bims-cadres Biomed News
on Cancer drug resistance
Issue of 2022‒09‒25
sixteen papers selected by
Rana Gbyli
Yale University
  1. The moving target of cancer cell plasticity.
  2. Spatio-temporal analysis of prostate tumors in situ suggests pre-existence of treatment-resistant clones.
  3. Targeting the USP7/RRM2 axis drives senescence and sensitizes melanoma cells to HDAC/LSD1 inhibitors.
  4. Clone wars: From molecules to cell competition in intestinal stem cell homeostasis and disease.
  5. Metabolic changes during prostate cancer development and progression.
  6. Unraveling phenotypic plasticity and evolution in small cell lung cancer.
  7. Crosstalk between Ca2+ Signaling and Cancer Stemness: The Link to Cisplatin Resistance.
  8. DNA-PKcs promotes fork reversal and chemoresistance.
  9. Interplays of glucose metabolism and KRAS mutation in pancreatic ductal adenocarcinoma.
  10. Epigenetic regulation of inflammation: The metabolomics connection.
  11. Resistance to tyrosine kinase inhibitors promotes renal cancer progression through MCPIP1 tumor-suppressor downregulation and c-Met activation.
  12. An EGFR/HER2-targeted conjugate sensitizes gemcitabine-sensitive and resistant pancreatic cancer through different SMAD4-mediated mechanisms.
  13. MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer.
  14. Targeting the Heterogeneous Genomic Landscape in Triple-Negative Breast Cancer through Inhibitors of the Transcriptional Machinery.
  15. Deciphering the evolutionary dynamics of extrachromosomal DNA in human cancer.
  16. Single-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPARγ during hyperlipidemia.
  1. Nat Cancer. 2022 Sep;3(9): 1013-1014
    The moving target of cancer cell plasticity.
      
    DOI:  https://doi.org/10.1038/s43018-022-00441-7
  2. Nat Commun. 2022 Sep 17. 13(1): 5475
    Spatio-temporal analysis of prostate tumors in situ suggests pre-existence of treatment-resistant clones.
    Maja Marklund, Niklas Schultz, Stefanie Friedrich, Emelie Berglund, Firas Tarish, Anna Tanoglidi, Yao Liu, Ludvig Bergenstråhle, Andrew Erickson, Thomas Helleday, Alastair D Lamb, Erik Sonnhammer, Joakim Lundeberg.
      The molecular mechanisms underlying lethal castration-resistant prostate cancer remain poorly understood, with intratumoral heterogeneity a likely contributing factor. To examine the temporal aspects of resistance, we analyze tumor heterogeneity in needle biopsies collected before and after treatment with androgen deprivation therapy. By doing so, we are able to couple clinical responsiveness and morphological information such as Gleason score to transcriptome-wide data. Our data-driven analysis of transcriptomes identifies several distinct intratumoral cell populations, characterized by their unique gene expression profiles. Certain cell populations present before treatment exhibit gene expression profiles that match those of resistant tumor cell clusters, present after treatment. We confirm that these clusters are resistant by the localization of active androgen receptors to the nuclei in cancer cells post-treatment. Our data also demonstrates that most stromal cells adjacent to resistant clusters do not express the androgen receptor, and we identify differentially expressed genes for these cells. Altogether, this study shows the potential to increase the power in predicting resistant tumors.
    DOI:  https://doi.org/10.1038/s41467-022-33069-3
  3. Cell Rep. 2022 Sep 20. pii: S2211-1247(22)01233-5. [Epub ahead of print]40(12): 111396
    Targeting the USP7/RRM2 axis drives senescence and sensitizes melanoma cells to HDAC/LSD1 inhibitors.
    Letizia Granieri, Federica Marocchi, Marine Melixetian, Neda Mohammadi, Paola Nicoli, Alessandro Cuomo, Tiziana Bonaldi, Stefano Confalonieri, Federica Pisati, Giuseppina Giardina, Giovanni Bertalot, Daniela Bossi, Luisa Lanfrancone.
