoikis in GC cells in vitro and in vivo. Staurosporine reduced nuclear MYH9 S1943 phosphorylation to inhibit CTNNB1 transcription, Wnt/β-catenin signaling activation and GC progression in both orthotropic xenograft GC nude mouse and transgenic GC mouse models. Conclusion: This study identified that nuclear MYH9-induced CTNNB1 expression promotes GC metastasis, which could be inhibited by staurosporine, indicating a novel therapy for GC peritoneal metastasis.
    Keywords:  CTNNB1; MYH9; anoikis resistance; gastric cancer; metastasis
  11. Methods Mol Biol. 2020 ;2171 293-302
    Dafflon C, Santamaría-Martínez A, Ordóñez-Morán P.
      In many tumor types, only a minor pool of cancer cells-the so-called cancer stem cells-is able to colonize distant organs and give rise to secondary tumors. In humans, the liver is one of the main target organs for many metastatic tumor types, including colorectal cancer. However, mouse tumour models only rarely spontaneously metastasize to the liver. Therefore, reliable in vivo experimental metastasis assays are crucial to study cell seeding capacity and the mechanisms controlling these metastatic stem cell properties. Here, we describe an intrasplenic injection model that mimics the process of liver metastasis occurring in cancer patients.
    Keywords:  Cancer; Cell lines; Liver metastases; Nude mice; Portal vein; Stem cells
  12. Cell Stem Cell. 2020 Jul 20. pii: S1934-5909(20)30289-7. [Epub ahead of print]
    Jia L, Zhang W, Wang CY.
      PD1 blockade-based combination therapy has been approved as a first-line treatment for head and neck squamous cell carcinoma (HNSCC). However, the response rate remains relatively low, and patients with HNSCC eventually relapse. Here, we show that the combination treatment of anti-PD1 and cisplatin enriched BMI1+ CSCs in HNSCC while inhibiting HNSCC growth. In contrast, the pharmacological and genetic inhibition of BMI1 eliminated BMI1+ CSCs and enabled PD1 blockade therapy, resulting in the inhibition of metastatic HNSCC and prevention of HNSCC relapses. BMI1 inhibition strongly induced tumor cell-intrinsic immune responses by recruiting and activating CD8+ T cells in addition to eliminating BMI1+ CSCs. Mechanistically, BMI1 inhibition induced CD8+ T cell-recruiting chemokines by stimulating IRF3-mediated transcription and erasing repressive H2A ubiquitination. Our results suggest that targeting BMI1 may enable immune checkpoint blockade to inhibit metastatic tumor growth and prevent tumor relapse by activating cell-intrinsic immunity, in addition to purging CSCs.
    Keywords:  BMI1; CD8+ T cells; HNSCC; PD1 blockade; antitumor immune response; cancer stem cells; immunotherapy; invasive growth; metastasis; squamous cell carcinoma
  13. Nat Chem Biol. 2020 Aug;16(8): 817-825
    Pisa R, Kapoor TM.
      Emergence of resistance is a major factor limiting the efficacy of molecularly targeted anticancer drugs. Understanding the specific mutations, or other genetic or cellular changes, that confer drug resistance can help in the development of therapeutic strategies with improved efficacies. Here, we outline recent progress in understanding chemotype-specific mechanisms of resistance and present chemical strategies, such as designing drugs with distinct binding modes or using proteolysis targeting chimeras, to overcome resistance. We also discuss how targeting multiple binding sites with bifunctional inhibitors or identifying collateral sensitivity profiles can be exploited to limit the emergence of resistance. Finally, we highlight how incorporating analyses of resistance early in drug development can help with the design and evaluation of therapeutics that can have long-term benefits for patients.
  14. EMBO J. 2020 Jul 21. e103209
    Feldker N, Ferrazzi F, Schuhwerk H, Widholz SA, Guenther K, Frisch I, Jakob K, Kleemann J, Riegel D, Bönisch U, Lukassen S, Eccles RL, Schmidl C, Stemmler MP, Brabletz T, Brabletz S.
