bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021‒08‒29
nineteen papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology
  1. Transcriptomic Profiling Reveals Novel Candidate Genes and Signalling Programs in Breast Cancer Quiescence and Dormancy.
  2. Off-Target Alterations Drive Resistance to TRK Inhibitors in Some Cancers.
  3. Translating the Science of Cancer Dormancy to the Clinic.
  4. Dysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer.
  5. Comparison of cfDNA and Tissue Biopsy Shows Heterogeneity in Resistance.
  6. ILC3 plasticity in microbiome-mediated tumor progression and immunotherapy.
  7. Metastasis-entrained eosinophils enhance lymphocyte-mediated anti-tumor immunity.
  8. Comprehensive molecular profiling of UV-induced metastatic melanoma in Nme1/Nme2-deficient mice reveals novel markers of survival in human patients.
  9. Deconvoluting mechanisms of acquired resistance to RAF inhibitors in BRAF V600E mutant human glioma.
  10. DDX56 modulates post-transcriptional Wnt signaling through miRNAs and is associated with early recurrence in squamous cell lung carcinoma.
  11. Co-targeting CDK4/6 and AKT with endocrine therapy prevents progression in CDK4/6 inhibitor and endocrine therapy-resistant breast cancer.
  12. Fam20C regulates bone resorption and breast cancer bone metastasis through osteopontin and BMP4.
  13. Pan-cancer analysis of longitudinal metastatic tumors reveals genomic alterations and immune landscape dynamics associated with pembrolizumab sensitivity.
  14. A pathway to therapy for HER2+ metastatic biliary tract cancer.
  15. Triplet Succeeds in Colorectal Cancer.
  16. Low-Heterogeneity Melanomas Are More Immunogenic and Less Aggressive.
  17. BEX2 is required for maintaining dormant cancer stem cell in hepatocellular carcinoma.
  18. The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance.
  19. TRIM47 activates NF-κB signaling via PKC-ε/PKD3 stabilization and contributes to endocrine therapy resistance in breast cancer.
  1. Cancers (Basel). 2021 Aug 04. pii: 3922. [Epub ahead of print]13(16):
    Transcriptomic Profiling Reveals Novel Candidate Genes and Signalling Programs in Breast Cancer Quiescence and Dormancy.
    Lewis A Quayle, Amy Spicer, Penelope D Ottewell, Ingunn Holen.
      Metastatic recurrence, the major cause of breast cancer mortality, is driven by reactivation of dormant disseminated tumour cells that are defined by mitotic quiescence and chemoresistance. The molecular mechanisms underpinning mitotic quiescence in cancer are poorly understood, severely limiting the development of novel therapies for removal of residual, metastasis-initiating tumour cells. Here, we present a molecular portrait of the quiescent breast cancer cell transcriptome across the four main breast cancer sub-types (luminal, HER2-enriched, basal-like and claudin-low) and identify a novel quiescence-associated 22-gene signature using an established lipophilic-dye (Vybrant® DiD) retention model and whole-transcriptomic profiling (mRNA-Seq). Using functional association network analysis, we elucidate the molecular interactors of these signature genes. We then go on to demonstrate that our novel 22-gene signature strongly correlates with low tumoural proliferative activity, and with dormant disease and late metastatic recurrence (≥5 years after primary tumour diagnosis) in metastatic breast cancer in multiple clinical cohorts. These genes may govern the formation and persistence of disseminated tumour cell populations responsible for breast cancer recurrence, and therefore represent prospective novel candidates to inform future development of therapeutic strategies to target disseminated tumour cells in breast cancer, eliminate minimal residual disease and prevent metastatic recurrence.
    Keywords:  RNA-Seq; breast cancer; dormancy; quiescence; transcriptomics
    DOI:  https://doi.org/10.3390/cancers13163922
  2. Cancer Discov. 2019 Oct;9(10): OF7
    Off-Target Alterations Drive Resistance to TRK Inhibitors in Some Cancers.
