bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021–05–16
24 papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. Thorny ground, rocky soil: tissue-specific mechanisms of tumor dormancy and relapse.
  2. Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers.
  3. Phenotypic heterogeneity and metastasis of breast cancer cells.
  4. Slow-Cycling (Dormant) Cancer Cells in Therapy Resistance, Cancer Relapse and Metastasis.
  5. A non-genetic, cell cycle dependent mechanism of platinum resistance in lung adenocarcinoma.
  6. The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy.
  7. An RFC4/Notch1 signaling feedback loop promotes NSCLC metastasis and stemness.
  8. Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia.
  9. Mitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance.
  10. Obesity Promotes Metastasis via Neutrophil-Mediated Vascular Damage.
  11. A prometastatic splicing program regulated by SNRPA1 interactions with structured RNA elements.
  12. C/EBPβ promotes poly(ADP-ribose) polymerase inhibitor resistance by enhancing homologous recombination repair in high-grade serous ovarian cancer.
  13. The MNK1/2-eIF4E axis supports immune suppression and metastasis in postpartum breast cancer.
  14. The extracellular-regulated protein kinase 5 (ERK5) enhances metastatic burden in triple-negative breast cancer through focal adhesion protein kinase (FAK)-mediated regulation of cell adhesion.
  15. NRF2 activates macropinocytosis upon autophagy inhibition.
  16. KSR1-and ERK-dependent translational regulation of the epithelial-to-mesenchymal transition.
  17. Mass spectrometry analysis of circulating breast cancer cells from a Xenograft mouse model.
  18. Disruption of FOXO3a-miRNA feedback inhibition of IGF2/IGF-1R/IRS1 signaling confers Herceptin resistance in HER2-positive breast cancer.
  19. Disrupting tumour vasculature and recruitment of aPDL1-loaded platelets control tumour metastasis.
  20. A mitochondrial gatekeeper that helps cells escape death by ferroptosis.
  21. Limited inhibition of multiple nodes in a driver network blocks metastasis.
  22. Metastatic urothelial carcinoma.
  23. Hypoxia-driven oncometabolite L-2HG maintains stemness-differentiation balance and facilitates immune evasion in pancreatic cancer.
  24. Lung cancer organoids analyzed on microwell arrays predict drug responses of patients within a week.
  1. Semin Cancer Biol. 2021 May 09. pii: S1044-579X(21)00135-8. [Epub ahead of print]
    Thorny ground, rocky soil: tissue-specific mechanisms of tumor dormancy and relapse.
    Andrea R Lim, Cyrus M Ghajar.
      Disseminated tumor cells (DTCs) spread systemically yet distinct patterns of metastasis indicate a range of tissue susceptibility to metastatic colonization. Distinctions between permissive and suppressive tissues are still being elucidated at cellular and molecular levels. Although there is a growing appreciation for the role of the microenvironment in regulating metastatic success, we have a limited understanding of how diverse tissues regulate DTC dormancy, the state of reversible quiescence and subsequent awakening thought to contribute to delayed relapse. Several themes of microenvironmental regulation of dormancy are beginning to emerge, including vascular association, co-option of pre-existing niches, metabolic adaptation, and immune evasion, with tissue-specific nuances. Conversely, DTC awakening is often associated with injury or inflammation-induced activation of the stroma, promoting a proliferative environment with DTCs following suit. We review what is known about tissue-specific regulation of tumor dormancy on a tissue-by-tissue basis, profiling major metastatic organs including the bone, lung, brain, liver, and lymph node. An aerial view of the barriers to metastatic growth may reveal common targets and dependencies to inform the therapeutic prevention of relapse.
    Keywords:  disseminated tumor cell dormancy; dormant niche; metastasis; microenvironment; quiescence
    DOI:  https://doi.org/10.1016/j.semcancer.2021.05.007
  2. Nat Commun. 2021 May 10. 12(1): 2606
    Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers.
    David H Peng, B Leticia Rodriguez, Lixia Diao, Pierre-Olivier Gaudreau, Aparna Padhye, Jessica M Konen, Joshua K Ochieng, Caleb A Class, Jared J Fradette, Laura Gibson, Limo Chen, Jing Wang, Lauren A Byers, Don L Gibbons.
