bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2022‒08‒14
twenty papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology
  1. Metastasis.
  2. Chemotherapy treatment induces pro-invasive changes in liver ECM composition.
  3. The lung fibroblast as "soil fertilizer" in breast cancer metastasis.
  4. Therapy-induced senescence promotes breast cancer cells plasticity by inducing Lipocalin-2 expression.
  5. A Distinct Chromatin State Drives Therapeutic Resistance in Invasive Lobular Breast Cancer.
  6. p38 MAPK-dependent phosphorylation of transcription factor SOX2 promotes an adaptive response to BRAF inhibitors in melanoma cells.
  7. Targeting FAPα-expressing hepatic stellate cells overcomes resistance to anti-angiogenics in colorectal cancer liver metastasis models.
  8. BTLA+CD200+ B cells dictate the divergent immune landscape and immunotherapeutic resistance in metastatic vs. primary pancreatic cancer.
  9. Temporal profiling of the breast tumour microenvironment reveals collagen XII as a driver of metastasis.
  10. Use of ctDNA Guides Panitumumab Rechallenge Efficacy in Colorectal Cancer.
  11. Combined MEK and STAT3 inhibition uncovers stromal plasticity by enriching for cancer-associated fibroblasts with mesenchymal stem cell-like features to overcome immunotherapy resistance in pancreatic cancer.
  12. A genome-wide CRISPR-Cas9 knockout screen identifies novel PARP inhibitor resistance genes in prostate cancer.
  13. Antibody-drug teamwork tames deadly metastatic brain tumours.
  14. A complex epigenome-splicing crosstalk governs epithelial-to-mesenchymal transition in metastasis and brain development.
  15. TIPE3 is a candidate prognostic biomarker promoting tumor progression via elevating RAC1 in pancreatic cancer.
  16. MYC sensitises cells to apoptosis by driving energetic demand.
  17. Adenoviral-based vaccine promotes neoantigen-specific CD8+ T cell stemness and tumor rejection.
  18. Phosphoproteomics of primary AML patient samples reveals rationale for AKT combination therapy and p53 context to overcome selinexor resistance.
  19. Cancer cells hijack nerve cells to storm through the brain.
  20. Targeting Plk1 sensitizes pancreatic cancer to immune checkpoint therapy.
  1. Cancer Cell. 2022 Aug 08. pii: S1535-6108(22)00323-3. [Epub ahead of print]40(8): 787-791
    Metastasis.
    David Lyden, Cyrus M Ghajar, Ana Luísa Correia, Julio A Aguirre-Ghiso, Shang Cai, Maria Rescigno, Peiyuan Zhang, Guohong Hu, Sarah-Maria Fendt, Adrienne Boire, Ralph R Weichselbaum, Rohan R Katipally.
      Metastasis, the major cause of cancer death, represents one of the major challenges in oncology. Scientists are still trying to understand the biological basis underlying the dissemination and outgrowth of tumor cells, why these cells can remain dormant for years, how they become resistant to the immune system or cytotoxic effects of systemic therapy, and how they interact with their new microenvironment. We asked experts to discuss some of the unknowns, advances, and areas of opportunity related to cancer metastasis.
    DOI:  https://doi.org/10.1016/j.ccell.2022.07.010
  2. Matrix Biol. 2022 Aug 05. pii: S0945-053X(22)00096-8. [Epub ahead of print]
    Chemotherapy treatment induces pro-invasive changes in liver ECM composition.
    Justinne R Guarin, Jackson P Fatherree, Madeleine J Oudin.
      Metastasis accounts for 90% of cancer-related deaths, yet the mechanisms by which cancer cells colonize secondary organs remain poorly understood. For breast cancer patients, metastasis to the liver is associated with poor prognosis and a median survival of 6 months. Standard of care is chemotherapy, but recurrence occurs in 30% of patients. Systemic chemotherapy has been shown to induce hepatotoxicity and fibrosis, but how chemotherapy impacts the composition of the liver extracellular matrix (ECM) remains unknown. Individual ECM proteins drive tumor cell proliferation and invasion, features that are essential for metastatic outgrowth in the liver. First, we find that the ECM of livers isolated from chemotherapy-treated MMTV-PyMT mice increases the invasion, but not proliferation, of metastatic breast cancer cells. Proteomic analysis of the liver ECM identified Collagen V to be more abundant in paclitaxel-treated livers. We show that Collagen V increases cancer cell invasion via α1β1 integrins and MAPK signaling, while also increasing the alignment of Collagen I, which has been associated with increased invasion. Treatment with obtustatin, an inhibitor specific to α1β1 integrins, inhibits tumor cell invasion in decellularized ECM from paclitaxel-treated livers. Overall, we show chemotherapy treatment alters the liver microenvironment, priming it as a pro-metastatic niche for cancer metastasis.