      Deubiquitinating enzymes are key regulators of the ubiquitin-proteasome system and cell cycle, and their dysfunction leads to tumorigenesis. Our in vivo drop-out screens in patient-derived xenograft models identify USP7 as a regulator of melanoma. We show that USP7 downregulation induces cellular senescence, arresting melanoma growth in vivo and proliferation in vitro in BRAF- and NRAS-mutant melanoma. We provide a comprehensive understanding of targets and networks affected by USP7 depletion by performing a global transcriptomic and proteomics analysis. We show that RRM2 is a USP7 target and is regulated by USP7 during S phase of the cell cycle. Ectopic expression of RRM2 in USP7-depleted cells rescues the senescent phenotype. Pharmacological inhibition of USP7 by P5091 phenocopies the shUSP7-induced senescent phenotype. We show that the bifunctional histone deacetylase (HDAC)/LSD1 inhibitor domatinostat has an additive antitumor effect, eliminating P5091-induced senescent cells, paving the way to a therapeutic combination for individuals with melanoma.
    Keywords:  CP: Cancer; DUBs; PDX; cellular senescence; combination therapy; metastatic melanoma
    DOI:  https://doi.org/10.1016/j.celrep.2022.111396
  4. Exp Mol Med. 2022 Sep 18.
    Clone wars: From molecules to cell competition in intestinal stem cell homeostasis and disease.
    Gabriele Colozza, So-Yeon Park, Bon-Kyoung Koo.
      The small intestine is among the fastest self-renewing tissues in adult mammals. This rapid turnover is fueled by the intestinal stem cells residing in the intestinal crypt. Wnt signaling plays a pivotal role in regulating intestinal stem cell renewal and differentiation, and the dysregulation of this pathway leads to cancer formation. Several studies demonstrate that intestinal stem cells follow neutral drift dynamics, as they divide symmetrically to generate other equipotent stem cells. Competition for niche space and extrinsic signals in the intestinal crypt is the governing mechanism that regulates stemness versus cell differentiation, but the underlying molecular mechanisms are still poorly understood, and it is not yet clear how this process changes during disease. In this review, we highlight the mechanisms that regulate stem cell homeostasis in the small intestine, focusing on Wnt signaling and its regulation by RNF43 and ZNRF3, key inhibitors of the Wnt pathway. Furthermore, we summarize the evidence supporting the current model of intestinal stem cell regulation, highlighting the principles of neutral drift at the basis of intestinal stem cell homeostasis. Finally, we discuss recent studies showing how cancer cells bypass this mechanism to gain a competitive advantage against neighboring normal cells.
    DOI:  https://doi.org/10.1038/s12276-022-00854-5
  5. J Cancer Res Clin Oncol. 2022 Sep 23.
    Metabolic changes during prostate cancer development and progression.
    Alicia-Marie K Beier, Martin Puhr, Matthias B Stope, Christian Thomas, Holger H H Erb.
      Metabolic reprogramming has been recognised as a hallmark in solid tumours. Malignant modification of the tumour's bioenergetics provides energy for tumour growth and progression. Otto Warburg first reported these metabolic and biochemical changes in 1927. In prostate cancer (PCa) epithelial cells, the tumour metabolism also changes during development and progress. These alterations are partly driven by the androgen receptor, the key regulator in PCa development, progress, and survival. In contrast to other epithelial cells of different entities, glycolytic metabolism in prostate cells sustains physiological citrate secretion in the normal prostatic epithelium. In the early stages of PCa, citrate is utilised to power oxidative phosphorylation and fuel lipogenesis, enabling tumour growth and progression. In advanced and incurable castration-resistant PCa, a metabolic shift towards choline, amino acid, and glycolytic metabolism fueling tumour growth and progression has been described. Therefore, even if the metabolic changes are not fully understood, the altered metabolism during tumour progression may provide opportunities for novel therapeutic strategies, especially in advanced PCa stages. This review focuses on the main differences in PCa's metabolism during tumourigenesis and progression highlighting glutamine's role in PCa.
