bims-cadres Biomed News
on Cancer drug resistance
Issue of 2022‒10‒30
ten papers selected by
Rana Gbyli
Yale University
  1. Regulation of Lipid Metabolism Under Stress and Its Role in Cancer.
  2. Retinoblastoma protein as an intrinsic BRD4 inhibitor modulates small molecule BET inhibitor sensitivity in cancer.
  3. UBE2O promotes lipid metabolic reprogramming and liver cancer progression by mediating HADHA ubiquitination.
  4. Dysregulated ceramides metabolism by fatty acid 2-hydroxylase exposes a metabolic vulnerability to target cancer metastasis.
  5. The oncoprotein MUC1 facilitates breast cancer progression by promoting Pink1-dependent mitophagy via ATAD3A destabilization.
  6. PTEN-knockout regulates metabolic rewiring and epigenetic reprogramming in prostate cancer and chemoprevention by triterpenoid ursolic acid.
  7. Addressing the benefits of inhibiting APOBEC3-dependent mutagenesis in cancer.
  8. Clinically relevant treatment of PDX models reveals patterns of neuroblastoma chemoresistance.
  9. Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer.
  10. BAF complex maintains glioma stem cells in pediatric H3K27M-glioma.
  1. Subcell Biochem. 2022 ;100 81-113
    Regulation of Lipid Metabolism Under Stress and Its Role in Cancer.
    Rimsha Munir, Nousheen Zaidi.
      Within the tumor microenvironment, cancer cells are often exposed to oxygen and nutrient deficiency, leading to various changes in their lipid composition and metabolism. These alterations have important therapeutic implications as they affect the cancer cells' survival, membrane dynamics, and therapy response. This chapter provides an overview of recent insights into the regulation of lipid metabolism in cancer cells under metabolic stress. We discuss how this metabolic adaptation helps cancer cells thrive in a harsh tumor microenvironment.
    Keywords:  Cancer; De Novo Fatty acid synthesis; Fatty acid synthase; Hypoxia; Lipid metabolism; Lipidomic profiles; Metabolic stress; Nutrient deprivation
    DOI:  https://doi.org/10.1007/978-3-031-07634-3_3
  2. Nat Commun. 2022 Oct 23. 13(1): 6311
    Retinoblastoma protein as an intrinsic BRD4 inhibitor modulates small molecule BET inhibitor sensitivity in cancer.
    Donglin Ding, Rongbin Zheng, Ye Tian, Rafael Jimenez, Xiaonan Hou, Saravut J Weroha, Liguo Wang, Lei Shi, Haojie Huang.
      Bromodomain and extraterminal (BET) proteins including BRD4 play important roles in oncogenesis and immune inflammation. Here we demonstrate that cancer cells with loss of the retinoblastoma (RB) tumor suppressor became resistant to small molecule bromodomain inhibitors of BET proteins. We find that RB binds to bromodomain-1 (BD1) of BRD4, but binding is impeded by CDK4/6-mediated RB phosphorylation at serine-249/threonine-252 (S249/T252). ChIP-seq analysis shows RB knockdown increases BRD4 occupancy at genomic loci of genes enriched in cancer-related pathways including the GPCR-GNBIL-CREB axis. S249/T252-phosphorylated RB positively correlates with GNBIL protein level in prostate cancer patient samples. BET inhibitor resistance in RB-deficient cells is abolished by co-administration of CREB inhibitor. Our study identifies RB protein as a bona fide intrinsic inhibitor of BRD4 and demonstrates that RB inactivation confers resistance to small molecule BET inhibitors, thereby revealing a regulatory hub that converges RB upstream signaling onto BRD4 functions in diseases such as cancer.
    DOI:  https://doi.org/10.1038/s41467-022-34024-y
  3. Oncogene. 2022 Oct 22.
    UBE2O promotes lipid metabolic reprogramming and liver cancer progression by mediating HADHA ubiquitination.
    Meilin Ma, Changhui Zhang, Rong Cao, Dongmei Tang, Xiongbo Sang, Sailan Zou, Xiuxuan Wang, Haixia Xu, Geng Liu, Lunzhi Dai, Yan Tian, Xiang Gao, Xianghui Fu.