    Keywords:  Breast Cancer; Chemotherapy; Collagens; Liver; Metastasis; Migration
    DOI:  https://doi.org/10.1016/j.matbio.2022.08.002
  3. Immunity. 2022 Aug 09. pii: S1074-7613(22)00344-2. [Epub ahead of print]55(8): 1336-1339
    The lung fibroblast as "soil fertilizer" in breast cancer metastasis.
    Julia M Houthuijzen, Karin E de Visser.
      Fibroblasts strongly impact tumor progression, but whether they prime the pre-metastatic niche is poorly understood. In this issue of Immunity, Gong and Li et al. identify lung-specific immunosuppressive fibroblasts, which are hijacked by breast cancer cells to facilitate metastasis.
    DOI:  https://doi.org/10.1016/j.immuni.2022.07.010
  4. Oncogene. 2022 Aug 11.
    Therapy-induced senescence promotes breast cancer cells plasticity by inducing Lipocalin-2 expression.
    Jorge Morales-Valencia, Lena Lau, Teresa Martí-Nin, Ugur Ozerdem, Gregory David.
      The acquisition of novel detrimental cellular properties following exposure to cytotoxic drugs leads to aggressive and metastatic tumors that often translates into an incurable disease. While the bulk of the primary tumor is eliminated upon exposure to chemotherapeutic treatment, residual cancer cells and non-transformed cells within the host can engage a stable cell cycle exit program named senescence. Senescent cells secrete a distinct set of pro-inflammatory factors, collectively termed the senescence-associated secretory phenotype (SASP). Upon exposure to the SASP, cancer cells undergo cellular plasticity resulting in increased proliferation, migration and epithelial-to-mesenchymal transition. The molecular mechanisms by which the SASP regulates these pro-tumorigenic features are poorly understood. Here, we report that breast cancer cells exposed to the SASP strongly upregulate Lipocalin-2 (LCN2). Furthermore, we demonstrate that LCN2 is critical for SASP-induced increased migration in breast cancer cells, and its inactivation potentiates the response to chemotherapeutic treatment in mouse models of breast cancer. Finally, we show that neoadjuvant chemotherapy treatment leads to LCN2 upregulation in residual human breast tumors, and correlates with worse overall survival. These findings provide the foundation for targeting LCN2 as an adjuvant therapeutic approach to prevent the emergence of aggressive tumors following chemotherapy.
    DOI:  https://doi.org/10.1038/s41388-022-02433-4
  5. Cancer Res. 2022 Aug 11. pii: CAN-21-3186. [Epub ahead of print]
    A Distinct Chromatin State Drives Therapeutic Resistance in Invasive Lobular Breast Cancer.
    Agostina Nardone, Xintao Qiu, Sandor Spisak, Zsuzsanna Nagy, Ariel Feiglin, Avery Feit, Gabriela Cohen Feit, Yingtian Xie, Alba Font-Tello, Cristina Guarducci, Francisco Hermida-Prado, Sudeepa Syamala, Klothilda Lim, Miguel Munoz Gomez, Matthew Pun, MacIntosh Cornwell, Weihan Liu, Aysegul Ors, Hisham Mohammed, Paloma Cejas, Jane B Brock, Matthew L Freedman, Eric P Winer, Xiaoyong Fu, Rachel Schiff, Henry W Long, Otto Metzger Filho, Rinath Jeselsohn.
