bims-cadres Biomed News
on Cancer drug resistance
Issue of 2022–09–18
ten papers selected by
Rana Gbyli, Yale University
  1. Targeting lineage plasticity overcomes chemoresistance.
  2. Acquired semi-squamatization during chemotherapy suggests differentiation as a therapeutic strategy for bladder cancer.
  3. SerpinB3 drives cancer stem cell survival in glioblastoma.
  4. A dormancy mechanism limits metastasis of early spreading cancer cells.
  5. BET inhibition induces vulnerability to MCL1 targeting through upregulation of fatty acid synthesis pathway in breast cancer.
  6. Involvement of cell shape and lipid metabolism in glioblastoma resistance to temozolomide.
  7. Sirtuin 6 inhibition protects against glucocorticoid-induced skeletal muscle atrophy by regulating IGF/PI3K/AKT signaling.
  8. Metabolic reprogramming in the OPA1-deficient cells.
  9. A happy cell stays home: When metabolic stress creates epigenetic advantages in the tumor microenvironment.
  10. Histone methyltransferase KMT2D mediated lipid metabolism via peroxisome proliferator-activated receptor gamma in prostate cancer.
  1. Cancer Cell. 2022 Sep 12. pii: S1535-6108(22)00384-1. [Epub ahead of print]40(9): 905-907
    Targeting lineage plasticity overcomes chemoresistance.
    Seishi Ogawa.
      In this issue of Cancer Cell, Wang et al. reveal that chemoresistant muscle-invasive bladder cancer is associated with partial squamous differentiation. Targeting of Cathepsin H overcomes this chemotherapy-induced semi-squamatization and promotes terminal squamous differentiation and tumor suppression.
    DOI:  https://doi.org/10.1016/j.ccell.2022.08.020
  2. Cancer Cell. 2022 Sep 12. pii: S1535-6108(22)00374-9. [Epub ahead of print]40(9): 1044-1059.e8
    Acquired semi-squamatization during chemotherapy suggests differentiation as a therapeutic strategy for bladder cancer.
    Manli Wang, Xuelan Chen, Ping Tan, Yiyun Wang, Xiangyu Pan, Tianhai Lin, Yong Jiang, Bo Wang, Huan Xu, Yuying Wang, Yucen Yang, Jian Wang, Lei Zhao, Jiapeng Zhang, Ailing Zhong, Yiman Peng, Jiajia Du, Qi Zhang, Jianan Zheng, Jingyao Chen, Siqi Dai, Feifei Na, Zhenghao Lu, Jiaming Liu, Xiaonan Zheng, Lu Yang, Peng Zhang, Ping Han, Qiyong Gong, Qian Zhong, Kai Xiao, Hanshuo Yang, Hongxin Deng, Yinglan Zhao, Hubing Shi, Jianghong Man, Maling Gou, Chengjian Zhao, Lunzhi Dai, Zhihong Xue, Lu Chen, Yuan Wang, Musheng Zeng, Canhua Huang, Qiang Wei, Yuquan Wei, Yu Liu, Chong Chen.
      Cisplatin-based chemotherapy remains the primary treatment for unresectable and metastatic muscle-invasive bladder cancers (MIBCs). However, tumors frequently develop chemoresistance. Here, we established a primary and orthotopic MIBC mouse model with gene-edited organoids to recapitulate the full course of chemotherapy in patients. We found that partial squamous differentiation, called semi-squamatization, is associated with acquired chemoresistance in both mice and human MIBCs. Multi-omics analyses showed that cathepsin H (CTSH) is correlated with chemoresistance and semi-squamatization. Cathepsin inhibition by E64 treatment induces full squamous differentiation and pyroptosis, and thus specifically restrains chemoresistant MIBCs. Mechanistically, E64 treatment activates the tumor necrosis factor pathway, which is required for the terminal differentiation and pyroptosis of chemoresistant MIBC cells. Our study revealed that semi-squamatization is a type of lineage plasticity associated with chemoresistance, suggesting that differentiation via targeting of CTSH is a potential therapeutic strategy for the treatment of chemoresistant MIBCs.
    Keywords:  E64; MIBC; TNF pathway; acquired chemoresistance; cathepsin H; differentiation therapy; lineage plasticity; pyroptosis; semi-squamatization
    DOI:  https://doi.org/10.1016/j.ccell.2022.08.010
  3. Cell Rep. 2022 Sep 13. pii: S2211-1247(22)01176-7. [Epub ahead of print]40(11): 111348
    SerpinB3 drives cancer stem cell survival in glioblastoma.
