bims-cadres 2022-12-25 papers

bims-cadres

Biomed News

on Cancer drug resistance

Issue of 2022–12–25
seven papers selected by
Rana Gbyli, Yale University

ΔNp63/p73 drive metastatic colonization by controlling a regenerative epithelial stem cell program in quasi-mesenchymal cancer stem cells.
The multifaceted role of MUC1 in tumor therapy resistance.
Nucleolar Stress Response via Ribosomal Protein L11 Regulates Topoisomerase Inhibitor Sensitivity of P53-Intact Cancers.
Chronic acidosis rewires cancer cell metabolism through PPARα signaling.
BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network.
Single cell analysis reveals transcriptomic features of drug tolerant persisters and stromal adaptation in a patient-derived EGFR-mutated lung adenocarcinoma xenograft model.
Stabilization of MCL-1 by E3 ligase TRAF4 confers radioresistance.

Dev Cell. 2022 Dec 19. pii: S1534-5807(22)00815-2. [Epub ahead of print]57(24): 2714-2730.e8

ΔNp63/p73 drive metastatic colonization by controlling a regenerative epithelial stem cell program in quasi-mesenchymal cancer stem cells.

Arthur W Lambert, Christopher Fiore, Yogesh Chutake, Elisha R Verhaar, Patrick C Strasser, Mei Wei Chen, Daneyal Farouq, Sunny Das, Xin Li, Elinor Ng Eaton, Yun Zhang, Joana Liu Donaher, Ian Engstrom, Ferenc Reinhardt, Bingbing Yuan, Sumeet Gupta, Bruce Wollison, Matthew Eaton, Brian Bierie, John Carulli, Eric R Olson, Matthew G Guenther, Robert A Weinberg.

  Cancer stem cells (CSCs) may serve as the cellular seeds of tumor recurrence and metastasis, and they can be generated via epithelial-mesenchymal transitions (EMTs). Isolating pure populations of CSCs is difficult because EMT programs generate multiple alternative cell states, and phenotypic plasticity permits frequent interconversions between these states. Here, we used cell-surface expression of integrin β4 (ITGB4) to isolate highly enriched populations of human breast CSCs, and we identified the gene regulatory network operating in ITGB4+ CSCs. Specifically, we identified ΔNp63 and p73, the latter of which transactivates ΔNp63, as centrally important transcriptional regulators of quasi-mesenchymal CSCs that reside in an intermediate EMT state. We found that the transcriptional program controlled by ΔNp63 in CSCs is largely distinct from the one that it orchestrates in normal basal mammary stem cells and, instead, it more closely resembles a regenerative epithelial stem cell response to wounding. Moreover, quasi-mesenchymal CSCs repurpose this program to drive metastatic colonization via autocrine EGFR signaling.

Keywords:  EMT; breast cancer; cancer stem cells; epigenetics; metastasis

DOI:  https://doi.org/10.1016/j.devcel.2022.11.015
Clin Exp Med. 2022 Dec 23.

The multifaceted role of MUC1 in tumor therapy resistance.

Weiqiu Jin, Mengwei Zhang, Changzi Dong, Lei Huang, Qingquan Luo.

  Tumor therapeutic resistances are frequently linked to the recurrence and poor prognosis of cancers and have been a key bottleneck in clinical tumor treatment. Mucin1 (MUC1), a heterodimeric transmembrane glycoprotein, exhibits abnormally overexpression in a variety of human tumors and has been confirmed to be related to the formation of therapeutic resistance. In this review, the multifaceted roles of MUC1 in tumor therapy resistance are summarized from aspects of pan-cancer principles shared among therapies and individual mechanisms dependent on different therapies. Concretely, the common mechanisms of therapy resistance across cancers include interfering with gene expression, promoting genome instability, modifying tumor microenvironment, enhancing cancer heterogeneity and stemness, and activating evasion and metastasis. Moreover, the individual mechanisms of therapy resistance in chemotherapy, radiotherapy, and biotherapy are introduced. Last but not least, MUC1-involved therapy resistance in different types of cancers and MUC1-related clinical trials are summarized.

Keywords:  Biotherapy; Cancer therapy resistance; Chemotherapy; MUC1; Radiation therapy

DOI:  https://doi.org/10.1007/s10238-022-00978-y
Int J Mol Sci. 2022 Dec 15. pii: 15986. [Epub ahead of print]23(24):

Nucleolar Stress Response via Ribosomal Protein L11 Regulates Topoisomerase Inhibitor Sensitivity of P53-Intact Cancers.

Yuka Ishihara, Kiyoshiro Nakamura, Shunsuke Nakagawa, Yasuhiro Okamoto, Masatatsu Yamamoto, Tatsuhiko Furukawa, Kohichi Kawahara.

