bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021–02–14
thirty papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. Epigenetic and transcriptional analysis reveals a core transcriptional program conserved in clonal prostate cancer metastases.
  2. A Malignant Case of Arrested Development: Cancer Cell Dormancy Mimics Embryonic Diapause.
  3. Interleukin-6 derived from cancer-associated fibroblasts attenuates the p53 response to doxorubicin in prostate cancer cells.
  4. PRMT5 inhibition disrupts splicing and stemness in glioblastoma.
  5. STAT3 promotes melanoma metastasis by CEBP-induced repression of the MITF pathway.
  6. NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy.
  7. Long non-coding RNAs and cancer metastasis: Molecular basis and therapeutic implications.
  8. Cell memory of epithelial-mesenchymal plasticity in cancer.
  9. Heterogeneity in Metastatic Potential of Cancer Cells Is Revealed En Masse.
  10. Malignant subclone drives metastasis of genetically and phenotypically heterogenous cell clusters through fibrotic niche generation.
  11. G9a controls pluripotent-like identity and tumor-initiating function in human colorectal cancer.
  12. Inflammatory cell-derived CXCL3 promotes pancreatic cancer metastasis through a novel myofibroblast-hijacked cancer escape mechanism.
  13. YAP and β-catenin cooperate to drive oncogenesis in basal breast cancer.
  14. The miR-181a-SFRP4 axis regulates Wnt activation to drive stemness and platinum resistance in ovarian cancer.
  15. Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma.
  16. Exosomal Delivery of FTO Confers Gefitinib Resistance to Recipient Cells through ABCC10 Regulation in an m6A-dependent Manner.
  17. Targeting the Microbiome to Overcome Resistance.
  18. SILAC-Based Quantitative Proteomic Analysis of Oxaliplatin-Resistant Pancreatic Cancer Cells.
  19. Genomic and evolutionary portraits of disease relapse in acute myeloid leukemia.
  20. Overcoming PARPi resistance: Preclinical and clinical evidence in ovarian cancer.
  21. Mutant-selective degradation by BRAF-targeting PROTACs.
  22. Tumour microenvironment markers predict risk of prostate cancer recurrence.
  23. Learning the dynamics of cell-cell interactions in confined cell migration.
  24. Progression to Metastasis of Solid Cancer.
  25. Senolytics for Cancer Therapy: Is All That Glitters Really Gold?
  26. Selective treatment pressure in colon cancer drives the molecular profile of resistant circulating tumor cell clones.
  27. Exploiting allosteric properties of RAF and MEK inhibitors to target therapy-resistant tumors driven by oncogenic BRAF signaling.
  28. Fueling Cell Invasion through Extracellular Matrix.
  29. TFEB-mediated lysosomal biogenesis and lysosomal drug sequestration confer resistance to MEK inhibition in pancreatic cancer.
  30. Mouse model of colorectal cancer: orthotopic co-implantation of tumor and stroma cells in cecum and rectum.
  1. Mol Oncol. 2021 Feb 11.
    Epigenetic and transcriptional analysis reveals a core transcriptional program conserved in clonal prostate cancer metastases.
    Tesa M Severson, Yanyun Zhu, Angelo M De Marzo, Tracy Jones, Jonathan W Simons, William G Nelson, Srinivasan Yegnasubramanian, Matthew L Freedman, Lodewyk Wessels, Andries M Bergman, Michael C Haffner, Wilbert Zwart.
      The epigenomic regulation of transcriptional programs in metastatic prostate cancer is poorly understood. We studied the epigenomic landscape of prostate cancer drivers using transcriptional profiling and chromatin immunoprecipitation sequencing (ChIP-seq) in four clonal metastatic tumors derived from a single prostate cancer patient. Our epigenomic analyses focused on Androgen Receptor (AR), which is a key oncogenic driver in prostate cancer , the AR pioneer factor FOXA1, chromatin insulator CTCF, as well as for modified histones H3K27ac and H3K27me3. The vast majority of AR binding sites were shared among healthy prostate, primary prostate cancer and metastatic tumor samples, signifying core AR-driven transcriptional regulation within the prostate cell lineage. Genes associated with core AR-binding events were significantly enriched for essential genes in prostate cancer cell proliferation. Remarkably, the metastasis-specific active AR binding sites showed no differential transcriptional output, indicating a robust transcriptional program across metastatic samples. Combined, our data reveal a core transcriptional program in clonal metastatic prostate cancer, despite epigenomic differences in the AR cistrome.
    Keywords:  ChIP-seq; cistrome; epigenomics; metastasis; prostate cancer; transcriptomics
    DOI:  https://doi.org/10.1002/1878-0261.12923
  2. Cancer Cell. 2021 Feb 08. pii: S1535-6108(21)00057-X. [Epub ahead of print]39(2): 142-144
    A Malignant Case of Arrested Development: Cancer Cell Dormancy Mimics Embryonic Diapause.
    Yu-Hsuan Lin, Hao Zhu.
      Writing in Cancer Cell and Cell, two groups investigate the nature of dormant cancer cells that persist after chemotherapy. These cells adopt a state that resembles diapause, an evolutionarily conserved adaptation used by embryos to survive inhospitable conditions. Understanding cancer diapause could uncover therapeutic strategies that reduce cancer relapse.
    DOI:  https://doi.org/10.1016/j.ccell.2021.01.013
  3. Cell Death Discov. 2020 Jun 02. 6(1): 42
    Interleukin-6 derived from cancer-associated fibroblasts attenuates the p53 response to doxorubicin in prostate cancer cells.
    Emarndeena H Cheteh, Victoria Sarne, Sophia Ceder, Julie Bianchi, Martin Augsten, Helene Rundqvist, Lars Egevad, Arne Östman, Klas G Wiman.