      Understanding resistance mechanisms to targeted therapies and immune checkpoint blockade in mutant KRAS lung cancers is critical to developing novel combination therapies and improving patient survival. Here, we show that MEK inhibition enhanced PD-L1 expression while PD-L1 blockade upregulated MAPK signaling in mutant KRAS lung tumors. Combined MEK inhibition with anti-PD-L1 synergistically reduced lung tumor growth and metastasis, but tumors eventually developed resistance to sustained combinatorial therapy. Multi-platform profiling revealed that resistant lung tumors have increased infiltration of Th17 cells, which secrete IL-17 and IL-22 cytokines to promote lung cancer cell invasiveness and MEK inhibitor resistance. Antibody depletion of IL-17A in combination with MEK inhibition and PD-L1 blockade markedly reduced therapy-resistance in vivo. Clinically, increased expression of Th17-associated genes in patients treated with PD-1 blockade predicted poorer overall survival and response in melanoma and predicated poorer response to anti-PD1 in NSCLC patients. Here we show a triple combinatorial therapeutic strategy to overcome resistance to combined MEK inhibitor and PD-L1 blockade.
    DOI:  https://doi.org/10.1038/s41467-021-22875-w
  3. Cancer Res. 2021 May 11. pii: canres.1799.2020. [Epub ahead of print]
    Phenotypic heterogeneity and metastasis of breast cancer cells.
    Lauren A Hapach, Shawn P Carey, Samantha C Schwager, Paul V Taufalele, Wenjun Wang, Jenna A Mosier, Nerymar Ortiz-Otero, Tanner J McArdle, Zachary E Goldblatt, Marsha C Lampi, Francois Bordeleau, Jocelyn R Marshall, Isaac M Richardson, Jiahe Li, Michael R King, Cynthia A Reinhart-King.
      While intratumoral genomic heterogeneity can impede cancer research and treatment, less is known about the effects of phenotypic heterogeneities. To investigate the role of cell migration heterogeneities in metastasis, we phenotypically sorted metastatic breast cancer cells into two subpopulations based on migration ability. While migration is typically considered to be associated with metastasis, when injected orthotopically in vivo, the weakly migratory subpopulation metastasized significantly more than the highly migratory subpopulation. To investigate the mechanism behind this observation, both subpopulations were assessed at each stage of the metastatic cascade, including dissemination from the primary tumor, survival in the circulation, extravasation, and colonization. While both subpopulations performed each step successfully, weakly migratory cells presented as circulating tumor cell (CTC) clusters in the circulation, suggesting clustering as one potential mechanism behind the increased metastasis of weakly migratory cells. RNA sequencing revealed weakly migratory subpopulations to be more epithelial and highly migratory subpopulations to be more mesenchymal. Depletion of E-cadherin expression from weakly migratory cells abrogated metastasis. Conversely, induction of E-cadherin expression in highly migratory cells increased metastasis. Clinical patient data and blood samples showed that CTC clustering and E-cadherin expression are both associated with worsened patient outcome. This study demonstrates that deconvolving phenotypic heterogeneities can reveal fundamental insights into metastatic progression. More specifically, these results indicate that migratory ability does not necessarily correlate with metastatic potential, and that E-cadherin promotes metastasis in phenotypically-sorted breast cancer cell subpopulations by enabling CTC clustering.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1799
  4. Semin Cancer Biol. 2021 May 09. pii: S1044-579X(21)00122-X. [Epub ahead of print]
    Slow-Cycling (Dormant) Cancer Cells in Therapy Resistance, Cancer Relapse and Metastasis.
    Sukanya Basu, Yang Dong, Rahul Kumar, Collene Jeter, Dean G Tang.
      It is increasingly appreciated that cancer cell heterogeneity and plasticity constitute major barriers to effective clinical treatments and long-term therapeutic efficacy. Research in the past two decades suggest that virtually all treatment-naive human cancers harbor subsets of cancer cells that possess many of the cardinal features of normal stem cells. Such stem-like cancer cells, operationally defined as cancer stem cells (CSCs), are frequently quiescent and dynamically change and evolve during tumor progression and therapeutic interventions. Intrinsic tumor cell heterogeneity is reflected in a different aspect in that tumors also harbor a population of slow-cycling cells (SCCs) that are not in the proliferative cell cycle and thus are intrinsically refractory to anti-mitotic drugs. In this Perspective, we focus our discussions on SCCs in cancer and on various methodologies that can be employed to enrich and purify SCCs, compare the similarities and differences between SCCs, CSCs and cancer cells undergoing EMT, and present evidence for the involvement of SCCs in surviving anti-neoplastic treatments, mediating tumor relapse, maintaining tumor dormancy and mediating metastatic dissemination. Our discussions make it clear that an in-depth understanding of the biological properties of SCCs in cancer will be instrumental to developing new therapeutic strategies to prevent tumor relapse and distant metastasis.
    Keywords:  Cancer stem cells; Metastasis; Quiescence; Slow-cycling cells; Therapy resistance
    DOI:  https://doi.org/10.1016/j.semcancer.2021.04.021
  5. Elife. 2021 May 13. pii: e65234. [Epub ahead of print]10
    A non-genetic, cell cycle dependent mechanism of platinum resistance in lung adenocarcinoma.