  Nucleolar stress response is caused by perturbations in ribosome biogenesis, induced by the inhibition of ribosomal RNA processing and synthesis, as well as ribosome assembly. This response induces p53 stabilization and activation via ribosomal protein L11 (RPL11), suppressing tumor progression. However, anticancer agents that kill cells via this mechanism, and their relationship with the therapeutic efficiency of these agents, remain largely unknown. Here, we sought to investigate whether topoisomerase inhibitors can induce nucleolar stress response as they reportedly block ribosomal RNA transcription. Using rhabdomyosarcoma and rhabdoid tumor cell lines that are sensitive to the nucleolar stress response, we evaluated whether nucleolar stress response is associated with sensitivity to topoisomerase inhibitors ellipticine, doxorubicin, etoposide, topotecan, and anthracyclines. Cell proliferation assay indicated that small interfering RNA-mediated RPL11 depletion resulted in decreased sensitivity to topoisomerase inhibitors. Furthermore, the expression of p53 and its downstream target proteins via western blotting showed the suppression of p53 pathway activation upon RPL11 knockdown. These results suggest that the sensitivity of cancer cells to topoisomerase inhibitors is regulated by RPL11-mediated nucleolar stress responses. Thus, RPL11 expression may contribute to the prediction of the therapeutic efficacy of topoisomerase inhibitors and increase their therapeutic effect of topoisomerase inhibitors.

Keywords:  RPL11; drug sensitivity; nucleolar stress response; p53; topoisomerase inhibitors

DOI:  https://doi.org/10.3390/ijms232415986
Int J Cancer. 2022 Dec 19.

Chronic acidosis rewires cancer cell metabolism through PPARα signaling.

Michala G Rolver, Lya K K Holland, Muthulakshmi Ponniah, Nanditha S Prasad, Jiayi Yao, Julie Schnipper, Signe Kramer, Line Elingaard-Larsen, Elena Pedraz-Cuesta, Bin Liu, Luis A Pardo, Kenji Maeda, Albin Sandelin, Stine F Pedersen.

  The mechanisms linking tumor microenvironment acidosis to disease progression are not understood. Here, we used mammary, pancreatic, and colon cancer cells to show that adaptation to growth at an extracellular pH (pHe ) mimicking acidic tumor niches is associated with upregulated net acid extrusion capacity and elevated intracellular pH at physiological pHe , but not at the acidic pHe . Using metabolic profiling, shotgun lipidomics, imaging, and biochemical analyses, we show that the acid adaptation-induced phenotype is characterized by a shift toward oxidative metabolism, increased lipid droplet-, triacylglycerol-, peroxisome content, and mitochondrial hyperfusion. Peroxisome proliferator-activated receptor-α (PPARA, PPARα) expression and activity are upregulated, at least in part by increased fatty acid uptake. PPARα upregulates genes driving increased mitochondrial and peroxisomal mass and β-oxidation capacity, including mitochondrial lipid import proteins CPT1A, CPT2, and SLC25A20, electron transport chain components, peroxisomal proteins PEX11A and ACOX1, and thioredoxin-interacting protein (TXNIP), a negative regulator of glycolysis. This endows acid-adapted cancer cells with increased capacity for utilizing fatty acids for metabolic needs, while limiting glycolysis. As a consequence, the acid-adapted cells exhibit increased sensitivity to PPARα inhibition. We conclude that PPARα is a key upstream regulator of metabolic changes favoring cancer cell survival in acidic tumor niches. This article is protected by copyright. All rights reserved.

Keywords:  PPARα; acidic microenvironment; cancer metabolism; fatty acid metabolism; β-oxidation

DOI:  https://doi.org/10.1002/ijc.34404
Nature. 2022 Dec 21.

BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network.

Xueqin Sun, Olaf Klingbeil, Bin Lu, Caizhi Wu, Carlos Ballon, Meng Ouyang, Xiaoli S Wu, Ying Jin, Yon Hwangbo, Yu-Han Huang, Tim D D Somerville, Kenneth Chang, Jung Park, Taemoon Chung, Scott K Lyons, Junwei Shi, Hannes Vogel, Michael Schulder, Christopher R Vakoc, Alea A Mills.

Inhibition of the tumour suppressive function of p53 (encoded by TP53) is paramount for cancer development in humans. However, p53 remains unmutated in the majority of cases of glioblastoma (GBM)-the most common and deadly adult brain malignancy1,2. Thus, how p53-mediated tumour suppression is countered in TP53 wild-type (TP53WT) GBM is unknown. Here we describe a GBM-specific epigenetic mechanism in which the chromatin regulator bromodomain-containing protein 8 (BRD8) maintains H2AZ occupancy at p53 target loci through the EP400 histone acetyltransferase complex. This mechanism causes a repressive chromatin state that prevents transactivation by p53 and sustains proliferation. Notably, targeting the bromodomain of BRD8 displaces H2AZ, enhances chromatin accessibility and engages p53 transactivation. This in turn enforces cell cycle arrest and tumour suppression in TP53WT GBM. In line with these findings, BRD8 is highly expressed with H2AZ in proliferating single cells of patient-derived GBM, and is inversely correlated with CDKN1A, a canonical p53 target that encodes p21 (refs. 3,4). This work identifies BRD8 as a selective epigenetic vulnerability for a malignancy for which treatment has not improved for decades. Moreover, targeting the bromodomain of BRD8 may be a promising therapeutic strategy for patients with TP53WT GBM.

