bims-cadres Biomed News
on Cancer drug resistance
Issue of 2022–11–06
eight papers selected by
Rana Gbyli, Yale University
  1. FOXA2 drives lineage plasticity and KIT pathway activation in neuroendocrine prostate cancer.
  2. Targeting UGCG overcomes resistance to lysosomal autophagy inhibition.
  3. Bromodomain-containing protein 4 (BRD4) as an epigenetic regulator of fatty acid metabolism genes and ferroptosis.
  4. Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment.
  5. Selective advantage of epigenetically disrupted cancer cells via phenotypic inertia.
  6. Metabolic regulation by p53 prevents R-loop-associated genomic instability.
  7. Leveraging the replication stress response to optimize cancer therapy.
  8. FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation.
  1. Cancer Cell. 2022 Oct 24. pii: S1535-6108(22)00502-5. [Epub ahead of print]
    FOXA2 drives lineage plasticity and KIT pathway activation in neuroendocrine prostate cancer.
    Ming Han, Fei Li, Yehan Zhang, Pengfei Dai, Juan He, Yunguang Li, Yiqin Zhu, Junke Zheng, Hai Huang, Fan Bai, Dong Gao.
      Prostate cancer adeno-to-neuroendocrine lineage transition has emerged as a mechanism of targeted therapeutic resistance. Identifying the direct molecular drivers and developing pharmacological strategies using clinical-grade inhibitors to overcome lineage transition-induced therapeutic resistance are imperative. Here, using single-cell multiomics analyses, we investigate the dynamics of cellular heterogeneity, transcriptome regulation, and microenvironmental factors in 107,201 cells from genetically engineered mouse prostate cancer samples with complete time series of tumor evolution seen in patients. We identify that FOXA2 orchestrates prostate cancer adeno-to-neuroendocrine lineage transition and that Foxa2 expression is significantly induced by androgen deprivation. Moreover, Foxa2 knockdown induces the reversal of adeno-to-neuroendocrine transition. The KIT pathway is directly regulated by FOXA2 and specifically activated in neuroendocrine prostate cancer (NEPC). Pharmacologic inhibition of KIT pathway significantly suppresses mouse and human NEPC tumor growth. These findings reveal that FOXA2 drives adeno-to-neuroendocrine lineage plasticity in prostate cancer and provides a potential pharmacological strategy for castration-resistant NEPC.
    Keywords:  Foxa1; Foxa2; KIT; clinical-grade inhibitors; pharmacological strategy; prostate cancer lineage plasticity; single-cell multiomics; therapeutic resistance
    DOI:  https://doi.org/10.1016/j.ccell.2022.10.011
  2. Cancer Discov. 2022 Nov 04. pii: CD-22-0535. [Epub ahead of print]
    Targeting UGCG overcomes resistance to lysosomal autophagy inhibition.
    Vaibhav Jain, Sandra L Harper, Amanda M Versace, Dylan Fingerman, Gregory Schuyler Brown, Monika Bhardwaj, Mary Ann S Crissey, Aaron R Goldman, Gordon Ruthel, Qin Liu, Aleksandra Zivkovic, Holger Stark, Meenhard Herlyn, Phyllis A Gimotty, David W Speicher, Ravi K Amaravadi.
      Lysosomal autophagy inhibition (LAI) with hydroxychloroquine or DC661 can enhance cancer therapy, but tumor regrowth is common. To elucidate LAI resistance, proteomics and immunoblotting demonstrated that LAI induced lipid metabolism enzymes in multiple cancer cell lines. Lipidomics showed that LAI increased cholesterol, sphingolipids, and glycosphingolipids. These changes were associated with striking levels of GM1+ membrane microdomains (GMM) in plasma membranes and lysosomes. Inhibition of cholesterol/sphingolipid metabolism proteins enhanced LAI cytotoxicity. Targeting UDP-glucose ceramide glucosyltransferase (UGCG) synergistically augmented LAI cytotoxicity. While UGCG inhibition decreased LAI-induced GMM and augmented cell death, UGCG overexpression led to LAI resistance. Melanoma patients with high UGCG expression had significantly shorter disease-specific survival. The FDA-approved UGCG inhibitor eliglustat combined with LAI significantly inhibited tumor growth and improved survival in syngeneic tumors and a therapy-resistant patient-derived xenograft. These findings nominate UGCG as a new cancer target, and clinical trials testing UGCG inhibition in combination with LAI are warranted.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0535
  3. Cell Death Dis. 2022 Oct 29. 13(10): 912
    Bromodomain-containing protein 4 (BRD4) as an epigenetic regulator of fatty acid metabolism genes and ferroptosis.
    Minghua Yang, Ke Liu, Pan Chen, Hongyi Zhu, Junjie Wang, Jun Huang.