      Cancer-associated fibroblasts (CAFs) promote tumor growth and progression, and increase drug resistance through several mechanisms. We have investigated the effect of CAFs on the p53 response to doxorubicin in prostate cancer cells. We show that CAFs produce interleukin-6 (IL-6), and that IL-6 attenuates p53 induction and upregulation of the pro-apoptotic p53 target Bax upon treatment with doxorubicin. This is associated with increased levels of MDM2 mRNA, Mdm2 protein bound to p53, and ubiquitinated p53. IL-6 also inhibited doxorubicin-induced cell death. Inhibition of JAK or STAT3 alleviated this effect, indicating that IL-6 attenuates p53 via the JAK/STAT signaling pathway. These results suggest that CAF-derived IL-6 plays an important role in protecting cancer cells from chemotherapy and that inhibition of IL-6 could have significant therapeutic value.
    DOI:  https://doi.org/10.1038/s41420-020-0272-5
  4. Nat Commun. 2021 Feb 12. 12(1): 979
    PRMT5 inhibition disrupts splicing and stemness in glioblastoma.
    Patty Sachamitr, Jolene C Ho, Felipe E Ciamponi, Wail Ba-Alawi, Fiona J Coutinho, Paul Guilhamon, Michelle M Kushida, Florence M G Cavalli, Lilian Lee, Naghmeh Rastegar, Victoria Vu, María Sánchez-Osuna, Jasmin Coulombe-Huntington, Evgeny Kanshin, Heather Whetstone, Mathieu Durand, Philippe Thibault, Kirsten Hart, Maria Mangos, Joseph Veyhl, Wenjun Chen, Nhat Tran, Bang-Chi Duong, Ahmed M Aman, Xinghui Che, Xiaoyang Lan, Owen Whitley, Olga Zaslaver, Dalia Barsyte-Lovejoy, Laura M Richards, Ian Restall, Amy Caudy, Hannes L Röst, Zahid Quyoom Bonday, Mark Bernstein, Sunit Das, Michael D Cusimano, Julian Spears, Gary D Bader, Trevor J Pugh, Mike Tyers, Mathieu Lupien, Benjamin Haibe-Kains, H Artee Luchman, Samuel Weiss, Katlin B Massirer, Panagiotis Prinos, Cheryl H Arrowsmith, Peter B Dirks.
      Glioblastoma (GBM) is a deadly cancer in which cancer stem cells (CSCs) sustain tumor growth and contribute to therapeutic resistance. Protein arginine methyltransferase 5 (PRMT5) has recently emerged as a promising target in GBM. Using two orthogonal-acting inhibitors of PRMT5 (GSK591 or LLY-283), we show that pharmacological inhibition of PRMT5 suppresses the growth of a cohort of 46 patient-derived GBM stem cell cultures, with the proneural subtype showing greater sensitivity. We show that PRMT5 inhibition causes widespread disruption of splicing across the transcriptome, particularly affecting cell cycle gene products. We identify a GBM splicing signature that correlates with the degree of response to PRMT5 inhibition. Importantly, we demonstrate that LLY-283 is brain-penetrant and significantly prolongs the survival of mice with orthotopic patient-derived xenografts. Collectively, our findings provide a rationale for the clinical development of brain penetrant PRMT5 inhibitors as treatment for GBM.
    DOI:  https://doi.org/10.1038/s41467-021-21204-5
  5. Oncogene. 2021 Feb;40(6): 1091-1105
    STAT3 promotes melanoma metastasis by CEBP-induced repression of the MITF pathway.
    Alexander Swoboda, Robert Soukup, Oliver Eckel, Katharina Kinslechner, Bettina Wingelhofer, David Schörghofer, Christina Sternberg, Ha T T Pham, Maria Vallianou, Jaqueline Horvath, Dagmar Stoiber, Lukas Kenner, Lionel Larue, Valeria Poli, Friedrich Beermann, Takashi Yokota, Stefan Kubicek, Thomas Krausgruber, André F Rendeiro, Christoph Bock, Rainer Zenz, Boris Kovacic, Fritz Aberger, Markus Hengstschläger, Peter Petzelbauer, Mario Mikula, Richard Moriggl.
      Metastatic melanoma is hallmarked by its ability of phenotype switching to more slowly proliferating, but highly invasive cells. Here, we tested the impact of signal transducer and activator of transcription 3 (STAT3) on melanoma progression in association with melanocyte inducing transcription factor (MITF) expression levels. We established a mouse melanoma model for deleting Stat3 in melanocytes with specific expression of human hyperactive NRASQ61K in an Ink4a-deficient background, two frequent driver mutations in human melanoma. Mice devoid of Stat3 showed early disease onset with higher proliferation in primary tumors, but displayed significantly diminished lung, brain, and liver metastases. Whole-genome expression profiling of tumor-derived cells also showed a reduced invasion phenotype, which was further corroborated by 3D melanoma model analysis. Notably, loss or knockdown of STAT3 in mouse or human cells resulted in the upregulation of MITF and induction of cell proliferation. Mechanistically we show that STAT3-induced CAAT Box Enhancer Binding Protein (CEBP) expression was sufficient to suppress MITF transcription. Epigenetic analysis by ATAC-seq confirmed that CEBPa/b binding to the MITF enhancer region silenced the MITF locus. Finally, by classification of patient-derived melanoma samples, we show that STAT3 and MITF act antagonistically and hence contribute differentially to melanoma progression. We conclude that STAT3 is a driver of the metastatic process in melanoma and able to antagonize MITF via direct induction of CEBP family member transcription.
    DOI:  https://doi.org/10.1038/s41388-020-01584-6
  6. Cancers (Basel). 2021 Feb 05. pii: 639. [Epub ahead of print]13(4):
    NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy.
    Viraj R Sanghvi, Prathibha Mohan, Kamini Singh, Linlin Cao, Marjan Berishaj, Andrew L Wolfe, Jonathan H Schatz, Nathalie Lailler, Elisa de Stanchina, Agnes Viale, Hans-Guido Wendel.