    Adam Lauko, Josephine Volovetz, Soumya M Turaga, Defne Bayik, Daniel J Silver, Kelly Mitchell, Erin E Mulkearns-Hubert, Dionysios C Watson, Kiran Desai, Manav Midha, Jing Hao, Kathleen McCortney, Alicia Steffens, Ulhas Naik, Manmeet S Ahluwalia, Shideng Bao, Craig Horbinski, Jennifer S Yu, Justin D Lathia.
      Despite therapeutic interventions for glioblastoma (GBM), cancer stem cells (CSCs) drive recurrence. The precise mechanisms underlying CSC resistance, namely inhibition of cell death, are unclear. We built on previous observations that the high cell surface expression of junctional adhesion molecule-A drives CSC maintenance and identified downstream signaling networks, including the cysteine protease inhibitor SerpinB3. Using genetic depletion approaches, we found that SerpinB3 is necessary for CSC maintenance, survival, and tumor growth, as well as CSC pathway activation. Knockdown of SerpinB3 also increased apoptosis and susceptibility to radiation therapy. SerpinB3 was essential to buffer cathepsin L-mediated cell death, which was enhanced with radiation. Finally, we found that SerpinB3 knockdown increased the efficacy of radiation in pre-clinical models. Taken together, our findings identify a GBM CSC-specific survival mechanism involving a cysteine protease inhibitor, SerpinB3, and provide a potential target to improve the efficacy of GBM therapies against therapeutically resistant CSCs.
    Keywords:  CP: Cancer; SerpinB3; cancer stem cell; cathepsin L; glioblastoma; lysosomal-mediated cell death
    DOI:  https://doi.org/10.1016/j.celrep.2022.111348
  4. Nat Cancer. 2022 Sep 14.
    A dormancy mechanism limits metastasis of early spreading cancer cells.
      
    DOI:  https://doi.org/10.1038/s43018-022-00425-7
  5. Cell Rep. 2022 Sep 13. pii: S2211-1247(22)01128-7. [Epub ahead of print]40(11): 111304
    BET inhibition induces vulnerability to MCL1 targeting through upregulation of fatty acid synthesis pathway in breast cancer.
    Gonghong Yan, Augustin Luna, Heping Wang, Behnaz Bozorgui, Xubin Li, Maga Sanchez, Zeynep Dereli, Nermin Kahraman, Goknur Kara, Xiaohua Chen, Caishang Zheng, Daniel McGrail, Nidhi Sahni, Yiling Lu, Ozgun Babur, Murat Cokol, Bora Lim, Bulent Ozpolat, Chris Sander, Gordon B Mills, Anil Korkut.
      Therapeutic options for treatment of basal-like breast cancers remain limited. Here, we demonstrate that bromodomain and extra-terminal (BET) inhibition induces an adaptive response leading to MCL1 protein-driven evasion of apoptosis in breast cancer cells. Consequently, co-targeting MCL1 and BET is highly synergistic in breast cancer models. The mechanism of adaptive response to BET inhibition involves the upregulation of lipid synthesis enzymes including the rate-limiting stearoyl-coenzyme A (CoA) desaturase. Changes in lipid synthesis pathway are associated with increases in cell motility and membrane fluidity as well as re-localization and activation of HER2/EGFR. In turn, the HER2/EGFR signaling results in the accumulation of and vulnerability to the inhibition of MCL1. Drug response and genomics analyses reveal that MCL1 copy-number alterations are associated with effective BET and MCL1 co-targeting. The high frequency of MCL1 chromosomal amplifications (>30%) in basal-like breast cancers suggests that BET and MCL1 co-targeting may have therapeutic utility in this aggressive subtype of breast cancer.
    Keywords:  BRD4; CP: Cancer; MCL1; adaptive responses; apoptosis; bioinformatics; combination therapy; drug resistance; fatty acid pathway; lipids; network models
    DOI:  https://doi.org/10.1016/j.celrep.2022.111304
  6. Acta Pharmacol Sin. 2022 Sep 13.
    Involvement of cell shape and lipid metabolism in glioblastoma resistance to temozolomide.
    Munki Choo, Van-Hieu Mai, Han Sun Kim, Dong-Hwa Kim, Ja-Lok Ku, Sang Kook Lee, Chul-Kee Park, Yong Jin An, Sunghyouk Park.