    Keywords:  CRPC; Glutamine; Metabolic reprogramming
    DOI:  https://doi.org/10.1007/s00432-022-04371-w
  6. Cell Syst. 2022 Sep 21. pii: S2405-4712(22)00349-0. [Epub ahead of print]13(9): 687-689
    Unraveling phenotypic plasticity and evolution in small cell lung cancer.
    Aritro Nath.
      Malignant cell populations in a tumor often exist in distinct phenotypic states. Deciphering tumor heterogeneity requires determining how many such unique states exist and what the biological traits associated with each are. Archetype analysis of SCLC transcriptomes reveals key phenotypic states in SCLC tumors and their patterns of evolution.
    DOI:  https://doi.org/10.1016/j.cels.2022.08.005
  7. Int J Mol Sci. 2022 Sep 14. pii: 10687. [Epub ahead of print]23(18):
    Crosstalk between Ca2+ Signaling and Cancer Stemness: The Link to Cisplatin Resistance.
    Sana Kouba, Frédéric Hague, Ahmed Ahidouch, Halima Ouadid-Ahidouch.
      In the fight against cancer, therapeutic strategies using cisplatin are severely limited by the appearance of a resistant phenotype. While cisplatin is usually efficient at the beginning of the treatment, several patients endure resistance to this agent and face relapse. One of the reasons for this resistant phenotype is the emergence of a cell subpopulation known as cancer stem cells (CSCs). Due to their quiescent phenotype and self-renewal abilities, these cells have recently been recognized as a crucial field of investigation in cancer and treatment resistance. Changes in intracellular calcium (Ca2+) through Ca2+ channel activity are essential for many cellular processes such as proliferation, migration, differentiation, and survival in various cell types. It is now proved that altered Ca2+ signaling is a hallmark of cancer, and several Ca2+ channels have been linked to CSC functions and therapy resistance. Moreover, cisplatin was shown to interfere with Ca2+ homeostasis; thus, it is considered likely that cisplatin-induced aberrant Ca2+ signaling is linked to CSCs biology and, therefore, therapy failure. The molecular signature defining the resistant phenotype varies between tumors, and the number of resistance mechanisms activated in response to a range of pressures dictates the global degree of cisplatin resistance. However, if we can understand the molecular mechanisms linking Ca2+ to cisplatin-induced resistance and CSC behaviors, alternative and novel therapeutic strategies could be considered. In this review, we examine how cisplatin interferes with Ca2+ homeostasis in tumor cells. We also summarize how cisplatin induces CSC markers in cancer. Finally, we highlight the role of Ca2+ in cancer stemness and focus on how they are involved in cisplatin-induced resistance through the increase of cancer stem cell populations and via specific pathways.
    Keywords:  calcium channels; calcium signaling; cancer stem cells; chemoresistance; cisplatin
    DOI:  https://doi.org/10.3390/ijms231810687
  8. Mol Cell. 2022 Sep 10. pii: S1097-2765(22)00848-6. [Epub ahead of print]
    DNA-PKcs promotes fork reversal and chemoresistance.
    Diego Dibitetto, Shannon Marshall, Andrea Sanchi, Martin Liptay, Jumana Badar, Massimo Lopes, Sven Rottenberg, Marcus B Smolka.