    Alvaro Gonzalez Rajal, Kamila A Marzec, Rachael A McCloy, Max Nobis, Venessa Chin, Jordan F Hastings, Kaitao Lai, Marina Kennerson, William E Hughes, Vijesh Vaghjiani, Paul Timpson, Jason E Cain, D Neil Watkins, David R Croucher, Andrew Burgess.
      We previously used a pulse-based in vitro assay to unveil targetable signalling pathways associated with innate cisplatin resistance in lung adenocarcinoma (Hastings et al., 2020). Here we advanced this model system and identified a non-genetic mechanism of resistance that drives recovery and regrowth in a subset of cells. Using RNAseq and a suite of biosensors to track single cell fates both in vitro and in vivo, we identified that early S phase cells have a greater ability to maintain proliferative capacity, which correlated with reduced DNA damage over multiple generations. In contrast, cells in G1, late S or those treated with PARP/RAD51 inhibitors, maintained higher levels of DNA damage and underwent prolonged S/G2 phase arrest and senescence. Combined with our previous work, these data indicate that there is a non-genetic mechanism of resistance in human lung adenocarcinoma that is dependent on the cell cycle stage at the time of cisplatin exposure.
    Keywords:  cancer biology; cell biology; human
    DOI:  https://doi.org/10.7554/eLife.65234
  6. Oncogene. 2021 May 14.
    The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy.
    Jian Chen, Risi Na, Chao Xiao, Xiao Wang, Yupeng Wang, Dongwang Yan, Guohe Song, Xueni Liu, Jiayi Chen, Huijun Lu, Chunyan Chen, Huamei Tang, Guohong Zhuang, Guangjian Fan, Zhihai Peng.
      5-Fluorouracil (5-FU)-based chemotherapy is the first-line treatment for colorectal cancer (CRC) but is hampered by chemoresistance. Despite its impact on patient survival, the mechanism underlying chemoresistance against 5-FU remains poorly understood. Here, we identified serine hydroxymethyltransferase-2 (SHMT2) as a critical regulator of 5-FU chemoresistance in CRC. SHMT2 inhibits autophagy by binding cytosolic p53 instead of metabolism. SHMT2 prevents cytosolic p53 degradation by inhibiting the binding of p53 and HDM2. Under 5-FU treatment, SHMT2 depletion promotes autophagy and inhibits apoptosis. Autophagy inhibitors decrease low SHMT2-induced 5-FU resistance in vitro and in vivo. Finally, the lethality of 5-FU treatment to CRC cells was enhanced by treatment with the autophagy inhibitor chloroquine in patient-derived and CRC cell xenograft models. Taken together, our findings indicate that autophagy induced by low SHMT2 levels mediates 5-FU resistance in CRC. These results reveal the SHMT2-p53 interaction as a novel therapeutic target and provide a potential opportunity to reduce chemoresistance.
    DOI:  https://doi.org/10.1038/s41388-021-01815-4
  7. Nat Commun. 2021 May 11. 12(1): 2693
    An RFC4/Notch1 signaling feedback loop promotes NSCLC metastasis and stemness.
    Lei Liu, Tianyu Tao, Shihua Liu, Xia Yang, Xuwei Chen, Jiaer Liang, Ruohui Hong, Wenting Wang, Yi Yang, Xiaoyi Li, Youhong Zhang, Quanfeng Li, Shujun Liang, Haocheng Yu, Yun Wu, Xinyu Guo, Yan Lai, Xiaofan Ding, Hongyu Guan, Jueheng Wu, Xun Zhu, Jie Yuan, Jun Li, Shicheng Su, Mengfeng Li, Xiuyu Cai, Junchao Cai, Han Tian.
      Notch signaling represents a key mechanism mediating cancer metastasis and stemness. To understand how Notch signaling is overactivated to couple tumor metastasis and self-renewal in NSCLC cells, we performed the current study and showed that RFC4, a DNA replication factor amplified in more than 40% of NSCLC tissues, directly binds to the Notch1 intracellular domain (NICD1) to competitively abrogate CDK8/FBXW7-mediated degradation of NICD1. Moreover, RFC4 is a functional transcriptional target gene of Notch1 signaling, forming a positive feedback loop between high RFC4 and NICD1 levels and sustained overactivation of Notch signaling, which not only leads to NSCLC tumorigenicity and metastasis but also confers NSCLC cell resistance to treatment with the clinically tested drug DAPT against NICD1 synthesis. Furthermore, together with our study, analysis of two public datasets involving more than 1500 NSCLC patients showed that RFC4 gene amplification, and high RFC4 and NICD1 levels were tightly correlated with NSCLC metastasis, progression and poor patient prognosis. Therefore, our study characterizes the pivotal roles of the positive feedback loop between RFC4 and NICD1 in coupling NSCLC metastasis and stemness properties and suggests its therapeutic and diagnostic/prognostic potential for NSCLC therapy.