      Most invasive lobular breast cancers (ILC) are of the luminal A subtype and are strongly hormone receptor positive. Yet, ILC is relatively resistant to tamoxifen and associated with inferior long-term outcomes compared to invasive ductal cancers (IDC). In this study, we sought to gain mechanistic insights into these clinical findings that are not explained by the genetic landscape of ILC and to identify strategies to improve patient outcomes. A comprehensive analysis of the epigenome of ILC in pre-clinical models and clinical samples showed that, compared to IDC, ILC harbored a distinct chromatin state linked to gained recruitment of FOXA1, a lineage-defining pioneer transcription factor. This resulted in an ILC-unique FOXA1-estrogen receptor (ER) axis that promoted the transcription of genes associated with tumor progression and poor outcomes. The ILC-unique FOXA1-ER axis led to retained ER chromatin binding after tamoxifen treatment, which facilitated tamoxifen resistance while remaining strongly dependent on ER signaling. Mechanistically, gained FOXA1 binding was associated with the auto-induction of FOXA1 in ILC through an ILC-unique FOXA1 binding site. Targeted silencing of this regulatory site resulted in the disruption of the feed-forward loop and growth inhibition in ILC. In summary, ILC is characterized by a unique chromatin state and FOXA1-ER axis that is associated with tumor progression, offering a novel mechanism of tamoxifen resistance. These results underscore the importance of conducting clinical trials dedicated to patients with ILC in order to optimize treatments in this breast cancer subtype.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3186
  6. J Biol Chem. 2022 Aug 06. pii: S0021-9258(22)00796-7. [Epub ahead of print] 102353
    p38 MAPK-dependent phosphorylation of transcription factor SOX2 promotes an adaptive response to BRAF inhibitors in melanoma cells.
    Silvia Pietrobono, Raffaella De Paolo, Domenico Mangiameli, Andrea Marranci, Ilaria Battisti, Cinzia Franchin, Giorgio Arrigoni, Davide Melisi, Laura Poliseno, Barbara Stecca.
      Despite recent advances in the development of BRAF kinase inhibitors (BRAFi) for BRAF-mutant melanomas, development of resistance remains a major clinical problem. In addition to genetic alterations associated with intrinsic resistance, several adaptive response mechanisms are known to be rapidly activated to allow cell survival in response to treatment, limiting efficacy. A better understanding of the mechanisms driving resistance is urgently needed to improve the success of BRAF-targeted therapies and to make therapeutic intervention more durable. In this study we identify the mitogen-activated protein kinase (MAPK) p38 as a novel mediator of the adaptive response of melanoma cells to BRAF-targeted therapy. Our findings demonstrate that BRAFi leads to an early increase in p38 activation, which promotes phosphorylation of the transcription factor SOX2 at Ser251, enhancing SOX2 stability, nuclear localization, and transcriptional activity. Furthermore, functional studies show that SOX2 depletion increases sensitivity of melanoma cells to BRAFi, whereas overexpression of a phosphomimetic SOX2-S251E mutant is sufficient to drive resistance and desensitize melanoma cells to BRAFi in vitro and in a Zebrafish xenograft model. We also found that SOX2 phosphorylation at serine 251 confers resistance to BRAFi by binding to the promoter and increasing transcriptional activation of the ATP-binding cassette (ABC) drug efflux transporter ABCG2. In summary, we unveil a p38/SOX2-mediated mechanism of adaptive response to BRAFi, which provides pro-survival signals to melanoma cells against the cytotoxic effects of BRAFi prior to acquiring resistance.
    Keywords:  BRAF inhibitor; SOX2; drug resistance; p38 MAPK
    DOI:  https://doi.org/10.1016/j.jbc.2022.102353
  7. J Clin Invest. 2022 Aug 11. pii: e157399. [Epub ahead of print]
    Targeting FAPα-expressing hepatic stellate cells overcomes resistance to anti-angiogenics in colorectal cancer liver metastasis models.
    Ming Qi, Shuran Fan, Maohua Huang, Jinghua Pan, Yong Li, Qun Miao, Wenyu Lyu, Xiaobo Li, Lijuan Deng, Shenghui Qiu, Tongzheng Liu, Weiqing Deng, Xiaodong Chu, Chang Jiang, Wenzhuo He, Liangping Xia, Yunlong Yang, Jian Hong, Qi Qi, Wenqian Yin, Xiangning Liu, Changzheng Shi, Minfeng Chen, Wencai Ye, Dongmei Zhang.