      Some cancers that acquired TRK-inhibitor resistance had alterations affecting BRAF, KRAS, or MET.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2019-133
  3. Cancer Res. 2021 Aug 24.
    Translating the Science of Cancer Dormancy to the Clinic.
    Julio A Aguirre-Ghiso.
      The paradigm of metastasis has been significantly remodeled by the incorporation of cancer dormancy as a mechanism to explain long-term remission intervals followed by relapse. There is overall consensus on the potential impact of better understanding dormancy. Key cancer-cell autonomous and microenvironmental mechanisms might explain this biology and, in turn, the timing of metastasis. However, the approach and feasibility to apply this biology to clinical trials has been controversial. The discussion here provides insight into how these controversies are being resolved by the development of active clinical trials, thus bringing to reality opportunities to target cancer dormancy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-1407
  4. Nat Commun. 2021 08 24. 12(1): 5103
    Dysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer.
    Wen Liu, Binita Chakraborty, Rachid Safi, Dmitri Kazmin, Ching-Yi Chang, Donald P McDonnell.
      Hypercholesterolemia and dyslipidemia are associated with an increased risk for many cancer types and with poor outcomes in patients with established disease. Whereas the mechanisms by which this occurs are multifactorial we determine that chronic exposure of cells to 27-hydroxycholesterol (27HC), an abundant circulating cholesterol metabolite, selects for cells that exhibit increased cellular uptake and/or lipid biosynthesis. These cells exhibit substantially increased tumorigenic and metastatic capacity. Notably, the metabolic stress imposed upon cells by the accumulated lipids requires sustained expression of GPX4, a negative regulator of ferroptotic cell death. We show that resistance to ferroptosis is a feature of metastatic cells and further demonstrate that GPX4 knockdown attenuates the enhanced tumorigenic and metastatic activity of 27HC resistant cells. These findings highlight the general importance of ferroptosis in tumor growth and metastasis and suggest that dyslipidemia/hypercholesterolemia impacts cancer pathogenesis by selecting for cells that are resistant to ferroptotic cell death.
    DOI:  https://doi.org/10.1038/s41467-021-25354-4
  5. Cancer Discov. 2019 Nov;9(11): 1479
    Comparison of cfDNA and Tissue Biopsy Shows Heterogeneity in Resistance.
      Liquid biopsy outperforms single-lesion tumor biopsy in detecting heterogeneous resistance alterations.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2019-147
  6. Cancer Cell. 2021 Aug 13. pii: S1535-6108(21)00442-6. [Epub ahead of print]
    ILC3 plasticity in microbiome-mediated tumor progression and immunotherapy.
    Lei Shen, Youqiong Ye, Hongxiang Sun, Bing Su.
      The precise role of intestinal ILC3s in cancer remains largely unknown. Published in Cell, Goc et al. describe ILC3 function and plasticity in tumors. ILC3s may lose their identity and thus become either ILC1s or exhausting-ILC3s, which could in turn reshape the gut microbiome for colorectal cancer progression and immunotherapy resistance.
    DOI:  https://doi.org/10.1016/j.ccell.2021.08.002
  7. Cancer Res. 2021 Aug 24. pii: canres.0839.2021. [Epub ahead of print]
    Metastasis-entrained eosinophils enhance lymphocyte-mediated anti-tumor immunity.
    Sharon Grisaru-Tal, Shai Dulberg, Lir Beck, Chunyan Zhang, Michal Itan, Soroor Hediyeh-Zadeh, Julie Caldwell, Perri Rozenberg, Avishay Dolitzky, Shmuel Avlas, Inbal Hazut, Yaara Gordon, Ophir Shani, Shlomo Tsuriel, Motti Gerlic, Neta Erez, Nicolas Jacquelot, Gabrielle Belz, Marc E Rothenberg, Melissa J Davis, Hua Yu, Tamar Geiger, Asaf Madi, Ariel Munitz.
