bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒06‒14
twenty-one papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology


  1. Mol Cancer Res. 2020 Jun 08. pii: molcanres.0046.2020. [Epub ahead of print]
    Ross C, Szczepanek K, Lee M, Yang H, Peer CJ, Kindrick J, Shankarappa P, Lin ZW, Sanford J, Figg WD, Hunter KW.
      Breast cancer metastasis is a leading cause of cancer-related death of women in the U.S. A hurdle in advancing metastasis-targeted intervention is the phenotypic heterogeneity between primary and secondary lesions. To identify metastasis-specific gene expression profiles we performed RNA sequencing of breast cancer mouse models; analyzing metastases from models of various drivers and routes. We contrasted the models and identified common, targetable signatures. Allograft models exhibited more mesenchymal-like gene expression than genetically engineered mouse models (GEMMs), and primary culturing of GEMM-derived metastatic tissue induced mesenchymal-like gene expression. Additionally, metastasis-specific transcriptomes differed between tail vein and orthotopic injection of the same cell line. Gene expression common to models of spontaneous metastasis included sildenafil response and nicotine degradation pathways. Strikingly, In vivo sildenafil treatment significantly reduced metastasis 54% while nicotine significantly increased metastasis 46%. These data suggest that (i) actionable metastasis-specific pathways can be readily identified, (ii) already-available drugs may have great potential to alleviate metastatic incidence, and (iii) metastasis may be influenced greatly by lifestyle choices such as the choice to consume nicotine products. In summary, while mouse models of breast cancer metastasis vary in in ways that must not be ignored, there are shared features that can be identified and potentially targeted therapeutically. Implications: The data we present here exposes critical variances between pre-clinical models of metastatic breast cancer and identifies targetable pathways integral to metastatic spread.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-20-0046
  2. Nature. 2020 Jun 11.
    Yang L, Liu Q, Zhang X, Liu X, Zhou B, Chen J, Huang D, Li J, Li H, Chen F, Liu J, Xing Y, Chen X, Su S, Song E.
      Neutrophil extracellular traps (NETs), which consist of chromatin DNA filaments coated with granule proteins, are released by neutrophils to trap microorganisms1-3. Recent studies have suggested that the DNA component of NETs (NET-DNA) is associated with cancer metastasis in mouse models4-6. However, the functional role and clinical importance of NET-DNA in metastasis in patients with cancer remain unclear. Here we show that NETs are abundant in the liver metastases of patients with breast and colon cancers, and that serum NETs can predict the occurrence of liver metastases in patients with early-stage breast cancer. NET-DNA acts as a chemotactic factor to attract cancer cells, rather than merely acting as a 'trap' for them; in several mouse models, NETs in the liver or lungs were found to attract cancer cells to form distant metastases. We identify the transmembrane protein CCDC25 as a NET-DNA receptor on cancer cells that senses extracellular DNA and subsequently activates the ILK-β-parvin pathway to enhance cell motility. NET-mediated metastasis is abrogated in CCDC25-knockout cells. Clinically, we show that the expression of CCDC25 on primary cancer cells is closely associated with a poor prognosis for patients. Overall, we describe a transmembrane DNA receptor that mediates NET-dependent metastasis, and suggest that targeting CCDC25 could be an appealing therapeutic strategy for the prevention of cancer metastasis.
    DOI:  https://doi.org/10.1038/s41586-020-2394-6
  3. Cancer Discov. 2020 Jun 12.
    Recondo G, Che J, Jänne PA, Awad MM.
      Aberrant MET signaling can drive tumorigenesis in several cancer types through a variety of molecular mechanisms including MET gene amplification, mutation, rearrangement, and overexpression. Improvements in biomarker discovery and testing have more recently enabled the selection of patients with MET-dependent cancers for treatment with potent, specific, and novel MET-targeting therapies. We review the known oncologic processes that activate MET, discuss therapeutic strategies for MET-dependent malignancies, and highlight emerging challenges in acquired drug resistance in these cancers. SIGNIFICANCE: Increasing evidence supports the use of MET-targeting therapies in biomarker-selected cancers that harbor molecular alterations in MET. Diverse mechanisms of resistance to MET inhibitors will require the development of novel strategies to delay and overcome drug resistance.