      Temozolomide (TMZ) has been used as standard-of-care for glioblastoma multiforme (GBM), but the resistance to TMZ develops quickly and frequently. Thus, more studies are needed to elucidate the resistance mechanisms. In the current study, we investigated the relationship among the three important phenotypes, namely TMZ-resistance, cell shape and lipid metabolism, in GBM cells. We first observed the distinct difference in cell shapes between TMZ-sensitive (U87) and resistant (U87R) GBM cells. We then conducted NMR-based lipid metabolomics, which revealed a significant increase in cholesterol and fatty acid synthesis as well as lower lipid unsaturation in U87R cells. Consistent with the lipid changes, U87R cells exhibited significantly lower membrane fluidity. The transcriptomic analysis demonstrated that lipid synthesis pathways through SREBP were upregulated in U87R cells, which was confirmed at the protein level. Fatostatin, an SREBP inhibitor, and other lipid pathway inhibitors (C75, TOFA) exhibited similar or more potent inhibition on U87R cells compared to sensitive U87 cells. The lower lipid unsaturation ratio, membrane fluidity and higher fatostatin sensitivity were all recapitulated in patient-derived TMZ-resistant primary cells. The observed ternary relationship among cell shape, lipid composition, and TMZ-resistance may be applicable to other drug-resistance cases. SREBP and fatostatin are suggested as a promising target-therapeutic agent pair for drug-resistant glioblastoma.
    Keywords:  SREBP; cell shape; fatostatin; glioblastoma; lipid metabolism; temozolomide resistance
    DOI:  https://doi.org/10.1038/s41401-022-00984-6
  7. Nat Commun. 2022 Sep 15. 13(1): 5415
    Sirtuin 6 inhibition protects against glucocorticoid-induced skeletal muscle atrophy by regulating IGF/PI3K/AKT signaling.
    Sneha Mishra, Claudia Cosentino, Ankit Kumar Tamta, Danish Khan, Shalini Srinivasan, Venkatraman Ravi, Elena Abbotto, Bangalore Prabhashankar Arathi, Shweta Kumar, Aditi Jain, Anand S Ramaian, Shruti M Kizkekra, Raksha Rajagopal, Swathi Rao, Swati Krishna, Ninitha Asirvatham-Jeyaraj, Elizabeth R Haggerty, Dafne M Silberman, Irwin J Kurland, Ravindra P Veeranna, Tamilselvan Jayavelu, Santina Bruzzone, Raul Mostoslavsky, Nagalingam R Sundaresan.
      Chronic activation of stress hormones such as glucocorticoids leads to skeletal muscle wasting in mammals. However, the molecular events that mediate glucocorticoid-induced muscle wasting are not well understood. Here, we show that SIRT6, a chromatin-associated deacetylase indirectly regulates glucocorticoid-induced muscle wasting by modulating IGF/PI3K/AKT signaling. Our results show that SIRT6 levels are increased during glucocorticoid-induced reduction of myotube size and during skeletal muscle atrophy in mice. Notably, overexpression of SIRT6 spontaneously decreases the size of primary myotubes in a cell-autonomous manner. On the other hand, SIRT6 depletion increases the diameter of myotubes and protects them against glucocorticoid-induced reduction in myotube size, which is associated with enhanced protein synthesis and repression of atrogenes. In line with this, we find that muscle-specific SIRT6 deficient mice are resistant to glucocorticoid-induced muscle wasting. Mechanistically, we find that SIRT6 deficiency hyperactivates IGF/PI3K/AKT signaling through c-Jun transcription factor-mediated increase in IGF2 expression. The increased activation, in turn, leads to nuclear exclusion and transcriptional repression of the FoxO transcription factor, a key activator of muscle atrophy. Further, we find that pharmacological inhibition of SIRT6 protects against glucocorticoid-induced muscle wasting in mice by regulating IGF/PI3K/AKT signaling implicating the role of SIRT6 in glucocorticoid-induced muscle atrophy.
    DOI:  https://doi.org/10.1038/s41467-022-32905-w
  8. Cell Mol Life Sci. 2022 Sep 14. 79(10): 517
    Metabolic reprogramming in the OPA1-deficient cells.
    Wenting Dai, Zhichao Wang, Qiong A Wang, David Chan, Lei Jiang.
      OPA1, a dynamin-related GTPase mutated in autosomal dominant optic atrophy, is essential for the fusion of the inner mitochondrial membrane. Although OPA1 deficiency leads to impaired mitochondrial morphology, the role of OPA1 in central carbon metabolism remains unclear. Here, we aim to explore the functional role and metabolic mechanism of OPA1 in cell fitness beyond the control of mitochondrial fusion. We applied [U-13C]glucose and [U-13C]glutamine isotope tracing techniques to OPA1-knockout (OPA1-KO) mouse embryonic fibroblasts (MEFs) compared to OPA1 wild-type (OPA1-WT) controls. Furthermore, the resulting tracing data were integrated by metabolic flux analysis to understand the underlying metabolic mechanism through which OPA1 deficiency reprograms cellular metabolism. OPA1-deficient MEFs were depleted of intracellular citrate, which was consistent with the decreased oxygen consumption rate in these cells with mitochondrial fission that is not balanced by mitochondrial fusion. Whereas oxidative glucose metabolism was impaired, OPA1-deficient cells activated glutamine-dependent reductive carboxylation and subsequently relied on this reductive metabolism to produce cytosolic citrate as a predominant acetyl-CoA source for de novo fatty acid synthesis. Prevention of cytosolic glutamine reductive carboxylation by GSK321, an inhibitor of isocitrate dehydrogenase 1 (IDH1), largely repressed lipid synthesis and blocked cell proliferation in OPA1-deficient MEFs. Our data support that, when glucose oxidation failed to support lipogenesis and proliferation in cells with unbalanced mitochondrial fission, OPA1 deficiency stimulated metabolic anaplerosis into glutamine-dependent reductive carboxylation in an IDH1-mediated manner.