      The recognition of the immune system as a key component of the tumor microenvironment (TME) led to promising therapeutics. Since such therapies benefit only subsets of patients, understanding the activities of immune cells in the TME is required. Eosinophils are an integral part of the TME especially in mucosal tumors. Nonetheless, their role in the TME and the environmental cues that direct their activities are largely unknown. We report that breast cancer lung metastasis are characterized by resident and recruited eosinophils. Eosinophil recruitment to the metastatic sites in the lung was regulated by G protein-coupled receptor signaling but independent of CCR3. Functionally, eosinophils promoted lymphocyte-mediated anti-tumor immunity. Transcriptome and proteomic analyses identified the TME rather than intrinsic differences between eosinophil subsets as a key instructing factor directing anti-tumorigenic eosinophil activities. Specifically, TNF-alpha/IFN-gamma-activated eosinophils facilitated CD4+ and CD8+ T cell infiltration and promoted anti-tumor immunity. Collectively, we identify a mechanism by which the TME trains eosinophils to adopt anti-tumorigenic properties, which may lead to the development of eosinophil-targeted therapeutics.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0839
  8. Oncogene. 2021 Aug 25.
    Comprehensive molecular profiling of UV-induced metastatic melanoma in Nme1/Nme2-deficient mice reveals novel markers of survival in human patients.
    M Kathryn Leonard, Gemma S Puts, Nidhi Pamidimukkala, Gautam Adhikary, Yili Xu, Eric Kwok, Yuxin Jin, Devin Snyder, Nicolette Matsangos, Marián Novak, Anup Mahurkar, Amol C Shetty, Radomir M Slominski, Edward C De Fabo, Frances P Noonan, Chi-Ping Day, Mohammed Rigi, Andrzej T Slominski, Michelle G Webb, David W Craig, Glenn Merlino, Richard L Eckert, John D Carpten, Zarko Manojlovic, David M Kaetzel.
      Hepatocyte growth factor-overexpressing mice that harbor a deletion of the Ink4a/p16 locus (HP mice) form melanomas with low metastatic potential in response to UV irradiation. Here we report that these tumors become highly metastatic following hemizygous deletion of the Nme1 and Nme2 metastasis suppressor genes (HPN mice). Whole-genome sequencing of melanomas from HPN mice revealed a striking increase in lung metastatic activity that is associated with missense mutations in eight signature genes (Arhgap35, Atp8b4, Brca1, Ift172, Kif21b, Nckap5, Pcdha2, and Zfp869). RNA-seq analysis of transcriptomes from HP and HPN primary melanomas identified a 32-gene signature (HPN lung metastasis signature) for which decreased expression is strongly associated with lung metastatic potential. Analysis of transcriptome data from The Cancer Genome Atlas revealed expression profiles of these genes that predict improved survival of patients with cutaneous or uveal melanoma. Silencing of three representative HPN lung metastasis signature genes (ARRDC3, NYNRIN, RND3) in human melanoma cells resulted in increased invasive activity, consistent with roles for these genes as mediators of the metastasis suppressor function of NME1 and NME2. In conclusion, our studies have identified a family of genes that mediate suppression of melanoma lung metastasis, and which may serve as prognostic markers and/or therapeutic targets for clinical management of metastatic melanoma.
    DOI:  https://doi.org/10.1038/s41388-021-01998-w
  9. Clin Cancer Res. 2021 Aug 25. pii: clincanres.CCR-21-2660-A.2021. [Epub ahead of print]
    Deconvoluting mechanisms of acquired resistance to RAF inhibitors in BRAF V600E mutant human glioma.
    Karisa C Schreck, Andrew Morin, Guisheng Zhao, Amy N Allen, Patrick Flannery, Michael Glantz, Adam L Green, Chris Jones, Kenneth L Jones, Lindsay B Kilburn, Kellie J Nazemi, David Samuel, Bridget Sanford, David A Solomon, Jiawan Wang, Christine A Pratilas, Theodore Nicolaides, Jean M Mulcahy Levy.