      The DNA-PKcs kinase mediates the repair of DNA double-strand breaks via classical non-homologous end joining (NHEJ). DNA-PKcs is also recruited to active replication forks, although a role for DNA-PKcs in the control of fork dynamics is unclear. Here, we identify a crucial role for DNA-PKcs in promoting fork reversal, a process that stabilizes stressed replication forks and protects genome integrity. DNA-PKcs promotes fork reversal and slowing in response to several replication stress-inducing agents in a manner independent of its role in NHEJ. Cells lacking DNA-PKcs activity show increased DNA damage during S-phase and cellular sensitivity to replication stress. Notably, prevention of fork slowing and reversal via DNA-PKcs inhibition efficiently restores chemotherapy sensitivity in BRCA2-deficient mammary tumors with acquired PARPi resistance. Together, our data uncover a new key regulator of fork reversal and show how DNA-PKcs signaling can be manipulated to alter fork dynamics and drug resistance in cancer.
    Keywords:  BRCA1; BRCA2; DNA replication; DNA-PKcs; NHEJ; PARP inhibitor; chemoresistance; fork reversal
    DOI:  https://doi.org/10.1016/j.molcel.2022.08.028
  9. Cell Death Dis. 2022 Sep 24. 13(9): 817
    Interplays of glucose metabolism and KRAS mutation in pancreatic ductal adenocarcinoma.
    Yu-Huei Liu, Chun-Mei Hu, Yuan-Sheng Hsu, Wen-Hwa Lee.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadliest cancer worldwide. The primary reasons for this are the lack of early detection methods and targeted therapy. Emerging evidence highlights the metabolic addiction of cancer cells as a potential target to combat PDAC. Oncogenic mutations of KRAS are the most common triggers that drive glucose uptake and utilization via metabolic reprogramming to support PDAC growth. Conversely, high glucose levels in the pancreatic microenvironment trigger genome instability and de novo mutations, including KRASG12D, in pancreatic cells through metabolic reprogramming. Here, we review convergent and diverse metabolic networks related to oncogenic KRAS mutations between PDAC initiation and progression, emphasizing the interplay among oncogenic mutations, glucose metabolic reprogramming, and the tumor microenvironment. Recognizing cancer-related glucose metabolism will provide a better strategy to prevent and treat the high risk PDAC population.
    DOI:  https://doi.org/10.1038/s41419-022-05259-w
  10. Semin Cell Dev Biol. 2022 Sep 17. pii: S1084-9521(22)00270-1. [Epub ahead of print]
    Epigenetic regulation of inflammation: The metabolomics connection.
    Suvasmita Rath, Yousef M Hawsawi, Faisal Alzahrani, Mohammad Imran Khan.
      Epigenetic factors are considered the regulator of complex machinery behind inflammatory disorders and significantly contributed to the expression of inflammation-associated genes. Epigenetic modifications modulate variation in the expression pattern of target genes without affecting the DNA sequence. The current knowledge of epigenetic research focused on their role in the pathogenesis of various inflammatory diseases that causes morbidity and mortality worldwide. Inflammatory diseases are categorized as acute and chronic based on the disease severity and are regulated by the expression pattern of various genes. Hence, understanding the role of epigenetic modifications during inflammation progression will contribute to the disease outcomes and therapeutic approaches. This review also focuses on the metabolomics approach associated with the study of inflammatory disorders. Inflammatory responses and metabolic regulation are highly integrated and various advanced techniques are adopted to study the metabolic signature molecules. Here we discuss several metabolomics approaches used to link inflammatory disorders and epigenetic changes. We proposed that deciphering the mechanism behind the inflammation-metabolism loop may have immense importance in biomarkers research and may act as a principal component in drug discovery as well as therapeutic applications.
    Keywords:  Acetylation; Epigenetics; Inflammation; Metabolomics; Methylation; MiRNA
    DOI:  https://doi.org/10.1016/j.semcdb.2022.09.008
  11. Cell Death Dis. 2022 Sep 22. 13(9): 814
    Resistance to tyrosine kinase inhibitors promotes renal cancer progression through MCPIP1 tumor-suppressor downregulation and c-Met activation.
    Paulina Marona, Judyta Górka, Oliwia Kwapisz, Jolanta Jura, Janusz Rys, Robert M Hoffman, Katarzyna Miekus.