    DOI:  https://doi.org/10.1158/2159-8290.CD-19-1446
  4. Cancer Cell. 2020 Jun 08. pii: S1535-6108(20)30255-5. [Epub ahead of print]37(6): 800-817.e7
    Shen Y, Wang X, Lu J, Salfenmoser M, Wirsik NM, Schleussner N, Imle A, Freire Valls A, Radhakrishnan P, Liang J, Wang G, Muley T, Schneider M, Ruiz de Almodovar C, Diz-Muñoz A, Schmidt T.
      Tumors are influenced by the mechanical properties of their microenvironment. Using patient samples and atomic force microscopy, we found that tissue stiffness is higher in liver metastases than in primary colorectal tumors. Highly activated metastasis-associated fibroblasts increase tissue stiffness, which enhances angiogenesis and anti-angiogenic therapy resistance. Drugs targeting the renin-angiotensin system, normally prescribed to treat hypertension, inhibit fibroblast contraction and extracellular matrix deposition, thereby reducing liver metastases stiffening and increasing the anti-angiogenic effects of bevacizumab. Patients treated with bevacizumab showed prolonged survival when concomitantly treated with renin-angiotensin inhibitors, highlighting the importance of modulating the mechanical microenvironment for therapeutic regimens.
    Keywords:  CAFs; MAFs; RAS signaling; anti-angiogenic therapy; atomic force microscopy; bevacizumab; fibroblasts; metastatic colorectal cancer; tissue stiffness
    DOI:  https://doi.org/10.1016/j.ccell.2020.05.005
  5. Cancer Cell. 2020 Jun 08. pii: S1535-6108(20)30261-0. [Epub ahead of print]37(6): 754-755
    Zhang J, Reinhart-King CA.
      Tissue stiffening plays a critical role in cancer progression. In this issue of Cancer Cell, Shen et al. demonstrated that highly activated fibroblasts in metastatic colorectal cancer increase tissue stiffness and angiogenesis. Targeting tissue stiffness improves the outcome of anti-angiogenic therapy and prolongs patient survival.
    DOI:  https://doi.org/10.1016/j.ccell.2020.05.011
  6. Elife. 2020 Jun 09. pii: e53367. [Epub ahead of print]9
    Hastings JF, Gonzalez Rajal A, Latham SL, Han JZ, McCloy RA, O'Donnell YE, Phimmachanh M, Murphy AD, Nagrial A, Daneshvar D, Chin V, Watkins DN, Burgess A, Croucher DR.
      The identification of clinically viable strategies for overcoming resistance to platinum chemotherapy in lung adenocarcinoma has previously been hampered by inappropriately tailored in vitro assays of drug response. Therefore, using a pulse model that closely mimics the in vivo pharmacokinetics of platinum therapy, we profiled cisplatin-induced signalling, DNA-damage and apoptotic responses across a panel of human lung adenocarcinoma cell lines. By coupling this data to real-time, single-cell imaging of cell cycle and apoptosis we provide a fine-grained stratification of response, where a P70S6K-mediated signalling axis promotes resistance on a TP53 wildtype or null background, but not a mutant TP53 background. This finding highlights the value of in vitro models that match the physiological pharmacokinetics of drug exposure. Furthermore, it also demonstrates the importance of a mechanistic understanding of the interplay between somatic mutations and the signalling networks that govern drug response for the implementation of any consistently effective, patient-specific therapy.
    Keywords:  P70S6K; cancer biology; chemoresistance; human; lung adenocarcinoma; p53; platinum chemotherapy; signalling dynamics
    DOI:  https://doi.org/10.7554/eLife.53367
  7. Cell Death Discov. 2020 ;6 42
    Cheteh EH, Sarne V, Ceder S, Bianchi J, Augsten M, Rundqvist H, Egevad L, Östman A, Wiman KG.
      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.