      Vessel co-option has been demonstrated to mediate colorectal cancer liver metastasis (CRCLM) resistance to anti-angiogenic therapy. The current mechanisms underlying vessel co-option have mainly focused on the "hijacker" tumor cells, whereas the function of the "hijackee" sinusoidal blood vessels has not been explored. Here, we found that the occurrence of vessel co-option in bevacizumab-resistant CRCLM xenografts was associated with increased expression of fibroblast activation protein alpha (FAPα) in the co-opted hepatic stellate cells (HSCs), which was dramatically attenuated in HSC-specific conditional Fap-knockout mice bearing CRCLM allografts. Mechanistically, bevacizumab treatment induced hypoxia to upregulate the expression of fibroblast growth factor-binding protein 1 (FGFBP1) in tumor cells. Gain- or loss-of-function experiments revealed that the bevacizumab-resistant tumor cell-derived FGFBP1 induced FAPα expression by enhancing the paracrine FGF2-FGFR1-ERK1/2-EGR1 signaling pathway in HSCs. FAPα promoted CXCL5 secretion in HSCs, which activated CXCR2 to promote the epithelial-mesenchymal transition of tumor cells and the recruitment of myeloid-derived suppressor cells. These findings were further validated in CRCLM patient-derived tumor tissues. Targeting FAPα+ HSCs effectively disrupted the co-opted sinusoidal blood vessels and overcame bevacizumab resistance. Our study highlights the role of FAPα+ HSCs in vessel co-option and provides an effective strategy to overcome the vessel co-option-mediated bevacizumab resistance.
    Keywords:  Colorectal cancer; Drug therapy; Gastroenterology; Pericytes; Therapeutics
    DOI:  https://doi.org/10.1172/JCI157399
  8. Oncogene. 2022 Aug 10.
    BTLA+CD200+ B cells dictate the divergent immune landscape and immunotherapeutic resistance in metastatic vs. primary pancreatic cancer.
    Brian Diskin, Salma Adam, Gustavo Sanchez Soto, Miguel Liria, Berk Aykut, Belen Sundberg, Eric Li, Joshua Leinwand, Ruonan Chen, Mirhee Kim, Ruben D Salas, Marcelo F Cassini, Chandan Buttar, Wei Wang, Mohammad Saad Farooq, Sorin A A Shadaloey, Gregor Werba, Amreek Fnu, Fan Yang, Carolina Hirsch, John Glinski, Angilee Panjwani, Yael Weitzner, Deirdre Cohen, George Miller.
      Response to cancer immunotherapy in primary versus metastatic disease has not been well-studied. We found primary pancreatic ductal adenocarcinoma (PDA) is responsive to diverse immunotherapies whereas liver metastases are resistant. We discovered divergent immune landscapes in each compartment. Compared to primary tumor, liver metastases in both mice and humans are infiltrated by highly anergic T cells and MHCIIloIL10+ macrophages that are unable to present tumor-antigen. Moreover, a distinctive population of CD24+CD44-CD40- B cells dominate liver metastases. These B cells are recruited to the metastatic milieu by Muc1hiIL18hi tumor cells, which are enriched >10-fold in liver metastases. Recruited B cells drive macrophage-mediated adaptive immune-tolerance via CD200 and BTLA. Depleting B cells or targeting CD200/BTLA enhanced macrophage and T-cell immunogenicity and enabled immunotherapeutic efficacy of liver metastases. Our data detail the mechanistic underpinnings for compartment-specific immunotherapy-responsiveness and suggest that primary PDA models are poor surrogates for evaluating immunity in advanced disease.
    DOI:  https://doi.org/10.1038/s41388-022-02425-4
  9. Nat Commun. 2022 Aug 06. 13(1): 4587
    Temporal profiling of the breast tumour microenvironment reveals collagen XII as a driver of metastasis.
    Michael Papanicolaou, Amelia L Parker, Michelle Yam, Elysse C Filipe, Sunny Z Wu, Jessica L Chitty, Kaitlin Wyllie, Emmi Tran, Ellie Mok, Audrey Nadalini, Joanna N Skhinas, Morghan C Lucas, David Herrmann, Max Nobis, Brooke A Pereira, Andrew M K Law, Lesley Castillo, Kendelle J Murphy, Anaiis Zaratzian, Jordan F Hastings, David R Croucher, Elgene Lim, Brian G Oliver, Fatima Valdes Mora, Benjamin L Parker, David Gallego-Ortega, Alexander Swarbrick, Sandra O'Toole, Paul Timpson, Thomas R Cox.