      Tyrosine kinase inhibitors (TKIs) are the most commonly used targeted therapeutics in clear-cell renal cell carcinoma (ccRCC); however, drug resistance limits their utility and can lead to tumor "flare-up" and progression. In this study, we show that RCC resistance to sunitinib and sorafenib involves different mechanisms and leads to increased malignancy. Sunitinib decreased tumor growth and cell motility along with increased E-cadherin expression and secretion of the proangiogenic cytokines IL6 and IL8, which activated senescence in ccRCC cells and led to VE-cadherin phosphorylation, enhancing tumor angiogenesis. Sorafenib resistance increased the levels of mesenchymal markers and the secretion of MMP9, which cleaved VE-cadherin and disrupted endothelial cell integrity. Both sunitinib resistance and sorafenib resistance led to activation of the c-Met receptor IRAK1 and downregulation of the tumor suppressor MCPIP1, resulting in an increase in the metastasis of resistant cells, possibly due in part to enhanced vascularization of ccRCC. MCPIP1 overexpression partially overcame resistance to these drugs by decreasing micrometastasis and decreasing the expression of factors involved in tumorigenesis. In tumor samples from ccRCC patients, we observed a significant increase in the level of the c-Met receptor, IRAK1 and a decrease in MCPIP1 with respect to normal kidney tissue. Our results indicate separate novel mechanisms for sunitinib and sorafenib resistance, which both lead to MCPIP1 inhibition and ccRCC progression. The presented study suggests caution in the treatment of RCC with TKIs, which may lead to the unintended outcome of tumor progression.
    DOI:  https://doi.org/10.1038/s41419-022-05251-4
  12. Nat Commun. 2022 Sep 20. 13(1): 5506
    An EGFR/HER2-targeted conjugate sensitizes gemcitabine-sensitive and resistant pancreatic cancer through different SMAD4-mediated mechanisms.
    Hongjuan Yao, Wenping Song, Rui Cao, Cheng Ye, Li Zhang, Hebing Chen, Junting Wang, Yuchen Shi, Rui Li, Yi Li, Xiujun Liu, Xiaofei Zhou, Rongguang Shao, Liang Li.
      Chemoresistance limits its clinical implementation for pancreatic ductal adenocarcinoma (PDAC). We previously generated an EGFR/HER2 targeted conjugate, dual-targeting ligand-based lidamycin (DTLL), which shows a highly potent antitumor effect. To overcome chemoresistance in PDAC, we aim to study DTLL efficacy when combined with gemcitabine and explore its mechanisms of action. DTLL in combination with gemcitabine show a superior inhibitory effect on the growth of gemcitabine-resistant/sensitive tumors. DTLL sensitizes gemcitabine efficacy via distinct action mechanisms mediated by mothers against decapentaplegic homolog 4 (SMAD4). It not only prevents neoplastic proliferation via ATK/mTOR blockade and NF-κB impaired function in SMAD4-sufficient PDACs, but also restores SMAD4 bioactivity to trigger downstream NF-κB-regulated signaling in SMAD4-deficient tumors and to overcome chemoresistance. DTLL seems to act as a SMAD4 module that normalizes its function in PDAC, having a synergistic effect in combination with gemcitabine. Our findings provide insight into a rational SMAD4-directed precision therapy in PDAC.
    DOI:  https://doi.org/10.1038/s41467-022-33037-x
  13. Cancer Cell. 2022 Sep 18. pii: S1535-6108(22)00379-8. [Epub ahead of print]
    MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer.
    Shunsuke Kitajima, Tetsuo Tani, Benjamin F Springer, Marco Campisi, Tatsuya Osaki, Koji Haratani, Minyue Chen, Erik H Knelson, Navin R Mahadevan, Jessica Ritter, Ryohei Yoshida, Jens Köhler, Atsuko Ogino, Ryu-Suke Nozawa, Shriram K Sundararaman, Tran C Thai, Mizuki Homme, Brandon Piel, Sophie Kivlehan, Bonje N Obua, Connor Purcell, Mamiko Yajima, Thanh U Barbie, Patrick H Lizotte, Pasi A Jänne, Cloud P Paweletz, Prafulla C Gokhale, David A Barbie.