      Inhibition of the eIF4A RNA helicase with silvestrol and related compounds is emerging as a powerful anti-cancer strategy. We find that a synthetic silvestrol analogue (CR-1-31 B) has nanomolar activity across many cancer cell lines. It is especially active against aggressive MYC+/BCL2+ B cell lymphomas and this likely reflects the eIF4A-dependent translation of both MYC and BCL2. We performed a genome-wide CRISPR/Cas9 screen and identified mechanisms of resistance to this new class of therapeutics. We identify three negative NRF2 regulators (KEAP1, CUL3, CAND1) whose inactivation is sufficient to cause CR1-31-B resistance. NRF2 is known to alter the oxidation state of translation factors and cause a broad increase in protein production. We find that NRF2 activation particularly increases the translation of some eIF4A-dependent mRNAs and restores MYC and BCL2 production. We know that NRF2 functions depend on removal of sugar adducts by the frutosamine-3-kinase (FN3K). Accordingly, loss of FN3K results in NRF2 hyper-glycation and inactivation and resensitizes cancer cells to eIF4A inhibition. Together, our findings implicate NRF2 in the translation of eIF4A-dependent mRNAs and point to FN3K inhibition as a new strategy to block NRF2 functions in cancer.
    Keywords:  G-quadruplex; KEAP1; NRF2; drug resistance; eIF4A; lymphoma; silvestrol
    DOI:  https://doi.org/10.3390/cancers13040639
  7. Biochim Biophys Acta Rev Cancer. 2021 Feb 04. pii: S0304-419X(21)00018-4. [Epub ahead of print]1875(2): 188519
    Long non-coding RNAs and cancer metastasis: Molecular basis and therapeutic implications.
    Hui Ming, Bowen Li, Li Zhou, Ajay Goel, Canhua Huang.
      Cancer metastasis, defined by the epithelial to mesenchymal transition (EMT) of tumor cells, disseminates from the primary site to progressively colonize in distant tissues, and accounts for most cancer-associated deaths. However, studies on the molecular basis of cancer metastasis are still in their infancy. Besides genetic mutations, accumulating evidence indicates that epigenetic alterations also contribute in a major way to the refractory nature of cancer metastasis. Considered as one of the essential epigenetic regulators, long non-coding RNAs (lncRNAs) can act as signaling regulators, decoys, guides and scaffolds, modulating key molecules in every step of cancer metastasis including dissemination of carcinoma cells, intravascular transit, and metastatic colonization. Although still having limited clinical application, it is encouraging to witness that several lncRNAs, including CCAT1 and HOTAIR, are under clinical evaluation as potential biomarkers for cancer staging and assessment of metastatic potential. In this review, we focus on the molecular mechanisms underlying lncRNAs in the regulation of cancer metastasis and discuss their clinical potential as novel therapeutic targets as well as their diagnostic and prognostic significance for cancer treatment. Gaining clear insights into the detailed molecular basis underlying lncRNA-modulated cancer metastasis may provide previously unrecognized diagnostic and therapeutic strategies for metastatic patients.
    Keywords:  Cancer; Cancer metastasis; Cancer therapy; EMT; LncRNA
    DOI:  https://doi.org/10.1016/j.bbcan.2021.188519
  8. Curr Opin Cell Biol. 2021 Feb 09. pii: S0955-0674(21)00001-6. [Epub ahead of print]69 103-110
    Cell memory of epithelial-mesenchymal plasticity in cancer.
    Jordi Berenguer, Toni Celià-Terrassa.
      Fundamental biological processes of cell identity and cell fate determination are controlled by complex regulatory networks. These processes require molecular mechanisms that confer cellular phenotypic memory and state persistence. In this minireview, we will summarize mechanisms of cell memory based on regulatory hysteretic feedback loops and explore epigenetic mechanisms widely represented in nature, with special focus on epithelial-to-mesenchymal plasticity. We will also discuss the functional consequences of cell memory and epithelial-to-mesenchymal plasticity dynamics during development and cancer metastasis.
    Keywords:  Cell plasticity; Cell state; Cellular memory; Dynamics; EMT; Feedback loops; Hysteresis; Multistability
    DOI:  https://doi.org/10.1016/j.ceb.2021.01.001
  9. Cancer Cell. 2021 Feb 08. pii: S1535-6108(21)00061-1. [Epub ahead of print]39(2): 148-150
    Heterogeneity in Metastatic Potential of Cancer Cells Is Revealed En Masse.
    Pavitra Viswanath, Alana L Welm.
      A new study in Nature determines metastatic tropism in xenograft mouse models. This results in a metastasis map for 21 tumor types, the utility of which is demonstrated by identifying lipid metabolism to be uniquely altered in breast cancer cell lines that metastasize to the brain.
    DOI:  https://doi.org/10.1016/j.ccell.2021.01.017
  10. Nat Commun. 2021 02 08. 12(1): 863
    Malignant subclone drives metastasis of genetically and phenotypically heterogenous cell clusters through fibrotic niche generation.
    Sau Yee Kok, Hiroko Oshima, Kei Takahashi, Mizuho Nakayama, Kazuhiro Murakami, Hiroki R Ueda, Kohei Miyazono, Masanobu Oshima.
      A concept of polyclonal metastasis has recently been proposed, wherein tumor cell clusters break off from the primary site and are disseminated. However, the involvement of driver mutations in such polyclonal mechanism is not fully understood. Here, we show that non-metastatic AP cells metastasize to the liver with metastatic AKTP cells after co-transplantation to the spleen. Furthermore, AKTP cell depletion after the development of metastases results in the continuous proliferation of the remaining AP cells, indicating a role of AKTP cells in the early step of polyclonal metastasis. Importantly, AKTP cells, but not AP cells, induce fibrotic niche generation when arrested in the sinusoid, and such fibrotic microenvironment promotes the colonization of AP cells. These results indicate that non-metastatic cells can metastasize via the polyclonal metastasis mechanism using the fibrotic niche induced by malignant cells. Thus, targeting the fibrotic niche is an effective strategy for halting polyclonal metastasis.