    Keywords:  Cancer microenvironment; Cancer therapeutic resistance; Tumour-suppressor proteins
    DOI:  https://doi.org/10.1038/s41420-020-0272-5
  8. Proc Natl Acad Sci U S A. 2020 Jun 12. pii: 201910278. [Epub ahead of print]
    Zhu N, Zhang J, Du Y, Qin X, Miao R, Nan J, Chen X, Sun J, Zhao R, Zhang X, Shi L, Li X, Lin Y, Wei W, Mao A, Zhang Z, Stark GR, Wang Y, Yang J.
      Tamoxifen, a widely used modulator of the estrogen receptor (ER), targets ER-positive breast cancer preferentially. We used a powerful validation-based insertion mutagenesis method to find that expression of a dominant-negative, truncated form of the histone deacetylase ZIP led to resistance to tamoxifen. Consistently, increased expression of full-length ZIP gives the opposite phenotype, inhibiting the expression of genes whose products mediate resistance. An important example is JAK2 By binding to two specific sequences in the promoter, ZIP suppresses JAK2 expression. Increased expression and activation of JAK2 when ZIP is inhibited lead to increased STAT3 phosphorylation and increased resistance to tamoxifen, both in cell culture experiments and in a mouse xenograft model. Furthermore, data from human tumors are consistent with the conclusion that decreased expression of ZIP leads to resistance to tamoxifen in ER-positive breast cancer.
    Keywords:  JAK/STAT; VBIM; ZIP; tamoxifen resistance
    DOI:  https://doi.org/10.1073/pnas.1910278117
  9. Mol Cancer Res. 2020 Jun 08. pii: molcanres.0051.2020. [Epub ahead of print]
    Schnepp PM, Shelley G, Dai J, Wakim N, Jiang H, Mizokami A, Keller ET.
      The majority of prostate cancer (PCa) patients treated with docetaxel develop resistance to it. In order to better understand the mechanism behind the acquisition of resistance, we conducted single cell RNA sequencing (scRNA-seq) of docetaxel sensitive and resistant variants of DU145 and PC3 PCa cell lines. Overall, sensitive and resistant cells clustered separately. Differential gene expression analysis between resistant and sensitive cells revealed 182 differentially expressed genes common to both PCa cell lines. A subset of these genes gave a gene expression profile in the resistant-transcriptome-like sensitive cells similar to the resistant cells. Exploration for functional gene pathways identified 218 common pathways between the two cell lines. Protein ubiquitination was the most differentially regulated pathway and was enriched in the resistant cells. Transcriptional regulator analysis identified potential 321 regulators across both cell lines. One of the top regulators identified was nuclear protein 1 (NUPR1). In contrast to the single cell analysis, bulk analysis of the cells did not reveal NUPR1 as a promising candidate. Knockdown and overexpression of NUPR1 in the PCa cells demonstrated that NUPR1 confers docetaxel resistance in both cell lines. Collectively, these data demonstrate the utility of scRNA-seq to identify regulators of drug resistance. Furthermore, NUPR1 was identified as a mediator of PCa drug resistance, which provides the rationale to explore NUPR1 and its target genes to for reversal of docetaxel resistance. Implications: Using single cell sequencing of PCa, we show that NUPR1 plays a role in docetaxel resistance.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-20-0051
  10. Cancer Discov. 2020 Jun 12.
      The small-molecule tyrosine kinase inhibitor tucatinib outperformed placebo against brain metastases.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-087
  11. Cancer Discov. 2020 Jun 12.
      MTOR was a critical node modulating stress-induced mutagenesis (SIM) in cancer in vitro and in vivo.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-090
  12. Cancers (Basel). 2020 Jun 09. pii: E1503. [Epub ahead of print]12(6):
    Gomez MK, Illuzzi G, Colomer C, Churchman M, Hollis RL, O'Connor MJ, Gourley C, Leo E, Melton DW.