    DOI:  https://doi.org/10.1038/s41467-021-22971-x
  8. Nat Commun. 2021 May 10. 12(1): 2607
    Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia.
    Feng Wang, Kiyomi Morita, Courtney D DiNardo, Ken Furudate, Tomoyuki Tanaka, Yuanqing Yan, Keyur P Patel, Kyle J MacBeth, Bin Wu, Guowen Liu, Mark Frattini, Jairo A Matthews, Latasha D Little, Curtis Gumbs, Xingzhi Song, Jianhua Zhang, Erika J Thompson, Tapan M Kadia, Guillermo Garcia-Manero, Elias Jabbour, Farhad Ravandi, Kapil N Bhalla, Marina Konopleva, Hagop M Kantarjian, P Andrew Futreal, Koichi Takahashi.
      Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we perform multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis reveals that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1/CEBPA or RAS-RTK pathway genes is the main driver of acquired resistance to IDHi, along with BCOR, homologous IDH gene, and TET2. These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML.
    DOI:  https://doi.org/10.1038/s41467-021-22874-x
  9. Nat Commun. 2021 May 14. 12(1): 2804
    Mitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance.
    Emily L Giddings, Devin P Champagne, Meng-Han Wu, Joshua M Laffin, Tina M Thornton, Felipe Valenca-Pereira, Rachel Culp-Hill, Karen A Fortner, Natalia Romero, James East, Phoebe Cao, Hugo Arias-Pulido, Karatatiwant S Sidhu, Brian Silverstrim, Yoonseok Kam, Shana Kelley, Mark Pereira, Susan E Bates, Janice Y Bunn, Steven N Fiering, Dwight E Matthews, Robert W Robey, Domink Stich, Angelo D'Alessandro, Mercedes Rincon.
      Chemotherapy remains the standard of care for most cancers worldwide, however development of chemoresistance due to the presence of the drug-effluxing ATP binding cassette (ABC) transporters remains a significant problem. The development of safe and effective means to overcome chemoresistance is critical for achieving durable remissions in many cancer patients. We have investigated the energetic demands of ABC transporters in the context of the metabolic adaptations of chemoresistant cancer cells. Here we show that ABC transporters use mitochondrial-derived ATP as a source of energy to efflux drugs out of cancer cells. We further demonstrate that the loss of methylation-controlled J protein (MCJ) (also named DnaJC15), an endogenous negative regulator of mitochondrial respiration, in chemoresistant cancer cells boosts their ability to produce ATP from mitochondria and fuel ABC transporters. We have developed MCJ mimetics that can attenuate mitochondrial respiration and safely overcome chemoresistance in vitro and in vivo. Administration of MCJ mimetics in combination with standard chemotherapeutic drugs could therefore become an alternative strategy for treatment of multiple cancers.
    DOI:  https://doi.org/10.1038/s41467-021-23071-6
  10. Cancer Discov. 2021 May 14.
    Obesity Promotes Metastasis via Neutrophil-Mediated Vascular Damage.
      Obesity compromised vascular integrity, enhancing breast cancer extravasation during metastasis.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2021-068
  11. Science. 2021 May 14. pii: eabc7531. [Epub ahead of print]372(6543):
    A prometastatic splicing program regulated by SNRPA1 interactions with structured RNA elements.
    Lisa Fish, Matvei Khoroshkin, Albertas Navickas, Kristle Garcia, Bruce Culbertson, Benjamin Hänisch, Steven Zhang, Hoang C B Nguyen, Larisa M Soto, Maria Dermit, Faraz K Mardakheh, Henrik Molina, Claudio Alarcón, Hamed S Najafabadi, Hani Goodarzi.
      Aberrant alternative splicing is a hallmark of cancer, yet the underlying regulatory programs that control this process remain largely unknown. Here, we report a systematic effort to decipher the RNA structural code that shapes pathological splicing during breast cancer metastasis. We discovered a previously unknown structural splicing enhancer that is enriched near cassette exons with increased inclusion in highly metastatic cells. We show that the spliceosomal protein small nuclear ribonucleoprotein polypeptide A' (SNRPA1) interacts with these enhancers to promote cassette exon inclusion. This interaction enhances metastatic lung colonization and cancer cell invasion, in part through SNRPA1-mediated regulation of PLEC alternative splicing, which can be counteracted by splicing modulating morpholinos. Our findings establish a noncanonical regulatory role for SNRPA1 as a prometastatic splicing enhancer in breast cancer.