      The tumour stroma, and in particular the extracellular matrix (ECM), is a salient feature of solid tumours that plays a crucial role in shaping their progression. Many desmoplastic tumours including breast cancer involve the significant accumulation of type I collagen. However, recently it has become clear that the precise distribution and organisation of matrix molecules such as collagen I is equally as important in the tumour as their abundance. Cancer-associated fibroblasts (CAFs) coexist within breast cancer tissues and play both pro- and anti-tumourigenic roles through remodelling the ECM. Here, using temporal proteomic profiling of decellularized tumours, we interrogate the evolving matrisome during breast cancer progression. We identify 4 key matrisomal clusters, and pinpoint collagen type XII as a critical component that regulates collagen type I organisation. Through combining our proteomics with single-cell transcriptomics, and genetic manipulation models, we show how CAF-secreted collagen XII alters collagen I organisation to create a pro-invasive microenvironment supporting metastatic dissemination. Finally, we show in patient cohorts that collagen XII may represent an indicator of breast cancer patients at high risk of metastatic relapse.
    DOI:  https://doi.org/10.1038/s41467-022-32255-7
  10. Cancer Discov. 2022 Aug 12. OF1
    Use of ctDNA Guides Panitumumab Rechallenge Efficacy in Colorectal Cancer.
      Use of ctDNA can effectively guide panitumumab rechallenge in metastatic colorectal cancer.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-145
  11. Gastroenterology. 2022 Aug 07. pii: S0016-5085(22)00905-2. [Epub ahead of print]
    Combined MEK and STAT3 inhibition uncovers stromal plasticity by enriching for cancer-associated fibroblasts with mesenchymal stem cell-like features to overcome immunotherapy resistance in pancreatic cancer.
    Jashodeep Datta, Xizi Dai, Anna Bianchi, Iago De Castro Silva, Siddharth Mehra, Vanessa Garrido, Purushottam Lamichhane, Samara Singh, Zhiqun Zhou, Austin R Dosch, Fanuel Messaggio, Yuguang Ban, Oliver Umland, Peter J Hosein, Nagaraj S Nagathihalli, Nipun B Merchant.
      BACKGROUND: We have shown that reciprocally activated RAS/MEK and JAK/STAT3 pathways mediate therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC), while combined MEK and STAT3 inhibition (MEKi+STAT3i) overcomes such resistance and alters stromal architecture. We now determine if MEKi+STAT3i reprograms the cancer-associated fibroblast (CAF) and immune microenvironment to overcome resistance to immune checkpoint inhibition in PDAC.METHODS: CAF and immune cell transcriptomes in MEKi (trametinib)+STAT3i(ruxolitinib)- vs. vehicle-treated Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) tumors were examined via single-cell RNA sequencing (scRNAseq). CRISPR/Cas9-silencing of CAF-restricted Map2k1/Mek1 and/or Stat3 enabled interrogation of CAF-dependent effects on immunologic remodeling in orthotopic models. Tumor growth, survival, and immune profiling via time-of-flight mass cytometry were examined in PKT mice treated with vehicle, anti-PD1 monotherapy, and MEKi+STAT3i combined with anti-PD1.
    RESULTS: MEKi+STAT3i attenuates Il6/Cxcl1-expressing pro-inflammatory and Lrrc15-expressing myofibroblastic CAF phenotypes while enriching for Ly6a/Cd34-expressing CAFs exhibiting mesenchymal stem cell-like features via scRNAseq in PKT mice. This CAF plasticity is associated with M2-to-M1 reprogramming of tumor-associated macrophages, and enhanced trafficking of CD8+ T-cells which exhibit distinct effector transcriptional programs. These MEKi+STAT3i-induced effects appear CAF-dependent, since CAF-restricted Mek1/Stat3 silencing mitigates inflammatory-CAF polarization and myeloid infiltration in-vivo. Addition of MEKi+STAT3i to PD-1 blockade not only dramatically improves anti-tumor responses and survival in PKT mice, but also augments recruitment of activated/memory T-cells while improving their degranulating and cytotoxic capacity, compared with anti-PD-1 monotherapy. Importantly, treatment of a patient with chemotherapy-refractory metastatic PDAC with MEKi (Trametinib), STAT3i (Ruxolitinib), and PD-1 inhibitor (Nivolumab) yielded clinical benefit.
    CONCLUSIONS: Combined MEKi+STAT3i mitigates stromal inflammation and enriches for CAF phenotypes with mesenchymal stem cell-like properties to overcome immunotherapy resistance in PDAC.