    Keywords:  Cell growth; Citrate; De novo lipogenesis; OPA1 dysfunction; Oxidative metabolism; Reductive carboxylation
    DOI:  https://doi.org/10.1007/s00018-022-04542-5
  9. Front Oncol. 2022 ;12 962928
    A happy cell stays home: When metabolic stress creates epigenetic advantages in the tumor microenvironment.
    Eric A Hanse, Mei Kong.
      A paradox of fast-proliferating tumor cells is that they deplete extracellular nutrients that often results in a nutrient poor microenvironment in vivo. Having a better understanding of the adaptation mechanisms cells exhibit in response to metabolic stress will open new therapeutic windows targeting the tumor's extreme nutrient microenvironment. Glutamine is one of the most depleted amino acids in the tumor core and here, we provide insight into how important glutamine and its downstream by-product, α-ketoglutarate (αKG), are to communicating information about the nutrient environment. This communication is key in the cell's ability to foster adaptation. We highlight the epigenetic changes brought on when αKG concentrations are altered in cancer and discuss how depriving cells of glutamine may lead to cancer cell de-differentiation and the ability to grow and thrive in foreign environments. When we starve cells, they adapt to survive. Those survival "skills" allow them to go out looking for other places to live and metastasize. We further examine current challenges to modelling the metabolic tumor microenvironment in the laboratory and discuss strategies that consider current findings to target the tumor's poor nutrient microenvironment.
    Keywords:  alpha ketoglutarate; epigenetics; glutamine; glutaminolysis-inhibition; metabolism; tumor; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.962928
  10. Transl Cancer Res. 2022 Aug;11(8): 2607-2621
    Histone methyltransferase KMT2D mediated lipid metabolism via peroxisome proliferator-activated receptor gamma in prostate cancer.
    Qiliang Zhai, Mayao Luo, Yifan Zhang, Wenqiang Zhang, Chenwei Wu, Shidong Lv, Qiang Wei.
       Background: Prostate cancer (PCa) is the most common type of cancer in men. Destruction of or blocking lipid metabolism impairs the growth, proliferation, and survival of tumor cells. Recent studies on hepatic steatosis suggest that kinase tethers histone-lysine N-methyltransferase 2D (KMT2D) to peroxisome proliferator-activated receptor gamma (PPARγ), transactivating its target genes. Here, to determine a therapeutic approach that may interfere with PCa lipid metabolism, the interaction mechanism of KMT2D and PPARγ was verified in PCa.
    Methods: Molecular techniques and bioinformatics analysis were used to explore the relationship between KMT2D and lipid metabolism pathways in PCa. Moreover, the changes of lipid droplets were detected by oil red O staining and BODIPY staining. Molecular techniques were used to investigate the effect of KMT2D on PPARγ signaling in PCa cells. Co-immunoprecipitation (Co-IP) and DNA pull-down verified the mechanism of interaction between KMT2D and PPARγ.
    Results: KMT2D knockdown reduced the lipid droplet content in PC-3 and DU-145 cells and downregulated the expression of lipid metabolic genes. Low-dose rosiglitazone (ROSI) effectively activated the PPARγ pathway to promote lipid droplet synthesis and cell proliferation and migration. However, ROSI could not function effectively after KMT2D knockdown. Both co-IP and DNA pull-down analyses showed that KMT2D and PPARγ could be tethered to regulate the expression of PPARγ target genes.
    Conclusions: In PCa, KMT2D interacted with PPARγ, which directly participated in the regulation of lipid metabolism-related genes and affected lipid synthesis. Therefore, inhibiting the interaction between KMT2D and PPARγ is a potential therapeutic strategy.
    Keywords:  Prostate cancer (PCa); kinase tethers histone-lysine N-methyltransferase 2D (KMT2D); lipid metabolism; peroxisome proliferator-activated receptor gamma (PPARγ); rosiglitazone (ROSI)
    DOI:  https://doi.org/10.21037/tcr-22-431
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