    DOI:  https://doi.org/10.1126/science.abc7531
  12. Oncogene. 2021 May 08.
    C/EBPβ promotes poly(ADP-ribose) polymerase inhibitor resistance by enhancing homologous recombination repair in high-grade serous ovarian cancer.
    Jiahong Tan, Xu Zheng, Mengchen Li, Fei Ye, Chunyan Song, Cheng Xu, Xiaoxue Zhang, Wenqian Li, Ya Wang, Shaoqing Zeng, Huayi Li, Gang Chen, Xiaoyuan Huang, Ding Ma, Dan Liu, Qinglei Gao.
      PARP inhibitors (PARPi) are efficacious in treating high-grade serous ovarian cancer (HG-SOC) with homologous recombination (HR) deficiency. However, they exhibit suboptimal efficiency in HR-proficient cancers. Here, we found that the expression of CCAAT/enhancer-binding protein β (C/EBPβ), a transcription factor, was inversely correlated with PARPi sensitivity in vitro and in vivo, both in HR-proficient condition. High C/EBPβ expression enhanced PARPi tolerance; PARPi treatment in turn induced C/EBPβ expression. C/EBPβ directly targeted and upregulated multiple HR genes (BRCA1, BRIP1, BRIT1, and RAD51), thereby inducing restoration of HR capacity and mediating acquired PARPi resistance. C/EBPβ is a key regulator of the HR pathway and an indicator of PARPi responsiveness. Targeting C/EBPβ could induce HR deficiency and rescue PARPi sensitivity accordingly. Our findings indicate that HR-proficient patients may benefit from PARPi via targeting C/EBPβ, and C/EBPβ expression levels enable predicting and tracking PARPi responsiveness during treatment.
    DOI:  https://doi.org/10.1038/s41388-021-01788-4
  13. Cancer Res. 2021 May 11. pii: canres.CAN-20-3143-A.2020. [Epub ahead of print]
    The MNK1/2-eIF4E axis supports immune suppression and metastasis in postpartum breast cancer.
    Qianyu Guo, Margarita Bartish, Christophe Gonçalves, Fan Huang, Julian Smith-Voudouris, Sai Sakktee Krisna, Samuel E J Preston, Audrey Emond, Vivian Z Li, Claudia U Duerr, Yirui Gui, Aurélie Cleret-Buhot, Pamela Thebault, Hanne Lefrère, Liesbeth Lenaerts, Dany Plourde, Jie Su, Barbara C Mindt, Shannon A Hewgill, Tiziana Cotechini, Charles C T Hindmarch, William Yang, Elie Khoury, Yao Zhan, Valeria Narykina, Yuhong Wei, Giuseppe Floris, Mark Basik, Frédéric Amant, Daniela F Quail, Réjean Lapointe, Jörg H Fritz, Sonia V Del Rincon, Wilson H Miller.
      Breast cancer diagnosed within 10 years following childbirth is defined as postpartum breast cancer (PPBC) and is highly metastatic. Interactions between immune cells and other stromal cells within the involuting mammary gland are fundamental in facilitating an aggressive tumor phenotype. The MNK1/2-eIF4E axis promotes translation of pro-metastatic mRNAs in tumor cells, but its role in modulating the function of non-tumor cells in the PPBC microenvironment has not been explored. Here we used a combination of in vivo PPBC models and in vitro assays to study the effects of inactivation of the MNK1/2-eIF4E axis on the pro-tumor function of select cells of the TME. PPBC mice deficient for phospho-eIF4E (eIF4ES209A) were protected against lung metastasis and exhibited differences in the tumor and lung immune microenvironment compared to wild-type mice. Moreover, expression of fibroblast-derived IL-33, an alarmin known to induce invasion, was repressed upon MNK1/2-eIF4E axis inhibition. Imaging mass cytometry on PPBC and non-PPBC patient samples indicated that human PPBC contains phospho-eIF4E high-expressing tumor cells and CD8+ T cells displaying markers of an activated dysfunctional phenotype. Finally, inhibition of MNK1/2 combined with anti-PD-1 therapy blocked lung metastasis of PPBC. These findings implicate the involvement of the MNK1/2-eIF4E axis during PPBC metastasis and suggest a promising immunomodulatory route to enhance the efficacy of immunotherapy by blocking phospho-eIF4E.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-3143
  14. Oncogene. 2021 May 12.
    The extracellular-regulated protein kinase 5 (ERK5) enhances metastatic burden in triple-negative breast cancer through focal adhesion protein kinase (FAK)-mediated regulation of cell adhesion.