    DOI:  https://doi.org/10.1038/s41467-021-21160-0
  11. Oncogene. 2021 Feb;40(6): 1191-1202
    G9a controls pluripotent-like identity and tumor-initiating function in human colorectal cancer.
    Christopher J Bergin, Aïcha Zouggar, Joshua R Haebe, Angelique N Masibag, François M Desrochers, Simon Y Reilley, Gautam Agrawal, Yannick D Benoit.
      Colorectal tumors are hierarchically organized and governed by populations of self-renewing cancer stem cells, representing one of the deadliest types of cancers worldwide. Emergence of cancer stemness phenotype depends on epigenetic reprogramming, associated with profound transcriptional changes. As described for pluripotent reprogramming, epigenetic modifiers play a key role in cancer stem cells by establishing embryonic stem-like transcriptional programs, thus impacting the balance between self-renewal and differentiation. We identified overexpression of histone methyltransferase G9a as a risk factor for colorectal cancer, associated with shorter relapse-free survival. Moreover, using human transformed pluripotent cells as a surrogate model for cancer stem cells, we observed that G9a activity is essential for the maintenance of embryonic-like transcriptional signature promoting self-renewal, tumorigenicity, and undifferentiated state. Such a role was also applicable to colorectal cancer, where inhibitors of G9a histone methyltransferase function induced intestinal differentiation while restricting tumor-initiating activity in patient-derived colorectal tumor samples. Finally, by integrating transcriptome profiling with G9a/H3K9me2 loci co-occupancy, we identified the canonical Wnt pathway, epithelial-to-mesenchyme transition, and extracellular matrix organization as potential targets of such a chromatin regulation mechanism in colorectal cancer stem cells. Overall, our findings provide novel insights on the role of G9a as a driver of cancer stem cell phenotype, promoting self-renewal, tumorigenicity, and undifferentiated state.
    DOI:  https://doi.org/10.1038/s41388-020-01591-7
  12. Gut. 2021 Feb 10. pii: gutjnl-2020-322744. [Epub ahead of print]
    Inflammatory cell-derived CXCL3 promotes pancreatic cancer metastasis through a novel myofibroblast-hijacked cancer escape mechanism.
    Xiaoting Sun, Xingkang He, Yin Zhang, Kayoko Hosaka, Patrik Andersson, Jing Wu, Jieyu Wu, Xu Jing, Qiqiao Du, Xiaoli Hui, Bo Ding, Ziheng Guo, An Hong, Xuan Liu, Yan Wang, Qing Ji, Rudi Beyaert, Yunlong Yang, Qi Li, Yihai Cao.
       OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy and lacks effective treatment. We aimed to understand molecular mechanisms of the intertwined interactions between tumour stromal components in metastasis and to provide a new paradigm for PDAC therapy.
    DESIGN: Two unselected cohorts of 154 and 20 patients with PDAC were subjected to correlation between interleukin (IL)-33 and CXCL3 levels and survivals. Unbiased expression profiling, and genetic and pharmacological gain-of-function and loss-of-function approaches were employed to identify molecular signalling in tumour-associated macrophages (TAMs) and myofibroblastic cancer-associated fibroblasts (myoCAFs). The role of the IL-33-ST2-CXCL3-CXCR2 axis in PDAC metastasis was evaluated in three clinically relevant mouse PDAC models.
    RESULTS: IL-33 was specifically elevated in human PDACs and positively correlated with tumour inflammation in human patients with PDAC. CXCL3 was highly upregulated in IL-33-stimulated macrophages that were the primary source of CXCL3. CXCL3 was correlated with poor survival in human patients with PDAC. Mechanistically, activation of the IL-33-ST2-MYC pathway attributed to high CXCL3 production. The highest level of CXCL3 was found in PDAC relative to other cancer types and its receptor CXCR2 was almost exclusively expressed in CAFs. Activation of CXCR2 by CXCL3 induced a CAF-to-myoCAF transition and α-smooth muscle actin (α-SMA) was uniquely upregulated by the CXCL3-CXCR2 signalling. Type III collagen was identified as the CXCL3-CXCR2-targeted adhesive molecule responsible for myoCAF-driven PDAC metastasis.
    CONCLUSIONS: Our work provides novel mechanistic insights into understanding PDAC metastasis by the TAM-CAF interaction and targeting each of these signalling components would provide an attractive and new paradigm for treating pancreatic cancer.
    Keywords:  chemokines; interleukins; macrophages; myofibroblasts; pancreatic cancer
    DOI:  https://doi.org/10.1136/gutjnl-2020-322744
  13. Cancer Res. 2021 Feb 11. pii: canres.2801.2020. [Epub ahead of print]
    YAP and β-catenin cooperate to drive oncogenesis in basal breast cancer.
    Hazel M Quinn, Regina Vogel, Oliver Popp, Philipp Mertins, Linxiang Lan, Clemens Messerschmidt, Alexandro Landshammer, Kamil Lisek, Sophie Chateau-Joubert, Elisabetta Marangoni, Elle Koren, Yaron Fuchs, Walter Birchmeier.
      Targeting cancer stem cells (CSC) can serve as an effective approach toward limiting resistance to therapies. While basal-like (triple-negative) breast cancers encompass cells with CSC features, rational therapies remain poorly established. We show here that the receptor tyrosine kinase Met promotes YAP activity in basal-like breast cancer and find enhanced YAP activity within the CSC population. Interfering with YAP activity delayed basal-like cancer formation, prevented luminal to basal trans-differentiation, and reduced CSC. YAP knockout mammary glands revealed a decrease in β-catenin target genes, suggesting that YAP is required for nuclear β-catenin activity. Mechanistically, nuclear YAP interacted with β-catenin and TEAD4 at gene regulatory elements. Proteomic patient data revealed an upregulation of the YAP signature in basal-like breast cancers. Our findings demonstrate that in basal-like breast cancers, β-catenin activity is dependent on YAP signalling and controls the CSC program. These findings suggest that targeting the YAP/TEAD4/β-catenin complex offers a potential therapeutic strategy for eradicating CSCs in basal-like breast cancers.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-2801
  14. Cancer Res. 2021 Feb 11. pii: canres.2041.2020. [Epub ahead of print]
    The miR-181a-SFRP4 axis regulates Wnt activation to drive stemness and platinum resistance in ovarian cancer.