      High grade serous ovarian cancer (HGSOC) is a major cause of female cancer mortality. The approval of poly (ADP-ribose) polymerase (PARP) inhibitors for clinical use has greatly improved treatment options for patients with homologous recombination repair (HRR)-deficient HGSOC, although the development of PARP inhibitor resistance in some patients is revealing limitations to outcome. A proportion of patients with HRR-proficient cancers also benefit from PARP inhibitor therapy. Our aim is to compare mechanisms of resistance to the PARP inhibitor olaparib in these two main molecular categories of HGSOC and investigate a way to overcome resistance that we considered particularly suited to a cancer like HGSOC, where there is a very high incidence of TP53 gene mutation, making HGSOC cells heavily reliant on the G2 checkpoint for repair of DNA damage and survival. We identified alterations in multiple factors involved in resistance to PARP inhibition in both HRR-proficient and -deficient cancers. The most frequent change was a major reduction in levels of poly (ADP-ribose) glycohydrolase (PARG), which would be expected to preserve a residual PARP1-initiated DNA damage response to DNA single-strand breaks. Other changes seen would be expected to boost levels of HRR of DNA double-strand breaks. Growth of all olaparib-resistant clones isolated could be controlled by WEE1 kinase inhibitor AZD1775, which inactivates the G2 checkpoint. Our work suggests that use of the WEE1 kinase inhibitor could be a realistic therapeutic option for patients that develop resistance to olaparib.
    Keywords:  DNA repair; PARP inhibitor; WEE1 kinase; olaparib; ovarian cancer; resistance mechanism
    DOI:  https://doi.org/10.3390/cancers12061503
  13. Cell Rep. 2020 Jun 09. pii: S2211-1247(20)30711-7. [Epub ahead of print]31(10): 107731
    Berthenet K, Castillo Ferrer C, Fanfone D, Popgeorgiev N, Neves D, Bertolino P, Gibert B, Hernandez-Vargas H, Ichim G.
      Triggering apoptosis remains an efficient strategy to treat cancer. However, apoptosis is no longer a final destination since cancer cells can undergo partial apoptosis without dying. Recent evidence shows that partial mitochondrial permeabilization and non-lethal caspase activation occur under certain circumstances, although it remains unclear how failed apoptosis affects cancer cells. Using a cancer cell model to trigger non-lethal caspase activation, we find that melanoma cancer cells undergoing failed apoptosis have a particular transcriptomic signature associated with focal adhesions, transendothelial migration, and modifications of the actin cytoskeleton. In line with this, cancer cells surviving apoptosis gain migration and invasion properties in vitro and in vivo. We further demonstrate that failed apoptosis-associated gain in invasiveness is regulated by the c-Jun N-terminal kinase (JNK) pathway, whereas its RNA sequencing signature is found in metastatic melanoma. These findings advance our understanding of how cell death can both cure and promote cancer.
    Keywords:  caspase reporter; failed apoptosis; invasion; melanoma; metastasis; migration
    DOI:  https://doi.org/10.1016/j.celrep.2020.107731
  14. Clin Cancer Res. 2020 Jun 11. pii: clincanres.3840.2019. [Epub ahead of print]
    Huang M, He M, Guo Y, Li H, Shen S, Xie Y, Li X, Xiao H, Fang L, Li D, Peng B, Liang LJ, Yu J, Kuang M, Xu L, Peng S.
      PURPOSE: Immune checkpoint inhibitor therapy is emerging as the promising option for patients with advanced hepatocellular carcinoma (HCC). We aimed to investigate the heterogeneity of different tumor nodules of the same patient with multifocal HCCs in response to immunotherapy and its molecular mechanisms.EXPERIMENTAL DESIGN: We attained 45 surgical tumor samples including 33 small and 12 large nodules from 12 multifocal HCC patients and evaluated genomic and immune heterogeneity among tumors through whole genome sequencing (WGS) and RNA sequencing. Immunohistochemistry was performed to validate the expression of immune markers. The responses to anti-programed cell death protein-1 (PD-1) therapy in multifocal HCC patients were evaluated.
    RESULTS: The small and large tumors within the same patient presented with similar genomic characteristics, indicating their same genomic origin. We further found the small tumors had higher immune cell infiltration including more CD8+ T cells, M1 macrophage and monocytes as compared to large tumors. Besides, the expression of interferon signature predictive of response to anti-PD-1 therapy was significantly upregulated in the small tumors. Moreover, the immune pathways were more vigorous along with less active proliferation pathways in the small tumors. In keeping with this, we found that small nodules were more sensitive to anti-PD-1 therapy than large nodules in multifocal HCC patients.