    Keywords:  Pancreatic ductal adenocarcinoma; immune checkpoint inhibition; immunotherapy; mesenchymal stem cell; stromal plasticity
    DOI:  https://doi.org/10.1053/j.gastro.2022.07.076
  12. Oncogene. 2022 Aug 06.
    A genome-wide CRISPR-Cas9 knockout screen identifies novel PARP inhibitor resistance genes in prostate cancer.
    Malene Blond Ipsen, Ea Marie Givskov Sørensen, Emil Aagaard Thomsen, Simone Weiss, Jakob Haldrup, Anders Dalby, Johan Palmfeldt, Peter Bross, Martin Rasmussen, Jacob Fredsøe, Søren Klingenberg, Mads R Jochumsen, Kirsten Bouchelouche, Benedicte Parm Ulhøi, Michael Borre, Jacob Giehm Mikkelsen, Karina Dalsgaard Sørensen.
      DNA repair gene mutations are frequent in castration-resistant prostate cancer (CRPC), suggesting eligibility for poly(ADP-ribose) polymerase inhibitor (PARPi) treatment. However, therapy resistance is a major clinical challenge and genes contributing to PARPi resistance are poorly understood. Using a genome-wide CRISPR-Cas9 knockout screen, this study aimed at identifying genes involved in PARPi resistance in CRPC. Based on the screen, we identified PARP1, and six novel candidates associated with olaparib resistance upon knockout. For validation, we generated multiple knockout populations/clones per gene in C4 and/or LNCaP CRPC cells, which confirmed that loss of PARP1, ARH3, YWHAE, or UBR5 caused olaparib resistance. PARP1 or ARH3 knockout caused cross-resistance to other PARPis (veliparib and niraparib). Furthermore, PARP1 or ARH3 knockout led to reduced autophagy, while pharmacological induction of autophagy partially reverted their PARPi resistant phenotype. Tumor RNA sequencing of 126 prostate cancer patients identified low ARH3 expression as an independent predictor of recurrence. Our results advance the understanding of PARPi response by identifying four novel genes that contribute to PARPi sensitivity in CRPC and suggest a new model of PARPi resistance through decreased autophagy.
    DOI:  https://doi.org/10.1038/s41388-022-02427-2
  13. Nature. 2022 Aug 08.
    Antibody-drug teamwork tames deadly metastatic brain tumours.
      
    Keywords:  Cancer
    DOI:  https://doi.org/10.1038/d41586-022-02131-x
  14. Nat Cell Biol. 2022 Aug;24(8): 1265-1277
    A complex epigenome-splicing crosstalk governs epithelial-to-mesenchymal transition in metastasis and brain development.
    Sanjeeb Kumar Sahu, Eneritz Agirre, Mohammed Inayatullah, Arun Mahesh, Neha Tiwari, Deborah P Lavin, Aditi Singh, Susanne Strand, Mustafa Diken, Reini F Luco, Juan Carlos Izpisua Belmonte, Vijay K Tiwari.
      Epithelial-to-mesenchymal transition (EMT) renders epithelial cells migratory properties. While epigenetic and splicing changes have been implicated in EMT, the mechanisms governing their crosstalk remain poorly understood. Here we discovered that a C2H2 zinc finger protein, ZNF827, is strongly induced during various contexts of EMT, including in brain development and breast cancer metastasis, and is required for the molecular and phenotypic changes underlying EMT in these processes. Mechanistically, ZNF827 mediated these responses by orchestrating a large-scale remodelling of the splicing landscape by recruiting HDAC1 for epigenetic modulation of distinct genomic loci, thereby slowing RNA polymerase II progression and altering the splicing of genes encoding key EMT regulators in cis. Our findings reveal an unprecedented complexity of crosstalk between epigenetic landscape and splicing programme in governing EMT and identify ZNF827 as a master regulator coupling these processes during EMT in brain development and breast cancer metastasis.
    DOI:  https://doi.org/10.1038/s41556-022-00971-3
  15. Mol Cancer. 2022 08 09. 21(1): 160
    TIPE3 is a candidate prognostic biomarker promoting tumor progression via elevating RAC1 in pancreatic cancer.
    Zequn Li, Shougen Cao, Yuqi Sun, Zhaojian Niu, Xiaodong Liu, Jun Niu, Yanbing Zhou.