    Qiuping Xu, Jingwei Zhang, Brian A Telfer, Hao Zhang, Nisha Ali, Fuhui Chen, Blanca Risa, Adam J Pearson, Wei Zhang, Katherine G Finegan, Ahmet Ucar, Emanuele Giurisato, Cathy Tournier.
      There is overwhelming clinical evidence that the extracellular-regulated protein kinase 5 (ERK5) is significantly dysregulated in human breast cancer. However, there is no definite understanding of the requirement of ERK5 in tumor growth and metastasis due to very limited characterization of the pathway in disease models. In this study, we report that a high level of ERK5 is a predictive marker of metastatic breast cancer. Mechanistically, our in vitro data revealed that ERK5 was critical for maintaining the invasive capability of triple-negative breast cancer (TNBC) cells through focal adhesion protein kinase (FAK) activation. Specifically, we found that phosphorylation of FAK at Tyr397 was controlled by a kinase-independent function of ERK5. Accordingly, silencing ERK5 in mammary tumor grafts impaired FAK phosphorylation at Tyr397 and suppressed TNBC cell metastasis to the lung without preventing tumor growth. Collectively, these results establish a functional relationship between ERK5 and FAK signaling in promoting malignancy. Thus, targeting the oncogenic ERK5-FAK axis represents a promising therapeutic strategy for breast cancer exhibiting aggressive clinical behavior.
    DOI:  https://doi.org/10.1038/s41388-021-01798-2
  15. Cancer Cell. 2021 May 10. pii: S1535-6108(21)00169-0. [Epub ahead of print]39(5): 596-598
    NRF2 activates macropinocytosis upon autophagy inhibition.
    Gourish Mondal, Jayanta Debnath.
      Su et al. demonstrate that upon inhibiting autophagy, an intracellular nutrient recycling pathway, pancreatic ductal adenocarcinoma cells upregulate NRF2-mediated transcription of macropinocytosis pathway components, thereby triggering an alternate route for tumors to scavenge nutrients from extracellular sources. Accordingly, the combined inhibition of autophagy and macropinocytosis may improve cancer treatment.
    DOI:  https://doi.org/10.1016/j.ccell.2021.03.011
  16. Elife. 2021 May 10. pii: e66608. [Epub ahead of print]10
    KSR1-and ERK-dependent translational regulation of the epithelial-to-mesenchymal transition.
    Chaitra Rao, Danielle E Frodyma, Siddesh Southekal, Robert A Svoboda, Adrian R Black, Chittibabu Guda, Tomohiro Mizutani, Hans Clevers, Keith R Johnson, Kurt W Fisher, Robert E Lewis.
      The epithelial-to-mesenchymal transition (EMT) is considered a transcriptional process that induces a switch in cells from a polarized state to a migratory phenotype. Here we show that KSR1 and ERK promote EMT-like phenotype through the preferential translation of Epithelial-Stromal Interaction 1 (EPSTI1), which is required to induce the switch from E- to N-cadherin and coordinate migratory and invasive behavior. EPSTI1 is overexpressed in human colorectal cancer (CRC) cells. Disruption of KSR1 or EPSTI1 significantly impairs cell migration and invasion in vitro, and reverses EMT-like phenotype, in part, by decreasing the expression of N-cadherin and the transcriptional repressors of E-cadherin expression, ZEB1 and Slug. In CRC cells lacking KSR1, ectopic EPSTI1 expression restored the E- to N-cadherin switch, migration, invasion, and anchorage-independent growth. KSR1-dependent induction of EMT-like phenotype via selective translation of mRNAs reveals its underappreciated role in remodeling the translational landscape of CRC cells to promote their migratory and invasive behavior.
    Keywords:  cancer biology; cell biology; human
    DOI:  https://doi.org/10.7554/eLife.66608
  17. STAR Protoc. 2021 Jun 18. 2(2): 100480
    Mass spectrometry analysis of circulating breast cancer cells from a Xenograft mouse model.
    Cinzia Donato, Katarzyna Buczak, Alexander Schmidt, Nicola Aceto.
      Circulating tumor cells (CTCs) are precursors of metastasis in various cancer types. Many aspects regarding CTC biology remain poorly understood. Here, we describe mass spectrometric analysis of CTCs from a breast cancer xenograft mouse model, including procedures comprising CTC enrichment, separation of different CTC subpopulations, and their quantitative proteomic assessment. This protocol aims to facilitate the identification of protein content dynamics in human CTCs that are physiologically shed from tumor-bearing xenografts, providing a framework for investigating metastasis biology. For complete details on the use and execution of this protocol, please refer to Donato et al. (2020).