      Cancer cells rely on heightened protein quality control mechanisms, including the ubiquitin-proteosome system that is predominantly driven by ubiquitination comprising E1, E2, and E3 trienzyme cascades. Although E3s have been extensively studied, the implication of E2s in tumorigenesis is poorly defined. Here we reveal a critical E2 in the pathogenesis of hepatocellular carcinoma (HCC). Among all of E2s, UBE2O shows the strongest association with HCC survival prognosis, and its expression is increased in HCC tumors. Accordingly, UBE2O deficiency inhibits HCC growth and metastasis both in vitro and in vivo, while its overexpression has opposite effects. Depending on both E2 and E3 enzymatic activities, UBE2O can interact with and mediate the ubiquitination and degradation of HADHA, a mitochondrial β-oxidation enzyme, thereby modulating lipid metabolic reprogramming. HADHA is reduced in HCC tumors and inversely correlated with UBE2O levels. Importantly, HADHA acts as a tumor suppressor and primarily mediates UBE2O's function on HCC. Moreover, liver-specific deletion of Ube2o in mice are resistant to DEN-induced hepatocarcinogenesis, along with HADHA upregulation and reduced hepatic lipid accumulation. These data reveal UBE2O as a novel oncogenic driver for metabolic reprogramming and HCC development, highlighting the potential of targeting UBE2O/HADHA axis for HCC therapy.
    DOI:  https://doi.org/10.1038/s41388-022-02509-1
  4. Signal Transduct Target Ther. 2022 Oct 24. 7(1): 370
    Dysregulated ceramides metabolism by fatty acid 2-hydroxylase exposes a metabolic vulnerability to target cancer metastasis.
    Xuantong Zhou, Furong Huang, Gang Ma, Wenqing Wei, Nan Wu, Zhihua Liu.
      Whereas it is appreciated that cancer cells rewire lipid metabolism to survive and propagate, the roles of lipid metabolism in metastasis remain largely unknown. In this study, using esophageal squamous cell carcinoma (ESCC) as a pulmonary metastasis model, we find that the enzyme fatty acid 2-hydroxylase (FA2H), which catalyzes the hydroxylation of free fatty acids (FAs), is enriched in a subpopulation of ESCC cells with high metastatic potential, and that FA2H knockdown markedly mitigates metastatic lesions. Moreover, increased FA2H expression is positively associated with poor survival in patients with ESCC. Lipidomics analysis identifies that two dihydroceramides-Cer(d18:0/24:0) and Cer(d18:0/24:1)-are increased in FA2H-depleted metastasizing ESCC cells. Upon administration, Cer(d18:0/24:0) and Cer(d18:0/24:1) impair the formation of overt metastases in a mouse experimental metastasis model. Then, forkhead box protein C2 (FOXC2) and FA2H are found to be co-upregulated in metastatic ESCC cell populations and ESCC specimens, and FA2H expression is further experimentally verified to be transcriptionally induced by FOXC2, which is boosted per se by tumour necrosis factor α (TNFα), a critical pro-metastasis cytokine in the tumour microenvironment, in metastasizing cells. Together, these results demonstrate that TNFα-FOXC2-FA2H is a novel signaling axis to promote metastasis, and its downstream dihydroceramide products could be promising drugs to intervene in metastasis.
    DOI:  https://doi.org/10.1038/s41392-022-01199-1
  5. Cell Death Dis. 2022 Oct 26. 13(10): 899
    The oncoprotein MUC1 facilitates breast cancer progression by promoting Pink1-dependent mitophagy via ATAD3A destabilization.
    Quanfu Li, Yunkai Chu, Shengze Li, Liping Yu, Huayun Deng, Chunhua Liao, Xiaodong Liao, Chihyu Yang, Min Qi, Jinke Cheng, Guoqiang Chen, Lei Huang.
      Mitophagy is a vital process that controls mitochondria quality, dysregulation of which can promote cancer. Oncoprotein mucin 1 (MUC1) targets mitochondria to attenuate drug-induced apoptosis. However, little is known about whether and how MUC1 contributes to mitochondrial homeostasis in cancer cells. We identified a novel role of MUC1 in promoting mitophagy. Increased mitophagy is coupled with the translocation of MUC1 to mitochondria, where MUC1 interacts with and induces degradation of ATPase family AAA domain-containing 3A (ATAD3A), resulting in protection of PTEN-induced kinase 1 (Pink1) from ATAD3A-mediated cleavage. Interestingly, MUC1-induced mitophagy is associated with increased oncogenicity of cancer cells. Similarly, inhibition of mitophagy significantly suppresses MUC1-induced cancer cell activity in vitro and in vivo. Consistently, MUC1 and ATAD3A protein levels present an inverse relationship in tumor tissues of breast cancer patients. Our data validate that MUC1/ATAD3A/Pink1 axis-mediated mitophagy constitutes a novel mechanism for maintaining the malignancy of cancer cells, providing a novel therapeutic approach for MUC1-positive cancers.