      Invasion, metastasis and therapy resistance are the major cause of cancer-associated deaths, and the EMT-inducing transcription factor ZEB1 is a crucial stimulator of these processes. While work on ZEB1 has mainly focused on its role as a transcriptional repressor, it can also act as a transcriptional activator. To further understand these two modes of action, we performed a genome-wide ZEB1 binding study in triple-negative breast cancer cells. We identified ZEB1 as a novel interactor of the AP-1 factors FOSL1 and JUN and show that, together with the Hippo pathway effector YAP, they form a transactivation complex, predominantly activating tumour-promoting genes, thereby synergising with its function as a repressor of epithelial genes. High expression of ZEB1, YAP, FOSL1 and JUN marks the aggressive claudin-low subtype of breast cancer, indicating the translational relevance of our findings. Thus, our results link critical tumour-promoting transcription factors: ZEB1, AP-1 and Hippo pathway factors. Disturbing their molecular interaction may provide a promising treatment option for aggressive cancer types.
    Keywords:  AP-1; ZEB1; breast cancer; epithelial to mesenchymal transition
  15. Cancer Res. 2020 Jul 22. pii: canres.1049.2020. [Epub ahead of print]
    Wang Y, Chen Y, Bao L, Zhang B, Wang JE, Kumar A, Xing C, Wang Y, Luo W.
      Recruitment of RNA polymerase II to hypoxia-inducible factor (HIF) target genes under normoxia is a prerequisite for HIF-mediated transactivation. However, the underlying mechanism of this recruitment remains unknown. Here we report that chromodomain helicase DNA-binding protein 4 (CHD4) physically interacts with alpha and beta subunits of HIF-1 and HIF-2 and enhances HIF-driven transcriptional programs to promote breast cancer progression. Loss of HIF-1/2alpha abolished CHD4-mediated breast tumor growth in mice. In breast cancer cells under normoxia, CHD4 enrichment at HIF target gene promoters increased RNA polymerase II loading through p300. Hypoxia further promoted CHD4 binding to the chromatin via HIF-1/2alpha, where CHD4 in turn enhanced recruitment of HIF-1alpha, leading to HIF target gene transcription. CHD4 was upregulated and correlated with HIF target gene expression in human breast tumors; upregulation of CHD4 and other known HIF coactivators in human breast tumors was mutually exclusive. Furthermore, CHD4 was associated with poor overall survival of breast cancer patients. Collectively, these findings reveal a new fundamental mechanism of HIF regulation in breast cancer, which has clinical relevance.
  16. Nat Commun. 2020 Jul 21. 11(1): 3660
    Yu JJ, Zhou DD, Yang XX, Cui B, Tan FW, Wang J, Li K, Shang S, Zhang C, Lv XX, Zhang XW, Liu SS, Yu JM, Wang F, Huang B, Hua F, Hu ZW.
      High expression or aberrant activation of epidermal growth factor receptor (EGFR) is related to tumor progression and therapy resistance across cancer types, including non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are first-line therapy for NSCLC. However, patients eventually deteriorate after inevitable acquisition of EGFR TKI-resistant mutations, highlighting the need for therapeutics with alternative mechanisms of action. Here, we report that the elevated tribbles pseudokinase 3 (TRIB3) is positively associated with EGFR stability and NSCLC progression. TRIB3 interacts with EGFR and recruits PKCα to induce a Thr654 phosphorylation and WWP1-induced Lys689 ubiquitination in the EGFR juxtamembrane region, which enhances EGFR recycling, stability, downstream activity, and NSCLC stemness. Disturbing the TRIB3-EGFR interaction with a stapled peptide attenuates NSCLC progression by accelerating EGFR degradation and sensitizes NSCLC cells to chemotherapeutic agents. These findings indicate that targeting EGFR degradation is a previously unappreciated therapeutic option in EGFR-related NSCLC.
  17. Nat Metab. 2019 Sep;1(9): 868-875
    Asano T, Okamoto K, Nakai Y, Tsutsumi M, Muro R, Suematsu A, Hashimoto K, Okamura T, Ehata S, Nitta T, Takayanagi H.
      Receptor activator of NF-κB ligand (RANKL) is a multifunctional cytokine known to affect immune and skeletal systems, as well as oncogenesis and metastasis1-4. RANKL is synthesized as a membrane-bound molecule, and cleaved into its soluble form by proteases5-7. As the soluble form of RANKL does not contribute greatly to bone remodelling or ovariectomy-induced bone loss8, whether soluble RANKL has a role in pathological settings remains unclear. Here we show that soluble RANKL promotes the formation of tumour metastases in bone. Mice that selectively lack soluble RANKL (Tnfsf11ΔS/ΔS)5-7,9 have normal bone homoeostasis and develop a normal immune system but display markedly reduced numbers of bone metastases after intracardiac injection of RANK-expressing melanoma and breast cancer cells. Deletion of soluble RANKL does not affect osteoclast numbers in metastatic lesions or tumour metastasis to non-skeletal tissues. Therefore, soluble RANKL is dispensable for physiological regulation of bone and immune systems, but has a distinct and pivotal role in the promotion of bone metastases.