DOI: https://doi.org/10.1038/s41586-022-05551-x
J Thorac Oncol. 2022 Dec 16. pii: S1556-0864(22)01964-5. [Epub ahead of print]

Single cell analysis reveals transcriptomic features of drug tolerant persisters and stromal adaptation in a patient-derived EGFR-mutated lung adenocarcinoma xenograft model.

Nadeem Moghal, Quan Li, Erin L Stewart, Masashi Mikubo, Roya Navab, Elisa D'Arcangelo, Sebastiao Martins-Filho, Vibha Raghavan, Nhu-An Pham, Ming Li, Frances A Shepherd, Geoffrey Liu, Ming-Sound Tsao.

   INTRODUCTION: Targeted therapies require life-long treatment, as drug discontinuation invariably leads to tumor recurrence. Recurrence is mainly driven by minor subpopulations of drug tolerant persister (DTP) cells that survive the cytotoxic drug effect. In lung cancer, DTP studies have mainly been conducted with cell line models.
METHODS: We conducted an in vivo DTP study using a lung adenocarcinoma (LUAD) patient-derived xenograft (PDX) tumor driven by an epidermal growth factor receptor (EGFR) mutation. Daily treatment of tumor-bearing mice for 5-6 weeks with the EGFR inhibitor erlotinib markedly shrunk tumors and generated DTPs, which were analyzed by whole exome, bulk population transcriptome, and single cell RNA sequencing (scRNA-seq).
RESULTS: DTP tumors maintained the genomic clonal architecture of untreated baseline (BL) tumors, but showed reduced proliferation. scRNA-seq identified a rare (∼4%) subpopulation of BL cells (DTP-like, DTPL) with transcriptomic similarity to DTP cells and intermediate activity of pathways that are upregulated in DTPs. Furthermore, the predominant TGF-β activated cancer-associated fibroblast (CAF) population in BL tumors was replaced by a CAF population enriched for IL6 production. In vitro experiments indicate that these populations interconvert depending on the levels of TGF-β versus NF-κB signaling, which is modulated by TKI presence. DTPs showed signs of increased NF-κB and STAT3 signaling, which may promote their survival.
CONCLUSION: DTPs may arise from a specific pre-existing subpopulation of cancer cells with partial activation of specific drug resistance pathways. TKI treatment induces DTPs showing greater activation of these pathways while converting the major pre-existing CAF population into a new state that may further promote DTP survival.

Keywords:  cancer-associated fibroblasts; drug tolerance; erlotinib; persisters; resistance; sensitizing mutation; stroma

DOI:  https://doi.org/10.1016/j.jtho.2022.12.003
Cell Death Dis. 2022 Dec 19. 13(12): 1053

Stabilization of MCL-1 by E3 ligase TRAF4 confers radioresistance.

Ming Li, Feng Gao, Xiaoying Li, Yu Gan, Shuangze Han, Xinfang Yu, Haidan Liu, Wei Li.

The E3 ligase TNF receptor-associated factor 4 (TRAF4) is frequently overexpressed and closely related to poor prognosis in human malignancies. However, its effect on carcinogenesis and radiosensitivity in oral squamous cell carcinoma (OSCC) remains unclear. The present study found that TRAF4 was significantly upregulated in primary and relapsed OSCC tumor tissues. Depletion of TRAF4 markedly improved the sensitivity of OSCC cells to irradiation (IR) treatment, showing that tumor cell proliferation, colony formation and xenograft tumor growth were reduced. Mechanistically, IR promoted the interaction between TRAF4 and Akt to induce Akt K63-mediated ubiquitination and activation. TRAF4 knockout inhibited the phosphorylation of Akt and upregulated GSK3β activity, resulting in increased myeloid cell leukemia-1 (MCL-1) S159 phosphorylation, which disrupted the interaction of MCL-1 with Josephin domain containing 1 (JOSD1), and ultimately induced MCL-1 ubiquitination and degradation. Moreover, TRAF4 was positively correlated with MCL-1 in primary and in radiotherapy-treated, relapsed tumor tissues. An MCL-1 inhibitor overcame radioresistance in vitro and in vivo. Altogether, the present findings suggest that TRAF4 confers radioresistance in OSCC by stabilizing MCL-1 through Akt signaling, and that targeting TRAF4 may be a promising therapeutic strategy to overcome radioresistance in OSCC.

DOI: https://doi.org/10.1038/s41419-022-05500-6