      PURPOSE: Selective RAF-targeted therapy is effective in some patients with BRAFV600E mutated glioma, though emergent and adaptive resistance occur through ill-defined mechanisms.EXPERIMENTAL DESIGN: Paired pre-/ post- RAF inhibitor (RAFi)-treated glioma samples (N=15) were obtained and queried for treatment-emergent genomic alterations using DNA and RNA sequencing. Functional validation of putative resistance mechanisms was performed using established and patient-derived BRAFV600E-mutant glioma cell lines.
    RESULTS: Analysis of 15 tissue sample pairs identified thirteen alterations conferring putative resistance were identified among nine paired samples (including mutations involving ERRFI1, BAP1, ANKHD1, and MAP2K1). We performed functional validation of mechanisms of resistance, including loss of NF1, PTEN, or CBL, in BRAFV600E mutant glioma lines, and demonstrate they are capable of conferring resistance in vitro Knockdown of CBL resulted in increased EGFR expression and phosphorylation, a possible mechanism for maintaining ERK signaling within the cell. Combination therapy with a MEKi or EGFR inhibitor was able to overcome resistance to BRAFi, in NF1 knockdown and CBL knockdown, respectively. Restoration of wild-type PTEN in B76 cells (PTEN-/-) restored sensitivity to BRAFi. We identified and validated CRAF upregulation as a mechanism of resistance in one resistant sample. RNAseq analysis identified two emergent expression patterns in resistant samples, consistent with expression patterns of known glioma subtypes.
    CONCLUSIONS: Resistance mechanisms to BRAFi in glioma are varied and may be predict effective precision combinations of targeted therapy, highlighting the importance of a personalized approach.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-2660
  10. Mol Cancer. 2021 Aug 26. 20(1): 108
    DDX56 modulates post-transcriptional Wnt signaling through miRNAs and is associated with early recurrence in squamous cell lung carcinoma.
    Qingqing Wu, Xiaoyang Luo, Mikkel G Terp, Qingrun Li, Yuan Li, Lei Shen, Ying Chen, Kirstine Jacobsen, Trever G Bivona, Haiquan Chen, Rong Zeng, Henrik J Ditzel.
      BACKGROUND: Early recurrence is a major obstacle to prolonged postoperative survival in squamous cell lung carcinoma (SqCLC). The molecular mechanisms underlying early SqCLC recurrence remain unclear, and effective prognostic biomarkers for predicting early recurrence are needed.METHODS: We analyzed primary tumor samples of 20 SqCLC patients using quantitative proteomics to identify differentially-expressed proteins in patients who experienced early versus late disease recurrence. The expression and prognostic significance of DDX56 was evaluated using a SqCLC tumor tissue microarray and further verified using different online databases. We performed in vitro and in vivo experiments to obtain detailed molecular insight into the functional role of DDX56 in SqCLC.
    RESULTS: We found that DDX56 exhibited increased expression in tumors of patients who experienced early versus late disease recurrence. Increased DDX56 expression in SqCLC tumors was subsequently confirmed as an independent prognostic factor of poor recurrence-free survival in independent SqCLC cohorts. Functionally, DDX56 promotes SqCLC cell growth and migration in vitro, and xenograft tumor progression in vivo. Mechanistically, DDX56 post-transcriptionally promotes expression of multiple Wnt signaling pathway-related genes, including CTNNB1, WNT2B, and represses a subset of miRNAs, including miR-378a-3p, a known suppressor of Wnt signaling. Detailed analysis revealed that DDX56 facilitated degradation of primary miR-378a, leading to down-regulation of mature miR-378a-3p and thus derepression of the target gene WNT2B.
    CONCLUSION: We identified DDX56 as a novel independent prognostic biomarker that exerts its oncogenic effects through miRNA-mediated post-transcriptional regulation of Wnt signaling genes to promote early SqCLC recurrence. DDX56 may assist in identifying SqCLC patients at increased risk of early recurrence and who could benefit from Wnt signaling-targeted therapies.
    Keywords:  DDX56; Squamous cell lung cancer; Wnt signaling pathway; miRNA
    DOI:  https://doi.org/10.1186/s12943-021-01403-w
  11. Nat Commun. 2021 08 25. 12(1): 5112
    Co-targeting CDK4/6 and AKT with endocrine therapy prevents progression in CDK4/6 inhibitor and endocrine therapy-resistant breast cancer.