    Anil Belur Nagaraj, Matthew Knarr, Sreeja Sekhar, R Shae Connor, Peronne Joseph, Olga Kovalenko, Alexis Fleming, Arshia Surti, Elmar Nurmemmedov, Luca Beltrame, Sergio Marchini, Michael Kahn, Analisa DiFeo.
      Wnt signaling is a major driver of stemness and chemo-resistance in ovarian cancer, yet the genetic drivers that stimulate its expression remain largely unknown. Unlike other cancers, mutations in the Wnt pathway are not reported in high-grade serous ovarian cancer (HGSOC). Hence, a key challenge that must be addressed in order to develop effective targeted therapies is to identify non-mutational drivers of Wnt activation. Using a miRNA sensor-based approach, we have identified miR-181a as a novel driver of Wnt/β-catenin signaling. miR-181ahigh primary HGSOC cells exhibited increased Wnt/β-catenin signaling, which was associated with increased stem-cell frequency and platinum resistance. Consistent with these findings, inhibition of β-catenin decreased stem-like properties in miR-181ahigh cell populations and downregulated miR-181a. The Wnt inhibitor SFRP4 was identified as a novel target of miR-181a. Overall, our results demonstrate that miR-181a is a non-mutational activator of Wnt signaling which drives stemness and chemoresistance in HGSOC, suggesting that the miR-181a-SFRP4 axis can be evaluated as a novel biomarker for β-catenin-targeted therapy in this disease.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-2041
  15. Nat Commun. 2021 Feb 12. 12(1): 1014
    Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma.
    Erik Jung, Matthias Osswald, Miriam Ratliff, Helin Dogan, Ruifan Xie, Sophie Weil, Dirk C Hoffmann, Felix T Kurz, Tobias Kessler, Sabine Heiland, Andreas von Deimling, Felix Sahm, Wolfgang Wick, Frank Winkler.
      Both the perivascular niche (PVN) and the integration into multicellular networks by tumor microtubes (TMs) have been associated with progression and resistance to therapies in glioblastoma, but their specific contribution remained unknown. By long-term tracking of tumor cell fate and dynamics in the live mouse brain, differential therapeutic responses in both niches are determined. Both the PVN, a preferential location of long-term quiescent glioma cells, and network integration facilitate resistance against cytotoxic effects of radiotherapy and chemotherapy-independently of each other, but with additive effects. Perivascular glioblastoma cells are particularly able to actively repair damage to tumor regions. Population of the PVN and resistance in it depend on proficient NOTCH1 expression. In turn, NOTCH1 downregulation induces resistant multicellular networks by TM extension. Our findings identify NOTCH1 as a central switch between the PVN and network niche in glioma, and demonstrate robust cross-compensation when only one niche is targeted.
    DOI:  https://doi.org/10.1038/s41467-021-21117-3
  16. Mol Cancer Res. 2021 Feb 09.
    Exosomal Delivery of FTO Confers Gefitinib Resistance to Recipient Cells through ABCC10 Regulation in an m6A-dependent Manner.
    Peng Xiao, Yu-Kang Liu, Wei Han, Yan Hu, Bo-You Zhang, Wen-Liang Liu.
      Gefitinib is suitable for the treatment of locally advanced or metastatic non-small cell lung cancer. However, the development of acquired resistance limits its long-term efficacy in regardless of significant clinical benefit to patients. Therefore, to elucidate the mechanism of gefitinib resistance in addition to target gene mutation may greatly increase its clinical efficacy. It was found first that N 6-methyladenosine RNA demethylase FTO was significantly enriched in serum exosomes of gefitinib-resistant (GR) patients compared with that of gefitinib-sensitive (GS) patients through exosomal RNA sequencing. Meanwhile, the average m6A proportion in GR patients was significantly lower when compared with that in GS patients. Besides, GR cell-derived exosome internalization attenuated the total m6A abundance and gefitinib sensitivity of PC9 cells. Not only FTO knockdown enhanced the gefitinib sensitivity of GR cells but also FTO reduction in donor exosomes alleviated the acquired resistance of recipient PC9 cells. GR cell-derived exosomal-FTO promoted ABCC10 of recipient cells in a m6A-dependent manner. FTO/YTHDF2/ABCC10 axis played a role in intercellular transmission of GR cell-derived exosome-mediated gefitinib resistance both in vitro and in vivo. In general, this research showed that m6A modification was involved in the decrease of gefitinib sensitivity. GR cell-derived exosomes could decrease gefitinib sensitivity of recipient cells in exosomal delivery of FTO-dependent manner. FTO/YTHDF2/ABCC10 axis played a role in intercellular transmission of GR cell-derived exosome-mediated gefitinib resistance. IMPLICATIONS: Our results elucidated another potential molecular mechanism of gefitinib resistance in non-small cell lung cancer besides secondary EGFR mutations.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-20-0541
  17. Cancer Cell. 2021 Feb 08. pii: S1535-6108(21)00060-X. [Epub ahead of print]39(2): 151-153
    Targeting the Microbiome to Overcome Resistance.
    Rebecca C Simpson, Erin Shanahan, Richard A Scolyer, Georgina V Long.
      Immune checkpoint inhibition has revolutionized the treatment of many cancers, including melanoma. However, primary and acquired resistance remain key challenges for the field. Promising results from a phase I clinical trial recently published in Science highlight the potential of modulating the microbiome via fecal transplant to overcome resistance to immunotherapy.