      
    DOI:  https://doi.org/10.1186/s12943-022-01626-5
  16. Nat Commun. 2022 Aug 09. 13(1): 4674
    MYC sensitises cells to apoptosis by driving energetic demand.
    Joy Edwards-Hicks, Huizhong Su, Maurizio Mangolini, Kubra K Yoneten, Jimi Wills, Giovanny Rodriguez-Blanco, Christine Young, Kevin Cho, Heather Barker, Morwenna Muir, Ania Naila Guerrieri, Xue-Feng Li, Rachel White, Piotr Manasterski, Elena Mandrou, Karen Wills, Jingyu Chen, Emily Abraham, Kianoosh Sateri, Bin-Zhi Qian, Peter Bankhead, Mark Arends, Noor Gammoh, Alex von Kriegsheim, Gary J Patti, Andrew H Sims, Juan Carlos Acosta, Valerie Brunton, Kamil R Kranc, Maria Christophorou, Erika L Pearce, Ingo Ringshausen, Andrew J Finch.
      The MYC oncogene is a potent driver of growth and proliferation but also sensitises cells to apoptosis, which limits its oncogenic potential. MYC induces several biosynthetic programmes and primary cells overexpressing MYC are highly sensitive to glutamine withdrawal suggesting that MYC-induced sensitisation to apoptosis may be due to imbalance of metabolic/energetic supply and demand. Here we show that MYC elevates global transcription and translation, even in the absence of glutamine, revealing metabolic demand without corresponding supply. Glutamine withdrawal from MRC-5 fibroblasts depletes key tricarboxylic acid (TCA) cycle metabolites and, in combination with MYC activation, leads to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses reveal that glutamine supports viability through TCA cycle energetics rather than asparagine biosynthesis and that TCA cycle inhibition confers tumour suppression on MYC-driven lymphoma in vivo. In summary, glutamine supports the viability of MYC-overexpressing cells through an energetic rather than a biosynthetic mechanism.
    DOI:  https://doi.org/10.1038/s41467-022-32368-z
  17. Sci Transl Med. 2022 Aug 10. 14(657): eabo7604
    Adenoviral-based vaccine promotes neoantigen-specific CD8+ T cell stemness and tumor rejection.
    Anna Morena D'Alise, Nadia Brasu, Carlo De Intinis, Guido Leoni, Valentina Russo, Francesca Langone, Denis Baev, Elisa Micarelli, Luca Petiti, Simone Picelli, Marwan Fakih, Dung T Le, Michael J Overman, Anthony F Shields, Katrina S Pedersen, Manish A Shah, Sarbajit Mukherjee, Thea Faivre, Patricia Delaite, Elisa Scarselli, Luigia Pace.
      Upon chronic antigen exposure, CD8+ T cells become exhausted, acquiring a dysfunctional state correlated with the inability to control infection or tumor progression. In contrast, stem-like CD8+ T progenitors maintain the ability to promote and sustain effective immunity. Adenovirus (Ad)-vectored vaccines encoding tumor neoantigens have been shown to eradicate large tumors when combined with anti-programmed cell death protein 1 (αPD-1) in murine models; however, the mechanisms and translational potential have not yet been elucidated. Here, we show that gorilla Ad vaccine targeting tumor neoepitopes enhances responses to αPD-1 therapy by improving immunogenicity and antitumor efficacy. Single-cell RNA sequencing demonstrated that the combination of Ad vaccine and αPD-1 increased the number of murine polyfunctional neoantigen-specific CD8+ T cells over αPD-1 monotherapy, with an accumulation of Tcf1+ stem-like progenitors in draining lymph nodes and effector CD8+ T cells in tumors. Combined T cell receptor (TCR) sequencing analysis highlighted a broader spectrum of neoantigen-specific CD8+ T cells upon vaccination compared to αPD-1 monotherapy. The translational relevance of these data is supported by results obtained in the first 12 patients with metastatic deficient mismatch repair (dMMR) tumors vaccinated with an Ad vaccine encoding shared neoantigens. Expansion and diversification of TCRs were observed in post-treatment biopsies of patients with clinical response, as well as an increase in tumor-infiltrating T cells with an effector memory signature. These findings indicate a promising mechanism to overcome resistance to PD-1 blockade by promoting immunogenicity and broadening the spectrum and magnitude of neoantigen-specific T cells infiltrating tumors.