    Keywords:  Cancer; Cell Biology; Cell isolation; Flow Cytometry/Mass Cytometry; Mass Spectrometry; Model Organisms; Proteomics
    DOI:  https://doi.org/10.1016/j.xpro.2021.100480
  18. Nat Commun. 2021 May 11. 12(1): 2699
    Disruption of FOXO3a-miRNA feedback inhibition of IGF2/IGF-1R/IRS1 signaling confers Herceptin resistance in HER2-positive breast cancer.
    Liyun Luo, Zhijie Zhang, Ni Qiu, Li Ling, Xiaoting Jia, Ying Song, Hongsheng Li, Jiansheng Li, Hui Lyu, Hao Liu, Zhimin He, Bolin Liu, Guopei Zheng.
      Resistance to Herceptin represents a significant challenge for successful treatment of HER2-positive breast cancer. Here, we show that in Herceptin-sensitive cells, FOXO3a regulates specific miRNAs to control IGF2 and IRS1 expression, retaining basic IGF2/IGF-1R/IRS1 signaling. The basic activity maintains expression of PPP3CB, a subunit of the serine/threonine-protein phosphatase 2B, to restrict FOXO3a phosphorylation (p-FOXO3a), inducing IGF2- and IRS1-targeting miRNAs. However, in Herceptin-resistant cells, p-FOXO3a levels are elevated due to transcriptional suppression of PPP3CB, disrupting the negative feedback inhibition loop formed by FOXO3a and the miRNAs, thereby upregulating IGF2 and IRS1. Moreover, we detect significantly increased IGF2 in blood and IRS1 in the tumors of breast cancer patients with poor response to Herceptin-containing regimens. Collectively, we demonstrate that the IGF2/IGF-1R/IRS1 signaling is aberrantly activated in Herceptin-resistant breast cancer via disruption of the FOXO3a-miRNA negative feedback inhibition. Such insights provide avenues to identify predictive biomarkers and effective strategies overcoming Herceptin resistance.
    DOI:  https://doi.org/10.1038/s41467-021-23052-9
  19. Nat Commun. 2021 May 13. 12(1): 2773
    Disrupting tumour vasculature and recruitment of aPDL1-loaded platelets control tumour metastasis.
    Hongjun Li, Zejun Wang, Zhaowei Chen, Tianyuan Ci, Guojun Chen, Di Wen, Ruoxin Li, Jinqiang Wang, Huan Meng, R Bryan Bell, Zhifeng Gu, Gianpietro Dotti, Zhen Gu.
      Although therapies of cancer are advancing, it remains challenging for therapeutics to reach the sites of metastasis, which accounts for majority of cancer associated death. In this study, we have developed a strategy that guides an anti-programmed cell death-ligand 1 (aPDL1) antibody to accumulate in metastatic lesions to promote anti-tumour immune responses. Briefly, we have developed a combination in which Vadimezan disrupts tumour blood vessels of tumour metastases and facilitates the recruitment and activation of adoptively transferred aPDL1-conjugated platelets. In situ activated platelets generate aPDL1-decorated platelet-derived microparticles (PMP) that diffuse within the tumour and elicit immune responses. The proposed combination increases 10-fold aPDL1 antibody accumulation in lung metastases as compared to the intravenous administration of the antibody and enhances the magnitude of immune responses leading to improved antitumour effects.
    DOI:  https://doi.org/10.1038/s41467-021-22674-3
  20. Nature. 2021 May 12.
    A mitochondrial gatekeeper that helps cells escape death by ferroptosis.
    Javier Garcia-Bermudez, Kıvanç Birsoy.
      
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-021-01203-8
  21. Elife. 2021 May 11. pii: e59696. [Epub ahead of print]10
    Limited inhibition of multiple nodes in a driver network blocks metastasis.
    Ali Ekrem Yesilkanal, Dongbo Yang, Andrea Valdespino, Payal Tiwari, Alan U Sabino, Long Chi Nguyen, Jiyoung Lee, Xiao-He Xie, Siqi Sun, Christopher Dann, Lydia Robinson-Mailman, Ethan Steinberg, Timothy Stuhlmiller, Casey Frankenberger, Elizabeth Goldsmith, Gary L Johnson, Alexandre F Ramos, Marsha R Rosner.
      Metastasis suppression by high-dose, multi-drug targeting is unsuccessful due to network heterogeneity and compensatory network activation. Here we show that targeting driver network signaling capacity by limited inhibition of core pathways is a more effective anti-metastatic strategy. This principle underlies the action of a physiological metastasis suppressor, Raf Kinase Inhibitory Protein (RKIP), that moderately decreases stress-regulated MAP kinase network activity, reducing output to transcription factors such as pro-metastastic BACH1 and motility-related target genes. We developed a low-dose four-drug mimic that blocks metastatic colonization in mouse breast cancer models and increases survival. Experiments and network flow modeling show limited inhibition of multiple pathways is required to overcome variation in MAPK network topology and suppress signaling output across heterogeneous tumor cells. Restricting inhibition of individual kinases dissipates surplus signal, preventing threshold activation of compensatory kinase networks. This low-dose multi-drug approach to decrease signaling capacity of driver networks represents a transformative, clinically-relevant strategy for anti-metastatic treatment.