    DOI:  https://doi.org/10.1016/j.ccell.2021.01.016
  18. Cancers (Basel). 2021 Feb 10. pii: 724. [Epub ahead of print]13(4):
    SILAC-Based Quantitative Proteomic Analysis of Oxaliplatin-Resistant Pancreatic Cancer Cells.
    Young Eun Kim, Eun-Kyung Kim, Min-Jeong Song, Tae-Young Kim, Ho Hee Jang, Dukjin Kang.
      Oxaliplatin is a commonly used chemotherapeutic drug for the treatment of pancreatic cancer. Understanding the cellular mechanisms of oxaliplatin resistance is important for developing new strategies to overcome drug resistance in pancreatic cancer. In this study, we performed a stable isotope labelling by amino acids in cell culture (SILAC)-based quantitative proteomics analysis of oxaliplatin-resistant and sensitive pancreatic cancer PANC-1 cells. We identified 107 proteins whose expression levels changed (thresholds of 2-fold changes and p-value ≤ 0.05) between oxaliplatin-resistant and sensitive cells, which were involved in multiple biological processes, including DNA repair, cell cycle process, and type I interferon signaling pathway. Notably, myristoylated alanine-rich C-kinase substrate (MARCKS) and Wntless homolog protein (WLS) were upregulated in oxaliplatin-resistant cells compared to sensitive cells, as confirmed by qRT-PCR and Western blot analysis. We further demonstrated the activation of AKT and β-catenin signaling (downstream targets of MARCKS and WLS, respectively) in oxaliplatin-resistant PANC-1 cells. Additionally, we show that the siRNA-mediated suppression of both MARCKS and WLS enhanced oxaliplatin sensitivity in oxaliplatin-resistant PANC-1 cells. Taken together, our results provide insights into multiple mechanisms of oxaliplatin resistance in pancreatic cancer cells and reveal that MARCKS and WLS might be involved in the oxaliplatin resistance.
    Keywords:  SILAC; drug resistance; oxaliplatin; pancreatic cancer; quantitative proteomics
    DOI:  https://doi.org/10.3390/cancers13040724
  19. Leukemia. 2021 Feb 12.
    Genomic and evolutionary portraits of disease relapse in acute myeloid leukemia.
    Franck Rapaport, Yaseswini Neelamraju, Timour Baslan, Duane Hassane, Agata Gruszczynska, Marc Robert de Massy, Noushin Farnoud, Samuel Haddox, Tak Lee, Juan Medina-Martinez, Caroline Sheridan, Alexis Thurmond, Michael Becker, Stefan Bekiranov, Martin Carroll, Heardly Moses Murdock, Peter J M Valk, Lars Bullinger, Richard D'Andrea, Scott W Lowe, Donna Neuberg, Ross L Levine, Ari Melnick, Francine E Garrett-Bakelman.
      
    DOI:  https://doi.org/10.1038/s41375-021-01153-0
  20. Drug Resist Updat. 2021 Jan 16. pii: S1368-7646(21)00002-9. [Epub ahead of print] 100744
    Overcoming PARPi resistance: Preclinical and clinical evidence in ovarian cancer.
    M Chiappa, F Guffanti, F Bertoni, I Colombo, G Damia.
      Ovarian cancer is the fifth cause of cancer-related deaths in women with high grade serous carcinoma (HGSOC) representing the most common histological subtype. Approximately 50 % of HGSOC are characterized by deficiency in homologous recombination (HR), one of the main cellular pathways to repair DNA double strand breaks and one of the well-described mechanisms is the loss of function of the BRCA1 or BRCA2 genes. Inhibition of the poly-ADP-ribose polymerase (PARP) is synthetic lethal with HR deficiency and the use of PARP inhibitors (PARPi) has significantly improved the outcome of patients with HGSOC with a greater benefit in patients with BRCA1/2 deficient tumors. However, intrinsic or acquired resistance to PARPi inevitably occurs in most HGSOC patients. Distinct heterogeneous mechanisms underlying the resistance to PARPi have been described, including a decrease in intracellular drug levels due to upregulation of multidrug efflux pumps, loss of expression/inactivating mutations in the PARP1 protein, restoration of HR and the protection of the replicative fork. Deciphering the molecular mechanisms of resistance to PARPi is of paramount importance towards the development of new treatment strategies and/or novel pharmacological agents to overcome this chemoresistance and optimize the treatment regimen for individual HGSOC patients. The current review summarizes the mechanisms underlying the resistance to PARPi, the available preclinical and clinical data on new combination treatment strategies (with chemotherapy, anti-angiogenic agents and immune checkpoint inhibitors) as well as agents under investigation which target the DNA damage response.
    Keywords:  Ovarian cancer; PARPi resistance
    DOI:  https://doi.org/10.1016/j.drup.2021.100744
  21. Nat Commun. 2021 02 10. 12(1): 920
    Mutant-selective degradation by BRAF-targeting PROTACs.
    Shanique Alabi, Saul Jaime-Figueroa, Zhan Yao, Yijun Gao, John Hines, Kusal T G Samarasinghe, Lea Vogt, Neal Rosen, Craig M Crews.
      Over 300 BRAF missense mutations have been identified in patients, yet currently approved drugs target V600 mutants alone. Moreover, acquired resistance inevitably emerges, primarily due to RAF lesions that prevent inhibition of BRAF V600 with current treatments. Therefore, there is a need for new therapies that target other mechanisms of activated BRAF. In this study, we use the Proteolysis Targeting Chimera (PROTAC) technology, which promotes ubiquitination and degradation of neo-substrates, to address the limitations of BRAF inhibitor-based therapies. Using vemurafenib-based PROTACs, we achieve low  nanomolar degradation of all classes of BRAF mutants, but spare degradation of WT RAF family members. Our lead PROTAC outperforms vemurafenib in inhibiting cancer cell growth and shows in vivo efficacy in a Class 2 BRAF xenograft model. Mechanistic studies reveal that BRAFWT is spared due to weak ternary complex formation in cells owing to its quiescent inactivated conformation, and activation of BRAFWT sensitizes it to degradation. This study highlights the degree of selectivity achievable with degradation-based approaches by targeting mutant BRAF-driven cancers while sparing BRAFWT, providing an anti-tumor drug modality that expands the therapeutic window.