    DOI:  https://doi.org/10.1038/s41419-022-05345-z
  6. FASEB J. 2022 Nov;36(11): e22626
    PTEN-knockout regulates metabolic rewiring and epigenetic reprogramming in prostate cancer and chemoprevention by triterpenoid ursolic acid.
    Lujing Wang, Chao Wang, Md Shahid Sarwar, Pochung Chou, Yujue Wang, Xiaoyang Su, Ah-Ng Tony Kong.
      PTEN (phosphatase and tensin homolog deleted on chromosome 10) is one of the most frequently mutated/deleted tumor suppressor genes in many human cancers. Ursolic acid (UA) is a natural triterpenoid possessing antioxidant, anti-inflammatory, and anticancer effects. However, how PTEN impacts metabolic rewiring and how UA modifies PTEN-driven metabolic and epigenetic reprogramming in prostate cancer (PCa) remains unknown. In the current study, we found that UA protects against PTEN knockout (KO)-induced tumorigenesis at different stages of PCa. Epigenomic CpG methyl-seq revealed UA attenuated PTEN KO-induced differentially methylated regions (DMRs) profiles. Transcriptomic RNA-seq showed UA abrogated PTEN KO-induced differentially expressed genes (DEGs) of PCa-related oncogenes' Has3, Cfh, and Msx1 overexpression, indicating UA plays a crucial role in PTEN KO-mediated gene regulation and its potential consequences on cancer interception. Association analysis of DEGs and DMRs identified that the mRNA expression of tumor suppressor gene BDH2, and oncogenes Ephas, Isg15, and Nos2 were correlated with the promoter CpG methylation status in the early-stage comparison groups indicating UA could regulate the oncogenes or tumor suppressor genes by modulating their promoter methylation at an early stage of prostate tumorigenesis. The metabolomic study showed UA attenuated PTEN KO-regulated cancer-associated metabolisms like purine metabolism/metabolites correlating with RNAseq findings, glycolysis/gluconeogenesis metabolism, as well as epigenetic-related metabolites pyruvate and lactate indicating UA plays a critical role in PTEN KO-mediated metabolic and epigenetic reprogramming and its consequences on cancer development. In this context, UA impacts metabolic rewiring causing epigenetic and transcriptomic reprogramming potentially contributing to the overall protection against prostate-specific PTEN KO-mediated PCa.
    Keywords:  PTEN; chemoprevention; epigenetic; metabolomics; prostate cancer; ursolic acid
    DOI:  https://doi.org/10.1096/fj.202201195R
  7. Nat Genet. 2022 Oct 24.
    Addressing the benefits of inhibiting APOBEC3-dependent mutagenesis in cancer.
    Mia Petljak, Abby M Green, John Maciejowski, Matthew D Weitzman.
      Mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC)3 cytosine deaminase activity have been found in over half of cancer types, including some therapy-resistant and metastatic tumors. Driver mutations can occur in APOBEC3-favored sequence contexts, suggesting that mutagenesis by APOBEC3 enzymes may drive cancer evolution. The APOBEC3-mediated signatures are often detected in subclonal branches of tumor phylogenies and ARE acquired in cancer cell lines over long periods of time, indicating that APOBEC3 mutagenesis can be ongoing in cancer. Collectively, these and other observations have led to the proposal that APOBEC3 mutagenesis represents a disease-modifying process that could be inhibited to limit tumor heterogeneity, metastasis and drug resistance. However, critical aspects of APOBEC3 biology in cancer and in healthy tissues have not been clearly defined, limiting well-grounded predictions regarding the benefits of inhibiting APOBEC3 mutagenesis in different settings in cancer. We discuss the relevant mechanistic gaps and strategies to address them to investigate whether inhibiting APOBEC3 mutagenesis may confer clinical benefits in cancer.
    DOI:  https://doi.org/10.1038/s41588-022-01196-8
  8. Sci Adv. 2022 Oct 28. 8(43): eabq4617
    Clinically relevant treatment of PDX models reveals patterns of neuroblastoma chemoresistance.
    Adriana Mañas, Kristina Aaltonen, Natalie Andersson, Karin Hansson, Aleksandra Adamska, Alexandra Seger, Hiroaki Yasui, Hilda van den Bos, Katarzyna Radke, Javanshir Esfandyari, Madhura Satish Bhave, Jenny Karlsson, Diana Spierings, Floris Foijer, David Gisselsson, Daniel Bexell.