    DOI:  https://doi.org/10.1126/scitranslmed.abo7604
  18. Cell Rep. 2022 Aug 09. pii: S2211-1247(22)00990-1. [Epub ahead of print]40(6): 111177
    Phosphoproteomics of primary AML patient samples reveals rationale for AKT combination therapy and p53 context to overcome selinexor resistance.
    Kristina B Emdal, Nicolàs Palacio-Escat, Caroline Wigerup, Akihiro Eguchi, Helén Nilsson, Dorte B Bekker-Jensen, Lars Rönnstrand, Julhash U Kazi, Alexandre Puissant, Raphaël Itzykson, Julio Saez-Rodriguez, Kristina Masson, Peter Blume-Jensen, Jesper V Olsen.
      Acute myeloid leukemia (AML) is a heterogeneous disease with variable patient responses to therapy. Selinexor, an inhibitor of nuclear export, has shown promising clinical activity for AML. To identify the molecular context for monotherapy sensitivity as well as rational drug combinations, we profile selinexor signaling responses using phosphoproteomics in primary AML patient samples and cell lines. Functional phosphosite scoring reveals that p53 function is required for selinexor sensitivity consistent with enhanced efficacy of selinexor in combination with the MDM2 inhibitor nutlin-3a. Moreover, combining selinexor with the AKT inhibitor MK-2206 overcomes dysregulated AKT-FOXO3 signaling in resistant cells, resulting in synergistic anti-proliferative effects. Using high-throughput spatial proteomics to profile subcellular compartments, we measure global proteome and phospho-proteome dynamics, providing direct evidence of nuclear translocation of FOXO3 upon combination treatment. Our data demonstrate the potential of phosphoproteomics and functional phosphorylation site scoring to successfully pinpoint key targetable signaling hubs for rational drug combinations.
    Keywords:  CP: Cancer; CP: Molecular biology; MK-2206; acute myeloid leukemia; combination therapy; drug resistance; functional scoring; mass spectrometry; nutlin-3a; phosphoproteomics; selinexor; subcellular proteomics
    DOI:  https://doi.org/10.1016/j.celrep.2022.111177
  19. Nature. 2022 Aug;608(7922): 242
    Cancer cells hijack nerve cells to storm through the brain.
      
    Keywords:  Cancer
    DOI:  https://doi.org/10.1038/d41586-022-02098-9
  20. Cancer Res. 2022 Aug 11. pii: CAN-22-0018. [Epub ahead of print]
    Targeting Plk1 sensitizes pancreatic cancer to immune checkpoint therapy.
    Zhuangzhuang Zhang, Lijun Cheng, Jie Li, Qi Qiao, Anju Karki, Derek B Allison, Nuha Shaker, Kunyu Li, Sagar M Utturkar, Nadia M Atallah Lanman, Xiongjian Rao, Piotr Rychahou, Daheng He, Stephen F Konieczny, Chi Wang, Qing Shao, B Mark Evers, Xiaoqi Liu.
      Polo-like kinase 1 (Plk1) plays an important role in cell cycle regulation. Recent work has suggested that Plk1 could be a biomarker of gemcitabine response in pancreatic ductal adenocarcinoma (PDAC). Although targeting Plk1 to treat PDAC has been attempted in clinical trials, the results were not promising, and the mechanisms of resistance to Plk1 inhibition is poorly understood. In addition, the role of Plk1 in PDAC progression requires further elucidation. Here, we showed that Plk1 was associated with poor outcomes in PDAC patients. In an inducible transgenic mouse line with specific expression of Plk1 in the pancreas, Plk1 overexpression significantly inhibited caerulein-induced acute pancreatitis and delayed development of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). Bioinformatics analyses identified the regulatory networks in which Plk1 is involved in PDAC disease progression, including multiple inflammation-related pathways. Unexpectedly, inhibition or depletion of Plk1 resulted in upregulation of PD-L1 via activation of the NFκB pathway. Mechanistically, Plk1-mediated phosphorylation of RB at S758 inhibited the translocation of NFκB to nucleus, inactivating the pathway. Inhibition of Plk1 sensitized PDAC to immune checkpoint blockade therapy through activation of an anti-tumor immune response. Together, Plk1 suppresses PDAC progression and inhibits NFκB activity, and targeting Plk1 can potentiate the efficacy of immunotherapy in PDAC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0018
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