    CONCLUSIONS: The small tumors in multifocal HCC patients had higher immune cell infiltration and upregulation of immune pathways as compared to the large tumors, which can partially explain the different responses of small and large tumors in the same case to anti-PD-1 therapy.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-19-3840
  15. Cancers (Basel). 2020 Jun 06. pii: E1484. [Epub ahead of print]12(6):
    Staumont B, Jamakhani M, Costa C, Vandermeers F, Sriramareddy SN, Redouté G, Mascaux C, Delvenne P, Hubert P, Safari R, Willems L.
      Background: There is no standard chemotherapy for refractory or relapsing malignant pleural mesothelioma (MPM). Our previous reports nevertheless indicated that a combination of an anthracycline (doxorubicin) and a lysine deacetylase inhibitor (valproic acid, VPA) synergize to induce the apoptosis of MPM cells and reduce tumor growth in mouse models. A Phase I/II clinical trial indicated that this regimen is a promising therapeutic option for a proportion of MPM patients. Methods: The transcriptomes of mesothelioma cells were compared after Illumina HiSeq 4000 sequencing. The expression of differentially expressed genes was inhibited by RNA interference. Apoptosis was determined by cell cycle analysis and Annexin V/7-AAD labeling. Protein expression was assessed by immunoblotting. Preclinical efficacy was evaluated in BALB/c and NOD-SCID mice. Results: To understand the mechanisms involved in chemoresistance, the transcriptomes of two MPM cell lines displaying different responses to VPA-doxorubicin were compared. Among the differentially expressed genes, transforming growth factor alpha (TGFα) was associated with resistance to this regimen. The silencing of TGFα by RNA interference correlated with a significant increase in apoptosis, whereas the overexpression of TGFα desensitized MPM cells to the apoptosis induced by VPA and doxorubicin. The multi-targeted inhibition of histone deacetylase (HDAC), HER2 and TGFα receptor (epidermal growth factor receptor/EGFR) improved treatment efficacy in vitro and reduced tumor growth in two MPM mouse models. Finally, TGFα expression but not EGFR correlated with patient survival. Conclusions: Our data show that TGFα but not its receptor EGFR is a key factor in resistance to MPM chemotherapy. This observation may contribute to casting light on the promising but still controversial role of EGFR signaling in MPM therapy.
    Keywords:  TGFα; chemoresistance; combination therapy; mesothelioma
    DOI:  https://doi.org/10.3390/cancers12061484
  16. Cancer Discov. 2020 Jun 08. pii: CD-19-1375. [Epub ahead of print]
    Yu J, Navickas A, Asgharian H, Culbertson B, Fish L, Garcia K, Olegario JP, Dermit M, Dodel M, Hanisch B, Luo Y, Weinberg EM, Dienstmann R, Warren RS, Mardakheh FK, Goodarzi H.
      Identifying master regulators that drive pathological gene expression is a key challenge in precision oncology. Here, we have developed an analytical framework, named PRADA, that identifies oncogenic RNA-binding proteins through the systematic detection of coordinated changes in their target regulons. Application of this approach to data collected from clinical samples, patient-derived xenografts, and cell line models of colon cancer metastasis revealed the RNA-binding protein RBMS1 as a suppressor of colon cancer progression. We observed that silencing RBMS1 results in increased metastatic capacity in xenograft mouse models, and that restoring its expression blunts metastatic liver colonization. We have found that RBMS1 functions as a post-transcriptional regulator of RNA stability by directly binding its target mRNAs. Together, our findings establish a role for RBMS1 as a previously unknown regulator of RNA stability and as a suppressor of colon cancer metastasis with clinical utility for risk stratification of patients.
    DOI:  https://doi.org/10.1158/2159-8290.CD-19-1375
  17. Blood. 2020 Jun 09. pii: blood.2019001982. [Epub ahead of print]
    DeWolf SE, Tallman MS.