    Carla L Alves, Sidse Ehmsen, Mikkel G Terp, Neil Portman, Martina Tuttolomondo, Odd L Gammelgaard, Monique F Hundebøl, Kamila Kaminska, Lene E Johansen, Martin Bak, Gabriella Honeth, Ana Bosch, Elgene Lim, Henrik J Ditzel.
      CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have shown impressive efficacy in estrogen receptor-positive advanced breast cancer. However, most patients will eventually experience disease progression on this combination, underscoring the need for effective subsequent treatments or better initial therapies. Here, we show that triple inhibition with fulvestrant, CDK4/6i and AKT inhibitor (AKTi) durably impairs growth of breast cancer cells, prevents progression and reduces metastasis of tumor xenografts resistant to CDK4/6i-fulvestrant combination or fulvestrant alone. Importantly, switching from combined fulvestrant and CDK4/6i upon resistance to dual combination with AKTi and fulvestrant does not prevent tumor progression. Furthermore, triple combination with AKTi significantly inhibits growth of patient-derived xenografts resistant to combined CDK4/6i and fulvestrant. Finally, high phospho-AKT levels in metastasis of breast cancer patients treated with a combination of CDK4/6i and endocrine therapy correlates with shorter progression-free survival. Our findings support the clinical development of ER, CDK4/6 and AKT co-targeting strategies following progression on CDK4/6i and endocrine therapy combination, and in tumors exhibiting high phospho-AKT levels, which are associated with worse clinical outcome.
    DOI:  https://doi.org/10.1038/s41467-021-25422-9
  12. Cancer Res. 2021 Aug 25. pii: canres.3328.2020. [Epub ahead of print]
    Fam20C regulates bone resorption and breast cancer bone metastasis through osteopontin and BMP4.
    Hao Zuo, Dengbao Yang, Yihong Wan.
      Fam20C is a kinase that generates the majority of secreted phosphoproteins and regulates biomineralization. However, its potential roles in bone resorption and breast cancer bone metastasis are unknown. Here we show that Fam20C in the myeloid lineage suppresses osteoclastogenesis and bone resorption, during which osteopontin (OPN) is the most abundant phosphoprotein secreted in a Fam20C-dependent manner. OPN phosphorylation by Fam20C decreased OPN secretion, and OPN neutralization reduced Fam20C-deficiency-induced osteoclast differentiation and bone metastasis. In contrast, Fam20C in breast cancer cells promoted bone metastasis by facilitating the phosphorylation and secretion of BMP4, which in turn enhanced osteoclastogenesis. Mutation of the BMP4 phosphorylation site elevated BMP4 lysosomal degradation and reduced BMP4 secretion. In breast cancer cells, BMP4 depletion or treatment with a BMP4 signaling inhibitor diminished osteoclast differentiation and bone metastasis and abolished Fam20C-mediated regulation of these processes. Collectively, this study discovers distinct roles for Fam20C in myeloid cells and breast cancer cells and highlights OPN and BMP4 as potential therapeutic targets for breast cancer bone metastasis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-3328
  13. Nat Commun. 2021 Aug 26. 12(1): 5137
    Pan-cancer analysis of longitudinal metastatic tumors reveals genomic alterations and immune landscape dynamics associated with pembrolizumab sensitivity.
    S Y Cindy Yang, Scott C Lien, Ben X Wang, Derek L Clouthier, Youstina Hanna, Iulia Cirlan, Kelsey Zhu, Jeffrey P Bruce, Samah El Ghamrasni, Marco A J Iafolla, Marc Oliva, Aaron R Hansen, Anna Spreafico, Philippe L Bedard, Stephanie Lheureux, Albiruni Razak, Vanessa Speers, Hal K Berman, Alexey Aleshin, Benjamin Haibe-Kains, David G Brooks, Tracy L McGaha, Marcus O Butler, Scott V Bratman, Pamela S Ohashi, Lillian L Siu, Trevor J Pugh.