      Chemotherapy resistance and relapses are common in high-risk neuroblastoma (NB). Here, we developed a clinically relevant in vivo treatment protocol mimicking the first-line five-chemotherapy treatment regimen of high-risk NB and applied this protocol to mice with MYCN-amplified NB patient-derived xenografts (PDXs). Genomic and transcriptomic analyses were used to reveal NB chemoresistance mechanisms. Intrinsic resistance was associated with high genetic diversity and an embryonic phenotype. Relapsed NB with acquired resistance showed a decreased adrenergic phenotype and an enhanced immature mesenchymal-like phenotype, resembling multipotent Schwann cell precursors. NBs with a favorable treatment response presented a lineage-committed adrenergic phenotype similar to normal neuroblasts. Novel integrated phenotypic gene signatures reflected treatment response and patient prognosis. NB organoids established from relapsed PDX tumors retained drug resistance, tumorigenicity, and transcriptional cell states. This work sheds light on the mechanisms of NB chemotherapy response and emphasizes the importance of transcriptional cell states in chemoresistance.
    DOI:  https://doi.org/10.1126/sciadv.abq4617
  9. Nat Commun. 2022 Oct 26. 13(1): 6360
    Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer.
    Filipe Correia Martins, Dominique-Laurent Couturier, Ines de Santiago, Carolin Margarethe Sauer, Maria Vias, Mihaela Angelova, Deborah Sanders, Anna Piskorz, James Hall, Karen Hosking, Anumithra Amirthanayagam, Sabina Cosulich, Larissa Carnevalli, Barry Davies, Thomas B K Watkins, Ionut G Funingana, Helen Bolton, Krishnayan Haldar, John Latimer, Peter Baldwin, Robin Crawford, Matthew Eldridge, Bristi Basu, Mercedes Jimenez-Linan, Andrew W Mcpherson, Nicholas McGranahan, Kevin Litchfield, Sohrab P Shah, Iain McNeish, Carlos Caldas, Gerard Evan, Charles Swanton, James D Brenton.
      Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma (HGSOC). Here we show that somatic copy number alterations (SCNAs) in frequently amplified HGSOC cancer genes significantly correlate with gene expression and methylation status. We identify five prevalent clonal driver SCNAs (chromosomal amplifications encompassing MYC, PIK3CA, CCNE1, KRAS and TERT) from multi-regional HGSOC data and reason that their strong selection should prioritise them as key biomarkers for targeted therapies. We use primary HGSOC spheroid models to test interactions between in vitro targeted therapy and SCNAs. MYC chromosomal copy number is associated with in-vitro and clinical response to paclitaxel and in-vitro response to mTORC1/2 inhibition. Activation of the mTOR survival pathway in the context of MYC-amplified HGSOC is statistically associated with increased prevalence of SCNAs in genes from the PI3K pathway. Co-occurrence of amplifications in MYC and genes from the PI3K pathway is independently observed in squamous lung cancer and triple negative breast cancer. In this work, we show that identifying co-occurrence of clonal driver SCNA genes could be used to tailor therapeutics for precision medicine.
    DOI:  https://doi.org/10.1038/s41467-022-33870-0
  10. Cancer Discov. 2022 Oct 28. pii: CD-21-1491. [Epub ahead of print]
    BAF complex maintains glioma stem cells in pediatric H3K27M-glioma.
    Eshini Panditharatna, Joana G Marques, Tingjian Wang, Maria C Trissal, Ilon Liu, Li Jiang, Alexander Beck, Andrew Groves, Neekesh V Dharia, Deyao Li, Samantha E Hoffman, Guillaume Kugener, McKenzie L Shaw, Hafsa M Mire, Olivia A Hack, Joshua M Dempster, Caleb Lareau, Lingling Dai, Logan H Sigua, Michael A Quezada, Ann-Catherine J Stanton, Meghan Wyatt, Zohra Kalani, Amy Goodale, Francisca Vazquez, Federica Piccioni, John G Doench, David E Root, Jamie N Anastas, Kristen L Jones, Amy Saur Conway, Sylwia Stopka, Michael S Regan, Yu Liang, Hyuk-Soo Seo, Kijun Song, Puspalata Bashyal, William P Jerome, Nathan D Mathewson, Sirano Dhe-Paganon, Mario L Suva, Angel M Carcaboso, Cinzia Lavarino, Jaume Mora, Quang-De Nguyen, Keith L Ligon, Yang Shi, Sameer Agnihotri, Nathalie Y R Agar, Kimberly Stegmaier, Charles D Stiles, Michelle Monje, Todd R Golub, Jun Qi, Mariella G Filbin.
      Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers, refractory to standard of care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell (OPC)-like state, where genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacological suppression opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of BAF complex has translational potential for children with H3K27M-gliomas.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-1491
This page is being maintained by Thomas Krichel. It was last updated on 2022‒10‒30 at 01:37:48.