      Reprogramming lipid metabolism is considered a fundamental step in tumourigenesis that influences ferroptosis. However, molecular mechanisms between lipid metabolism and ferroptosis remain largely unknown. Results from the drug screening of 464 inhibitors (for 164 targets) applied to ferroptosis cells indicated that 4 inhibitors targeted bromodomain-containing protein 4 (BRD4) significantly inhibiting erastin-induced ferroptosis. Functional studies proved that the loss of BRD4 weakened oxidative catabolism in mitochondria, protecting cells from the excessive accumulation of lipid peroxides. Mechanism research revealed that the transcriptional levels of fatty acid metabolism-related genes (HADH, ACSL1 and ACAA2) participating in the β-oxidation of fatty acids (FAO) and polyunsaturated fatty acids (PUFAs) synthesis depended on the activity of super-enhancers (SEs) formed by BRD4 and HMGB2 in their promoter regions. Conclusively, this study demonstrated that BRD4 was indispensable for fatty acid metabolism based on its epigenetic regulatory mechanisms and affecting erastin-induced ferroptosis, providing a new theoretical reference for understanding the relationship between lipid metabolism and ferroptosis deeply.
    DOI:  https://doi.org/10.1038/s41419-022-05344-0
  4. Nat Commun. 2022 Nov 04. 13(1): 6619
    Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment.
    Han Luo, Xuyang Xia, Li-Bin Huang, Hyunsu An, Minyuan Cao, Gyeong Dae Kim, Hai-Ning Chen, Wei-Han Zhang, Yang Shu, Xiangyu Kong, Zhixiang Ren, Pei-Heng Li, Yang Liu, Huairong Tang, Ronghao Sun, Chao Li, Bing Bai, Weiguo Jia, Yi Liu, Wei Zhang, Li Yang, Yong Peng, Lunzhi Dai, Hongbo Hu, Yong Jiang, Yiguo Hu, Jingqiang Zhu, Hong Jiang, Zhihui Li, Carlos Caulin, Jihwan Park, Heng Xu.
      Cancer-associated fibroblasts (CAFs) are the predominant components of the tumor microenvironment (TME) and influence cancer hallmarks, but without systematic investigation on their ubiquitous characteristics across different cancer types. Here, we perform pan-cancer analysis on 226 samples across 10 solid cancer types to profile the TME at single-cell resolution, illustrating the commonalities/plasticity of heterogenous CAFs. Activation trajectory of the major CAF types is divided into three states, exhibiting distinct interactions with other cell components, and relating to prognosis of immunotherapy. Moreover, minor CAF components represent the alternative origin from other TME components (e.g., endothelia and macrophages). Particularly, the ubiquitous presentation of endothelial-to-mesenchymal transition CAF, which may interact with proximal SPP1+ tumor-associated macrophages, is implicated in endothelial-to-mesenchymal transition and survival stratifications. Our study comprehensively profiles the shared characteristics and dynamics of CAFs, and highlight their heterogeneity and plasticity across different cancer types. Browser of integrated pan-cancer single-cell information is available at https://gist-fgl.github.io/sc-caf-atlas/ .
    DOI:  https://doi.org/10.1038/s41467-022-34395-2
  5. Cancer Cell. 2022 Oct 27. pii: S1535-6108(22)00493-7. [Epub ahead of print]
    Selective advantage of epigenetically disrupted cancer cells via phenotypic inertia.
    Ioannis Loukas, Fabrizio Simeoni, Marta Milan, Paolo Inglese, Harshil Patel, Robert Goldstone, Philip East, Stephanie Strohbuecker, Richard Mitter, Bhavik Talsania, Wenhao Tang, Colin D H Ratcliffe, Erik Sahai, Vahid Shahrezaei, Paola Scaffidi.
      The evolution of established cancers is driven by selection of cells with enhanced fitness. Subclonal mutations in numerous epigenetic regulator genes are common across cancer types, yet their functional impact has been unclear. Here, we show that disruption of the epigenetic regulatory network increases the tolerance of cancer cells to unfavorable environments experienced within growing tumors by promoting the emergence of stress-resistant subpopulations. Disruption of epigenetic control does not promote selection of genetically defined subclones or favor a phenotypic switch in response to environmental changes. Instead, it prevents cells from mounting an efficient stress response via modulation of global transcriptional activity. This "transcriptional numbness" lowers the probability of cell death at early stages, increasing the chance of long-term adaptation at the population level. Our findings provide a mechanistic explanation for the widespread selection of subclonal epigenetic-related mutations in cancer and uncover phenotypic inertia as a cellular trait that drives subclone expansion.
    Keywords:  adaptation; cancer epigenetics; chromatin modifiers; environmental stress; mechanisms of cancer evolution; mutations; pan-cancer; plasticity; subclonal; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2022.10.002
  6. Cell Rep. 2022 Nov 01. pii: S2211-1247(22)01429-2. [Epub ahead of print]41(5): 111568
    Metabolic regulation by p53 prevents R-loop-associated genomic instability.
    Emanuele Panatta, Alessio Butera, Eleonora Mammarella, Consuelo Pitolli, Alessandro Mauriello, Marcel Leist, Richard A Knight, Gerry Melino, Ivano Amelio.