    Keywords:  cancer biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.59696
  22. Cancer Cell. 2021 May 10. pii: S1535-6108(21)00220-8. [Epub ahead of print]39(5): 583-585
    Metastatic urothelial carcinoma.
    Margaret Knowles, Lars Dyrskjøt, Elisabeth I Heath, Joaquim Bellmunt, Arlene Odelia Siefker-Radtke.
      Discovery-driven research and clinical research have worked together to change the outcomes of many cancer patients. We choose urothelial carcinoma as an example to showcase how recent diagnostic and therapeutic innovations have re-shaped cancer clinical practice.
    DOI:  https://doi.org/10.1016/j.ccell.2021.04.012
  23. Cancer Res. 2021 May 14. pii: canres.CAN-20-2562-A.2020. [Epub ahead of print]
    Hypoxia-driven oncometabolite L-2HG maintains stemness-differentiation balance and facilitates immune evasion in pancreatic cancer.
    Vineet K Gupta, Nikita S Sharma, Brittany Durden, Vanessa T Garrido, Kousik Kesh, Dujon Edwards, Dezhen Wang, Ciara Myer, Beatriz Mateo-Victoriano, Sai Sundeep Kollala, Yuguang Ban, Zhen Gao, Sanjoy K Bhattacharya, Ashok Saluja, Pankaj K Singh, Sulagna Banerjee.
      In pancreatic cancer, the robust fibroinflammatory stroma contributes to immune suppression and renders tumors hypoxic, altering intra-tumoral metabolic pathways and leading to poor survival. One metabolic enzyme activated during hypoxia is lactate dehydrogenase A (LDHA). As a result of its promiscuous activity under hypoxia, LDHA produces L-2 hydroxyglutarate, an epigenetic modifier, that regulates the tumor transcriptome. However, the role of L-2HG in remodeling the pancreatic tumor microenvironment is not known. Here we used mass spectrometry to detect L-2HG in serum samples from pancreatic cancer patients, comprising tumor cells as well as stromal cells. Both hypoxic pancreatic tumors as well as serum from pancreatic cancer patients accumulated L-2HG as a result of promiscuous activity of LDHA. This abnormally accumulated L-2HG led to H3 hypermethylation and altered gene expression, which regulated a critical balance between stemness and differentiation in pancreatic tumors. Secreted L-2HG inhibited T cell proliferation and migration, suppressing anti-tumor immunity. In a syngeneic orthotopic model of pancreatic cancer, inhibition of LDHA with GSK2837808A decreased L-2HG, induced tumor regression, and sensitized tumors to anti-PD1 therapy. In conclusion, hypoxia-mediated promiscuous activity of LDHA produces L-2HG in pancreatic tumor cells, regulating the stemness-differentiation balance and contributing to immune evasion. Targeting LDHA can be developed as a potential therapy to sensitize pancreatic tumors to checkpoint inhibitor therapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-2562
  24. Nat Commun. 2021 May 10. 12(1): 2581
    Lung cancer organoids analyzed on microwell arrays predict drug responses of patients within a week.
    Yawei Hu, Xizhao Sui, Fan Song, Yaqian Li, Kaiyi Li, Zhongyao Chen, Fan Yang, Xiuyuan Chen, Yaohua Zhang, Xianning Wang, Qiang Liu, Cong Li, Binbin Zou, Xiaofang Chen, Jun Wang, Peng Liu.
      While the potential of patient-derived organoids (PDOs) to predict patients' responses to anti-cancer treatments has been well recognized, the lengthy time and the low efficiency in establishing PDOs hamper the implementation of PDO-based drug sensitivity tests in clinics. We first adapt a mechanical sample processing method to generate lung cancer organoids (LCOs) from surgically resected and biopsy tumor tissues. The LCOs recapitulate the histological and genetic features of the parental tumors and have the potential to expand indefinitely. By employing an integrated superhydrophobic microwell array chip (InSMAR-chip), we demonstrate hundreds of LCOs, a number that can be generated from most of the samples at passage 0, are sufficient to produce clinically meaningful drug responses within a week. The results prove our one-week drug tests are in good agreement with patient-derived xenografts, genetic mutations of tumors, and clinical outcomes. The LCO model coupled with the microwell device provides a technically feasible means for predicting patient-specific drug responses in clinical settings.
    DOI:  https://doi.org/10.1038/s41467-021-22676-1
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:30.