      Serial circulating tumor DNA (ctDNA) monitoring is emerging as a non-invasive strategy to predict and monitor immune checkpoint blockade (ICB) therapeutic efficacy across cancer types. Yet, limited data exist to show the relationship between ctDNA dynamics and tumor genome and immune microenvironment in patients receiving ICB. Here, we present an in-depth analysis of clinical, whole-exome, transcriptome, and ctDNA profiles of 73 patients with advanced solid tumors, across 30 cancer types, from a phase II basket clinical trial of pembrolizumab (NCT02644369) and report changes in genomic and immune landscapes (primary outcomes). Patients stratified by ctDNA and tumor burden dynamics correspond with survival and clinical benefit. High mutation burden, high expression of immune signatures, and mutations in BRCA2 are associated with pembrolizumab molecular sensitivity, while abundant copy-number alterations and B2M loss-of-heterozygosity corresponded with resistance. Upon treatment, induction of genes expressed by T cell, B cell, and myeloid cell populations are consistent with sensitivity and resistance. We identified the upregulated expression of PLA2G2D, an immune-regulating phospholipase, as a potential biomarker of adaptive resistance to ICB. Together, these findings provide insights into the diversity of immunogenomic mechanisms that underpin pembrolizumab outcomes.
    DOI:  https://doi.org/10.1038/s41467-021-25432-7
  14. Nat Rev Gastroenterol Hepatol. 2021 Aug 24.
    A pathway to therapy for HER2+ metastatic biliary tract cancer.
    Katrina Ray.
      
    DOI:  https://doi.org/10.1038/s41575-021-00515-4
  15. Cancer Discov. 2019 Dec;9(12): OF5
    Triplet Succeeds in Colorectal Cancer.
      A drug trio consisting of BRAF, MEK, and EGFR inhibitors may become the new standard of care in BRAF-mutant metastatic colorectal cancer. In the phase III BEACON CRC trial, encorafenib, binimetinib, and cetuximab significantly extended overall and progression-free survival and increased the objective response rate compared with cetuximab plus chemotherapy.
    DOI:  https://doi.org/10.1158/2159-8290.CD-NB2019-122
  16. Cancer Discov. 2019 Nov;9(11): 1483
    Low-Heterogeneity Melanomas Are More Immunogenic and Less Aggressive.
      In mouse models of melanoma, lower intratumoral heterogeneity (ITH) correlated with lower tumor growth.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2019-144
  17. Cancer Sci. 2021 Aug 23.
    BEX2 is required for maintaining dormant cancer stem cell in hepatocellular carcinoma.
    Daisuke Fukushi, Rie Shibuya-Takahashi, Mai Mochizuki, Haruna Fujimori, Takayuki Kogure, Takahiro Sugai, Wataru Iwai, Yuta Wakui, Makoto Abue, Kazuhiro Murakami, Yasuhiro Nakamura, Jun Yasuda, Kazunori Yamaguchi, Kazuo Sugamura, Chikashi Shibata, Yu Katayose, Kennichi Satoh, Keiichi Tamai.
      Cancer stem cells (CSCs) are responsible for therapy resistance and share several properties with normal stem cells. Here, we show that BEX2 (brain expressed X-linked gene 2), which is essential for dormant CSCs in cholangiocarcinoma, is highly expressed in human hepatocellular carcinoma (HCC) lesions compared to the adjacent normal lesions, and that in 41 HCC cases the BEX2high expression group is correlated with a poor prognosis. BEX2 localizes to Ki67-negative (non-proliferative) cancer cells in HCC tissues, and is highly expressed in the dormant fraction of HCC cell lines. Knockdown of BEX2 attenuates CSC phenotypes, including sphere formation ability and aldefluor activity, and BEX2 overexpression enhances these phenotypes. Moreover, BEX2 knockdown increases cisplatin sensitivity, and BEX2 expression is induced by cisplatin treatment. Taken together, these data suggest that BEX2 induces dormant CSC properties and affects the prognosis of patients with HCC.