  18. Nat Rev Cancer. 2020 Jul 21.
    Jaillon S, Ponzetta A, Di Mitri D, Santoni A, Bonecchi R, Mantovani A.
      Neutrophils play a key role in defence against infection and in the activation and regulation of innate and adaptive immunity. In cancer, tumour-associated neutrophils (TANs) have emerged as an important component of the tumour microenvironment. Here, they can exert dual functions. TANs can be part of tumour-promoting inflammation by driving angiogenesis, extracellular matrix remodelling, metastasis and immunosuppression. Conversely, neutrophils can also mediate antitumour responses by direct killing of tumour cells and by participating in cellular networks that mediate antitumour resistance. Neutrophil diversity and plasticity underlie the dual potential of TANs in the tumour microenvironment. Myeloid checkpoints as well as the tumour and tissue contexture shape neutrophil function in response to conventional therapies and immunotherapy. We surmise that neutrophils can provide tools to tailor current immunotherapy strategies and pave the way to myeloid cell-centred therapeutic strategies, which would be complementary to current approaches.
  19. Nat Protoc. 2020 Jul 20.
    Padmanaban V, Grasset EM, Neumann NM, Fraser AK, Henriet E, Matsui W, Tran PT, Cheung KJ, Georgess D, Ewald AJ.
      Cancer invasion and metastasis are challenging to study in vivo since they occur deep inside the body over extended time periods. Organotypic 3D culture of fresh tumor tissue enables convenient real-time imaging, genetic and microenvironmental manipulation and molecular analysis. Here, we provide detailed protocols to isolate and culture heterogenous organoids from murine and human primary and metastatic site tumors. The time required to isolate organoids can vary based on the tissue and organ type but typically takes <7 h. We describe a suite of assays that model specific aspects of metastasis, including proliferation, survival, invasion, dissemination and colony formation. We also specify comprehensive protocols for downstream applications of organotypic cultures that will allow users to (i) test the role of specific genes in regulating various cellular processes, (ii) distinguish the contributions of several microenvironmental factors and (iii) test the effects of novel therapeutics.
  20. Theranostics. 2020 ;10(17): 7656-7670
    Li Y, Zhang B, Xiang L, Xia S, Kucuk O, Deng X, Boise LH, Dong JT.
      Prostate cancer is the second leading cause of cancer-related death in the United States. As a first line treatment for hormone-refractory prostate cancer, docetaxel (DTX) treatment leads to suboptimal effect since almost all patients eventually develop DTX resistance. In this study, we investigated whether and how TGF-β affects DTX resistance of prostate cancer. Methods: Cytotoxicity of DTX in DU 145 and PC-3 cells was measured by CCK-8 and Matrigel colony formation assays. Resistance to DTX in DU 145 cells was examined in a xenograft tumorigenesis model. A luciferase reporter system was used to determine transcriptional activities. Gene expression was analyzed by RT-qPCR and Western blotting. Results: We found that KLF5 is indispensable in TGF-β-induced DTX resistance. Moreover, KLF5 acetylation at lysine 369 mediates DTX resistance in vitro and in vivo. We showed that the TGF-β/acetylated KLF5 signaling axis activates Bcl-2 expression transcriptionally. Furthermore, DTX-induced Bcl-2 degradation depends on a proteasome pathway, and TGF-β inhibits DTX-induced Bcl-2 ubiquitination. Conclusion: Our study demonstrated that the TGF-β-acetylated KLF5-Bcl-2 signaling axis mediates DTX resistance in prostate cancer and blockade of this pathway could provide clinical insights into chemoresistance of prostate cancer.
    Keywords:  Bcl-2 degradation; KLF5 acetylation; TGF-β; docetaxel resistance; prostate cancer
  21. Nat Metab. 2020 Jan;2(1): 62-80
    Papalazarou V, Zhang T, Paul NR, Juin A, Cantini M, Maddocks ODK, Salmeron-Sanchez M, Machesky LM.