    DOI:  https://doi.org/10.1038/s41467-021-21159-7
  22. Nat Rev Urol. 2021 Feb 09.
    Tumour microenvironment markers predict risk of prostate cancer recurrence.
    Rebecca Tregunna.
      
    DOI:  https://doi.org/10.1038/s41585-021-00435-7
  23. Proc Natl Acad Sci U S A. 2021 Feb 16. pii: e2016602118. [Epub ahead of print]118(7):
    Learning the dynamics of cell-cell interactions in confined cell migration.
    David B Brückner, Nicolas Arlt, Alexandra Fink, Pierre Ronceray, Joachim O Rädler, Chase P Broedersz.
      The migratory dynamics of cells in physiological processes, ranging from wound healing to cancer metastasis, rely on contact-mediated cell-cell interactions. These interactions play a key role in shaping the stochastic trajectories of migrating cells. While data-driven physical formalisms for the stochastic migration dynamics of single cells have been developed, such a framework for the behavioral dynamics of interacting cells still remains elusive. Here, we monitor stochastic cell trajectories in a minimal experimental cell collider: a dumbbell-shaped micropattern on which pairs of cells perform repeated cellular collisions. We observe different characteristic behaviors, including cells reversing, following, and sliding past each other upon collision. Capitalizing on this large experimental dataset of coupled cell trajectories, we infer an interacting stochastic equation of motion that accurately predicts the observed interaction behaviors. Our approach reveals that interacting noncancerous MCF10A cells can be described by repulsion and friction interactions. In contrast, cancerous MDA-MB-231 cells exhibit attraction and antifriction interactions, promoting the predominant relative sliding behavior observed for these cells. Based on these experimentally inferred interactions, we show how this framework may generalize to provide a unifying theoretical description of the diverse cellular interaction behaviors of distinct cell types.
    Keywords:  cell migration; cell–cell interactions; contact inhibition of locomotion; stochastic inference
    DOI:  https://doi.org/10.1073/pnas.2016602118
  24. Cancers (Basel). 2021 Feb 10. pii: 717. [Epub ahead of print]13(4):
    Progression to Metastasis of Solid Cancer.
    Eldad Zacksenhaus, Sean E Egan.
      Metastatic dissemination of cancer cells, their colonization at distal sites, and ultimate disruption of tissue physiology are the root causes of most deaths from solid cancers, particularly in tumor types where the primary lesion can be easily dissected and discarded [...].
    DOI:  https://doi.org/10.3390/cancers13040717
  25. Cancers (Basel). 2021 Feb 10. pii: 723. [Epub ahead of print]13(4):
    Senolytics for Cancer Therapy: Is All That Glitters Really Gold?
    Valerie J Carpenter, Tareq Saleh, David A Gewirtz.
      Senolytics represent a group of mechanistically diverse drugs that can eliminate senescent cells, both in tumors and in several aging-related pathologies. Consequently, senolytic use has been proposed as a potential adjuvant approach to improve the response to senescence-inducing conventional and targeted cancer therapies. Despite the unequivocal promise of senolytics, issues of universality, selectivity, resistance, and toxicity remain to be further clarified. In this review, we attempt to summarize and analyze the current preclinical literature involving the use of senolytics in senescent tumor cell models, and to propose tenable solutions and future directions to improve the understanding and use of this novel class of drugs.
    Keywords:  ABT-263; adjuvant; cancer; chemotherapy; dormancy; navitoclax; recurrence; senescence; senolytic
    DOI:  https://doi.org/10.3390/cancers13040723
  26. Mol Cancer. 2021 02 08. 20(1): 30
    Selective treatment pressure in colon cancer drives the molecular profile of resistant circulating tumor cell clones.
    Laure Cayrefourcq, Frédéric Thomas, Thibault Mazard, Eric Assenat, Said Assou, Catherine Alix-Panabières.
      The characterization of circulating tumor cells (CTCs) holds promises for precision medicine because these cells are an important clinical indicator of treatment efficacy. We established the first and still only nine permanent colon CTC lines from peripheral blood samples of a patient with metastatic colon cancer collected at different time points during treatment and cancer progression. The study objectives were (i) to compare the gene expression profiles of these CTC lines, and (ii) to determine the main features acquired during treatment. The number of upregulated genes was higher in the CTC lines obtained after treatment, indicating that they acquired properties to escape treatment pressure. Among these upregulated genes, some are involved in the mTOR and PI3K/AKT signaling pathways. Moreover, cytidine deaminase expression was significantly increased in the CTC lines obtained after failure of the first- and second-line 5-fluorouracile-based treatments, suggesting that these CTCs can eliminate this specific drug and resist to therapy. Several enzymes involved in xenobiotic metabolism also were upregulated after treatment, suggesting the activation of detoxification mechanisms in response to chemotherapy. Finally, the significant higher expression of aldolase B in four of the six CTC lines obtained after treatment withdrawal and cancer progression indicated that these clones originated from liver metastases. In conclusion, these CTC lines generated at different time points during treatment of metastatic colon cancer in a single patient are characterized by the deregulation of different genes that promote (i) drug resistance, (ii) xenobiotic and energy metabolism, and (iii) stem cell properties and plasticity.