      Treatment of relapsed or refractory acute myeloid leukemia (AML) has presented challenges for hematologists for decades. Despite numerous clinical studies, outcomes are consistently disappointing with 5-year overall survival rates of approximately 10%. Allogeneic hematopoietic cell transplantation at the time of second complete remission remains the only reliable option with curative potential. However, recent approval of several new agents has transformed treatment paradigms in AML that had been in place for almost half a century. This new therapeutic landscape provides the opportunity to revisit the approach to relapsed or refractory AML. Through illustrative cases we describe our approach, which increasingly relies on specific disease biology. We focus on treatment outside the context of clinical trials since such trials are not available in most parts of the world. Primarily we consider age, fitness to tolerate intensive chemotherapy, remission duration, and presence of a targetable mutation to guide treatment. It is inevitable that the coming years will bring new targets and agents which may prove most effective when combined with each other and/or chemotherapy. Future studies are needed to determine how best to implement this evolving armamentarium of treatment options, to elucidate mechanisms of resistance, and to continue to pursue novel drug discovery.
    DOI:  https://doi.org/10.1182/blood.2019001982
  18. Mol Ther. 2020 Jun 01. pii: S1525-0016(20)30290-2. [Epub ahead of print]
    Qiao Y, Wang Z, Tan F, Chen J, Lin J, Yang J, Li H, Wang X, Sali A, Zhang L, Zhong G.
      Transcription growth factor β (TGF-β) signaling-triggered epithelial-to-mesenchymal transition (EMT) process is associated with tumor stemness, metastasis, and chemotherapy resistance. However, the epigenomic basis for TGF-β-induced EMT remains largely unknown. Here we reveal that HDAC1-mediated global histone deacetylation and the gain of specific histone H3 lysine 27 acetylation (H3K27ac)-marked enhancers are essential for the TGF-β-induced EMT process. Enhancers gained upon TGF-β treatment are linked to gene activation of EMT markers and cancer metastasis. Notably, dynamic enhancer gain or loss mainly occurs within pre-existing topologically associated domains (TADs) in epithelial cells, with minimal three-dimensional (3D) genome architecture reorganization. Through motif enrichment analysis of enhancers that are lost or gained upon TGF-β stimulation, we identify FOXA2 as a key factor to activate epithelial-specific enhancer activity, and we also find that TEAD4 forms a complex with SMAD2/3 to mediate TGF-β signaling-triggered mesenchymal enhancer reprogramming. Together, our results implicate that key transcription-factor (TF)-mediated enhancer reprogramming modulates the developmental transition in TGF-β signaling-associated cancer metastasis.
    Keywords:  EMT; FOXA2; Hi-C; TEAD2; TEAD4; TGFβ; enhancer reprogramming; epithelial-to-mesenchymal transition; metastasis
    DOI:  https://doi.org/10.1016/j.ymthe.2020.05.026
  19. Nat Commun. 2020 Jun 10. 11(1): 2936
    Reich S, Nguyen CDL, Has C, Steltgens S, Soni H, Coman C, Freyberg M, Bichler A, Seifert N, Conrad D, Knobbe-Thomsen CB, Tews B, Toedt G, Ahrends R, Medenbach J.
      Stress response pathways are critical for cellular homeostasis, promoting survival through adaptive changes in gene expression and metabolism. They play key roles in numerous diseases and are implicated in cancer progression and chemoresistance. However, the underlying mechanisms are only poorly understood. We have employed a multi-omics approach to monitor changes to gene expression after induction of a stress response pathway, the unfolded protein response (UPR), probing in parallel the transcriptome, the proteome, and changes to translation. Stringent filtering reveals the induction of 267 genes, many of which have not previously been implicated in stress response pathways. We experimentally demonstrate that UPR-mediated translational control induces the expression of enzymes involved in a pathway that diverts intermediate metabolites from glycolysis to fuel mitochondrial one-carbon metabolism. Concomitantly, the cells become resistant to the folate-based antimetabolites Methotrexate and Pemetrexed, establishing a direct link between UPR-driven changes to gene expression and resistance to pharmacological treatment.
    DOI:  https://doi.org/10.1038/s41467-020-16747-y