    DOI:  https://doi.org/10.1111/cas.15115
  18. Cancer Metastasis Rev. 2021 Aug 28.
    The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance.
    Kalyani Patil, Farheen B Khan, Sabah Akhtar, Aamir Ahmad, Shahab Uddin.
      The ever-growing perception of cancer stem cells (CSCs) as a plastic state rather than a hardwired defined entity has evolved our understanding of the functional and biological plasticity of these elusive components in malignancies. Pancreatic cancer (PC), based on its biological features and clinical evolution, is a prototypical example of a CSC-driven disease. Since the discovery of pancreatic CSCs (PCSCs) in 2007, evidence has unraveled their control over many facets of the natural history of PC, including primary tumor growth, metastatic progression, disease recurrence, and acquired drug resistance. Consequently, the current near-ubiquitous treatment regimens for PC using aggressive cytotoxic agents, aimed at ''tumor debulking'' rather than eradication of CSCs, have proven ineffective in providing clinically convincing improvements in patients with this dreadful disease. Herein, we review the key hallmarks as well as the intrinsic and extrinsic resistance mechanisms of CSCs that mediate treatment failure in PC and enlist the potential CSC-targeting 'natural agents' that are gaining popularity in recent years. A better understanding of the molecular and functional landscape of PCSC-intrinsic evasion of chemotherapeutic drugs offers a facile opportunity for treating PC, an intractable cancer with a grim prognosis and in dire need of effective therapeutic advances.
    Keywords:  Cancer stem cells; Drug resistance; Epithelial to mesenchymal transition; Oncogenic signaling; Pancreatic cancer
    DOI:  https://doi.org/10.1007/s10555-021-09979-x
  19. Proc Natl Acad Sci U S A. 2021 Aug 31. pii: e2100784118. [Epub ahead of print]118(35):
    TRIM47 activates NF-κB signaling via PKC-ε/PKD3 stabilization and contributes to endocrine therapy resistance in breast cancer.
    Kotaro Azuma, Kazuhiro Ikeda, Takashi Suzuki, Kenjiro Aogi, Kuniko Horie-Inoue, Satoshi Inoue.
      Increasing attention has been paid to roles of tripartite motif-containing (TRIM) family proteins in cancer biology, often functioning as E3 ubiquitin ligases. In the present study, we focus on a contribution of TRIM47 to breast cancer biology, particularly to endocrine therapy resistance, which is a major clinical problem in breast cancer treatment. We performed immunohistochemical analysis of TRIM47 protein expression in 116 clinical samples of breast cancer patients with postoperative endocrine therapy using tamoxifen. Our clinicopathological study showed that higher immunoreactivity scores of TRIM47 were significantly associated with higher relapse rate of breast cancer patients (P = 0.012). As functional analyses, we manipulated TRIM47 expression in estrogen receptor-positive breast cancer cells MCF-7 and its 4-hydroxytamoxifen (OHT)-resistant derivative OHTR, which was established in a long-term culture with OHT. TRIM47 promoted both MCF-7 and OHTR cell proliferation. MCF-7 cells acquired tamoxifen resistance by overexpressing exogenous TRIM47. We found that TRIM47 enhances nuclear factor kappa-B (NF-κB) signaling, which further up-regulates TRIM47. We showed that protein kinase C epsilon (PKC-ε) and protein kinase D3 (PKD3), known as NF-κB-activating protein kinases, are directly associated with TRIM47 and stabilized in the presence of TRIM47. As an underlying mechanism, we showed TRIM47-dependent lysine 27-linked polyubiquitination of PKC-ε. These results indicate that TRIM47 facilitates breast cancer proliferation and endocrine therapy resistance by forming a ternary complex with PKC-ε and PKD3. TRIM47 and its associated kinases can be a potential diagnostic and therapeutic target for breast cancer refractory to endocrine therapy.
    Keywords:  breast cancer; nuclear factor kappa-B signaling; protein kinase C epsilon; protein kinase D3; tripartite motif containing 47
    DOI:  https://doi.org/10.1073/pnas.2100784118
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