    Keywords:  ALDOB; CDA; Circulating tumor cells; Clonal evolution; Colon cancer; Gene expression
    DOI:  https://doi.org/10.1186/s12943-021-01326-6
  27. Cancer Discov. 2021 Feb 10. pii: candisc.1351.2020. [Epub ahead of print]
    Exploiting allosteric properties of RAF and MEK inhibitors to target therapy-resistant tumors driven by oncogenic BRAF signaling.
    Christos Adamopoulos, Tamer A Ahmed, Maxwell R Tucker, Peter M U Ung, Min Xiao, Zoi Karoulia, Angelo Amabile, Xuewei Wu, Stuart A Aaronson, Celina Ang, Vito W Rebecca, Brian D Brown, Avner Schlessinger, Meenhard Herlyn, Qi Wang, David E Shaw, Poulikos I Poulikakos.
      Current clinical RAF inhibitors (RAFi) inhibit monomeric BRAF (mBRAF), but are less potent against dimeric BRAF (dBRAF). RAFi equipotent for mBRAF and dBRAF have been developed, but are predicted to have lower therapeutic index. Here we identify a third class of RAFi that selectively inhibits dBRAF over mBRAF. Molecular Dynamic simulations reveal restriction of the movement of the BRAF αC-helix as the basis of inhibitor selectivity. Combination of inhibitors based on their conformation selectivity (mBRAF- plus dBRAF-selective plus the most potent BRAF-MEK disruptor MEK inhibitor) promoted suppression of tumor growth in BRAF(V600E) therapy-resistant models. Strikingly, the triple combination showed no toxicities, whereas dBRAF-selective plus MEK inhibitor treatment caused weight loss in mice. Finally, the triple combination achieved durable response and improved clinical wellbeing in a stage IV colorectal cancer patient. Thus, exploiting allosteric properties of RAF and MEK inhibitors enables the design of effective and well-tolerated therapies for BRAF(V600E) tumors.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1351
  28. Trends Cell Biol. 2021 Feb 03. pii: S0962-8924(21)00010-6. [Epub ahead of print]
    Fueling Cell Invasion through Extracellular Matrix.
    Aastha Garde, David R Sherwood.
      Cell invasion through extracellular matrix (ECM) has pivotal roles in cell dispersal during development, immune cell trafficking, and cancer metastasis. Many elegant studies have revealed the specialized cellular protrusions, proteases, and distinct modes of migration invasive cells use to overcome ECM barriers. Less clear, however, is how invasive cells provide energy, specifically ATP, to power the energetically demanding membrane trafficking, F-actin polymerization, and actomyosin machinery that mediate break down, remodeling, and movement through ECMs. Here, we provide an overview of the challenges of examining ATP generation and delivery within invading cells and how recent studies using diverse invasion models, experimental approaches, and energy biosensors are revealing that energy metabolism is an integral component of cell invasive behavior that is dynamically tuned to overcome the ECM environment.
    Keywords:  Cell invasion; adaptive ATP metabolism; extracellular matrix; glycolysis; mitochondrial localization; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.tcb.2021.01.006
  29. Cell Death Discov. 2020 Mar 11. 6(1): 12
    TFEB-mediated lysosomal biogenesis and lysosomal drug sequestration confer resistance to MEK inhibition in pancreatic cancer.
    Ben Zhao, Laura Dierichs, Jiang-Ning Gu, Marija Trajkovic-Arsic, Ralf Axel Hilger, Konstantinos Savvatakis, Silvia Vega-Rubin-de-Celis, Sven-Thorsten Liffers, Samuel Peña-Llopis, Diana Behrens, Stephan Hahn, Jens T Siveke, Smiths S Lueong.
      Oncogenic KRAS mutations are encountered in more than 90% of pancreatic ductal adenocarcinomas. MEK inhibition has failed to procure any clinical benefits in mutant RAS-driven cancers including pancreatic ductal adenocarcinoma (PDAC). To identify potential resistance mechanisms underlying MEK inhibitor (MEKi) resistance in PDAC, we investigated lysosomal drug accumulation in PDAC models both in vitro and in vivo. Mouse PDAC models and human PDAC cell lines as well as human PDAC xenografts treated with the MEK inhibitor trametinib or refametinib led to an enhanced expression of lysosomal markers and enrichment of lysosomal gene sets. A time-dependent, increase in lysosomal content was observed upon MEK inhibition. Strikingly, there was a strong activation of lysosomal biogenesis in cell lines of the classical compared to the basal-like molecular subtype. Increase in lysosomal content was associated with nuclear translocation of the Transcription Factor EB (TFEB) and upregulation of TFEB target genes. siRNA-mediated depletion of TFEB led to a decreased lysosomal biogenesis upon MEK inhibition and potentiated sensitivity. Using LC-MS, we show accumulation of MEKi in the lysosomes of treated cells. Therefore, MEK inhibition triggers lysosomal biogenesis and subsequent drug sequestration. Combined targeting of MEK and lysosomal function may improve sensitivity to MEK inhibition in PDAC.
    DOI:  https://doi.org/10.1038/s41420-020-0246-7
  30. STAR Protoc. 2021 Mar 19. 2(1): 100297
    Mouse model of colorectal cancer: orthotopic co-implantation of tumor and stroma cells in cecum and rectum.
    Hiroaki Kasashima, Angeles Duran, Tania Cid-Diaz, Yu Muta, Hiroto Kinoshita, Eduard Batlle, Maria T Diaz-Meco, Jorge Moscat.
      In vivo interrogation of the functional role of genes implicated in colorectal cancer (CRC) is limited by the need for physiological models that mimic the disease. Here, we describe a protocol that provides the steps required for the orthotopic co-implantation of tumoral and stromal cells into the cecum and rectum to investigate the crosstalk between the tumor and its microenvironment. This protocol recapitulates metastases to the lymph nodes, liver, and lungs observed in human CRC. For complete details on the use and execution of this protocol, please refer to Kasashima et al. (2020).
    Keywords:  Cancer; Model organisms; Organoids
    DOI:  https://doi.org/10.1016/j.xpro.2021.100297
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