      Gene-environment interactions can perturb the epigenome, triggering network alterations that participate in cancer pathogenesis. Integrating epigenomics, transcriptomics, and metabolic analyses with functional perturbation, we show that the tumor suppressor p53 preserves genomic integrity by empowering adequate levels of the universal methyl donor S-adenosylmethionine (SAM). In p53-deficient cells, perturbation of DNA methylation promotes derepression of heterochromatin, massive loss of histone H3-lysine 9 methylation, and consequent upregulation of satellite RNAs that triggers R-loop-associated replication stress and chromosomal aberrations. In p53-deficient cells, the inadequate SAM level underlies the inability to respond to perturbation because exogenous reintroduction of SAM represses satellite elements and restores the ability to cope with stress. Mechanistically, p53 transcriptionally controls genes involved in one-carbon metabolism, including Slc43a2, the methionine uptake transporter that is critical for SAM synthesis. Supported by clinical data, our findings shed light on the role of p53-mediated metabolism in preventing unscheduled R-loop-associated genomic instability.
    Keywords:  CP: Molecular biology; cancer; chromosome stability; epigenetic integrity; p53; tumor suppression
    DOI:  https://doi.org/10.1016/j.celrep.2022.111568
  7. Nat Rev Cancer. 2022 Nov 02.
    Leveraging the replication stress response to optimize cancer therapy.
    Emily Cybulla, Alessandro Vindigni.
      High-fidelity DNA replication is critical for the faithful transmission of genetic information to daughter cells. Following genotoxic stress, specialized DNA damage tolerance pathways are activated to ensure replication fork progression. These pathways include translesion DNA synthesis, template switching and repriming. In this Review, we describe how DNA damage tolerance pathways impact genome stability, their connection with tumorigenesis and their effects on cancer therapy response. We discuss recent findings that single-strand DNA gap accumulation impacts chemoresponse and explore a growing body of evidence that suggests that different DNA damage tolerance factors, including translesion synthesis polymerases, template switching proteins and enzymes affecting single-stranded DNA gaps, represent useful cancer targets. We further outline how the consequences of DNA damage tolerance mechanisms could inform the discovery of new biomarkers to refine cancer therapies.
    DOI:  https://doi.org/10.1038/s41568-022-00518-6
  8. Nat Commun. 2022 Nov 02. 13(1): 6575
    FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation.
    Joshua I Warrick, Wenhuo Hu, Hironobu Yamashita, Vonn Walter, Lauren Shuman, Jenna M Craig, Lan L Gellert, Mauro A A Castro, A Gordon Robertson, Fengshen Kuo, Irina Ostrovnaya, Judy Sarungbam, Ying-Bei Chen, Anuradha Gopalan, Sahussapont J Sirintrapun, Samson W Fine, Satish K Tickoo, Kwanghee Kim, Jasmine Thomas, Nagar Karan, Sizhi Paul Gao, Timothy N Clinton, Andrew T Lenis, Timothy A Chan, Zhiyu Chen, Manisha Rao, Travis J Hollman, Yanyun Li, Nicholas D Socci, Shweta Chavan, Agnes Viale, Neeman Mohibullah, Bernard H Bochner, Eugene J Pietzak, Min Yuen Teo, Gopa Iyer, Jonathan E Rosenberg, Dean F Bajorin, Matthew Kaag, Suzanne B Merrill, Monika Joshi, Rosalyn Adam, John A Taylor, Peter E Clark, Jay D Raman, Victor E Reuter, Yu Chen, Samuel A Funt, David B Solit, David J DeGraff, Hikmat A Al-Ahmadie.
      Cancers arising from the bladder urothelium often exhibit lineage plasticity with regions of urothelial carcinoma adjacent to or admixed with regions of divergent histomorphology, most commonly squamous differentiation. To define the biologic basis for and clinical significance of this morphologic heterogeneity, here we perform integrated genomic analyses of mixed histology bladder cancers with separable regions of urothelial and squamous differentiation. We find that squamous differentiation is a marker of intratumoral genomic and immunologic heterogeneity in patients with bladder cancer and a biomarker of intrinsic immunotherapy resistance. Phylogenetic analysis confirms that in all cases the urothelial and squamous regions are derived from a common shared precursor. Despite the presence of marked genomic heterogeneity between co-existent urothelial and squamous differentiated regions, no recurrent genomic alteration exclusive to the urothelial or squamous morphologies is identified. Rather, lineage plasticity in bladder cancers with squamous differentiation is associated with loss of expression of FOXA1, GATA3, and PPARG, transcription factors critical for maintenance of urothelial cell identity. Of clinical significance, lineage plasticity and PD-L1 expression is coordinately dysregulated via FOXA1, with patients exhibiting morphologic heterogeneity pre-treatment significantly less likely to respond to immune checkpoint inhibitors.
    DOI:  https://doi.org/10.1038/s41467-022-34251-3
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