      Pancreatic ductal adenocarcinoma is particularly metastatic, with dismal survival rates and few treatment options. Stiff fibrotic stroma is a hallmark of pancreatic tumours, but how stromal mechanosensing affects metastasis is still unclear. Here, we show that mechanical changes in the pancreatic cancer cell environment affect not only adhesion and migration, but also ATP/ADP and ATP/AMP ratios. Unbiased metabolomic analysis reveals that the creatine-phosphagen ATP-recycling system is a major mechanosensitive target. This system depends on arginine flux through the urea cycle, which is reflected by the increased incorporation of carbon and nitrogen from L-arginine into creatine and phosphocreatine on stiff matrix. We identify that CKB is a mechanosensitive transcriptional target of YAP, and thus it increases phosphocreatine production. We further demonstrate that the creatine-phosphagen system has a role in invasive migration, chemotaxis and liver metastasis of cancer cells.
  22. J Biol Chem. 2020 Jul 24. pii: jbc.RA120.013805. [Epub ahead of print]
    Li K, Liu T, Chen J, Ni H, Li W.
      Cancer-associated fibroblasts (CAFs) play a critical role in the coevolution of breast tumor cells and their microenvironment by modifying cellular compartments and regulating cancer cell functions via stromal-epithelial dialogue. However, the relationship and interaction between stromal and epithelial cells are still poorly understood. Herein, we revealed that breast cancer cells have a stronger ability to activate fibroblasts and transform them into myofibroblasts (CAF-like) than normal breast epithelial cells, and this stronger ability occurs through paracrine signaling. In turn, myofibroblasts promote the proliferation, epithelial-to-mesenchymal transition (EMT), and stemness of breast cancer cells. Detailed regulatory mechanisms showed that, compared to normal cells, Survivin is overexpressed in breast cancer cells and secreted extracellularly in the form of exosomes, which are then internalized by fibroblasts. Breast cancer cell-derived Survivin upregulates SOD1 expression in fibroblasts and then converts them into myofibroblasts, conversely inducing breast cancer progression in vitro and in vivo. Thus, our results indicate that Survivin acts as an activator of the tumor microenvironment and that SOD1 upregulation in fibroblasts can promote breast cancer progression. These results suggest that targeting Survivin and SOD1 may be a potential therapeutic strategy for breast cancer.
    Keywords:  breast cancer; exosome (vesicle); myofibroblast; survivin; tumor microenvironment
  23. Theranostics. 2020 ;10(17): 7775-7786
    Lee J, You JH, Shin D, Roh JL.
      Rationale: Loss of iron-sulfur cluster function predisposes cancer cells to ferroptosis by upregulating iron-starvation response, but the role of glutaredoxin 5 (GLRX5) silencing in ferroptosis remains unknown. We examined the role of GLRX5 functional loss in promoting ferroptosis in cisplatin-resistant head and neck cancer (HNC) cells. Methods: The effects of sulfasalazine treatment and GLRX5 gene silencing were tested on HNC cell lines and mouse tumor xenograft models. These effects were analyzed concerning cell viability and death, lipid reactive oxygen species (ROS) and mitochondrial iron production, labile iron pool, mRNA/protein expression, and malondialdehyde assays. Results: Cyst(e)ine deprivation, erastin, or sulfasalazine induced ferroptosis in HNC cells, which was relatively less sensitive in cisplatin-resistant HNC cells. Sulfasalazine or cyst(e)ine deprivation-induced ferroptosis resulted from increased lipid peroxidation and intracellular free iron, which were significantly promoted by short-interfering RNA or short hairpin RNA (shRNA) targeting GLRX5 (P<0.05). GLRX5 silencing activated iron-starvation response and boosted up intracellular free iron through the iron-responsive element-binding activity of increased iron regulatory protein (increased transferrin receptor and decreased ferritin). These effects were rescued by resistant GLRX5 cDNA but not by catalytically inactive mutant GLRX5 K101Q. The same results were noted in an in vivo mouse model transplanted with vector or shGLRX5-transduced HNC cells and treated with sulfasalazine. Conclusion: Our data suggest that inhibition of GLRX5 predisposes therapy-resistant HNC cells to ferroptosis.
    Keywords:  Ferroptosis; cancer cells; free iron; gene silencing; glutaredoxin 5