      KRAS-LKB1 (KL) mutant lung cancers silence STING owing to intrinsic mitochondrial dysfunction, resulting in T cell exclusion and resistance to programmed cell death (ligand) 1 (PD-[L]1) blockade. Here we discover that KL cells also minimize intracellular accumulation of 2'3'-cyclic GMP-AMP (2'3'-cGAMP) to further avoid downstream STING and STAT1 activation. An unbiased screen to co-opt this vulnerability reveals that transient MPS1 inhibition (MPS1i) potently re-engages this pathway in KL cells via micronuclei generation. This effect is markedly amplified by epigenetic de-repression of STING and only requires pulse MPS1i treatment, creating a therapeutic window compared with non-dividing cells. A single course of decitabine treatment followed by pulse MPS1i therapy restores T cell infiltration in vivo, enhances anti-PD-1 efficacy, and results in a durable response without evidence of significant toxicity.
    Keywords:  2’3’-cGAMP; DNMT1; EZH2; KRAS-LKB1 mutant lung adenocarcinoma; STING; cGAS; monopolar spindle kinase 1
    DOI:  https://doi.org/10.1016/j.ccell.2022.08.015
  14. Cancers (Basel). 2022 Sep 07. pii: 4353. [Epub ahead of print]14(18):
    Targeting the Heterogeneous Genomic Landscape in Triple-Negative Breast Cancer through Inhibitors of the Transcriptional Machinery.
    Vera E van der Noord, Bob van de Water, Sylvia E Le Dévédec.
      Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer defined by lack of the estrogen, progesterone and human epidermal growth factor receptor 2. Although TNBC tumors contain a wide variety of oncogenic mutations and copy number alterations, the direct targeting of these alterations has failed to substantially improve therapeutic efficacy. This efficacy is strongly limited by interpatient and intratumor heterogeneity, and thereby a lack in uniformity of targetable drivers. Most of these genetic abnormalities eventually drive specific transcriptional programs, which may be a general underlying vulnerability. Currently, there are multiple selective inhibitors, which target the transcriptional machinery through transcriptional cyclin-dependent kinases (CDKs) 7, 8, 9, 12 and 13 and bromodomain extra-terminal motif (BET) proteins, including BRD4. In this review, we discuss how inhibitors of the transcriptional machinery can effectively target genetic abnormalities in TNBC, and how these abnormalities can influence sensitivity to these inhibitors. These inhibitors target the genomic landscape in TNBC by specifically suppressing MYC-driven transcription, inducing further DNA damage, improving anti-cancer immunity, and preventing drug resistance against MAPK and PI3K-targeted therapies. Because the transcriptional machinery enables transcription and propagation of multiple cancer drivers, it may be a promising target for (combination) treatment, especially of heterogeneous malignancies, including TNBC.
    Keywords:  bromodomain and extra-terminal (BET) proteins; transcription-associated cyclin-dependent kinases (CDKs); transcriptional machinery; triple-negative breast cancer
    DOI:  https://doi.org/10.3390/cancers14184353
  15. Nat Genet. 2022 Sep 23.
    Deciphering the evolutionary dynamics of extrachromosomal DNA in human cancer.
      
    DOI:  https://doi.org/10.1038/s41588-022-01183-z
  16. Nat Commun. 2022 Sep 17. 13(1): 5461
    Single-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPARγ during hyperlipidemia.
    Seung Hyun Lee, Nayoung Kim, Minkyu Kim, Sang-Ho Woo, Inhee Han, Jisu Park, Kyeongdae Kim, Kyu Seong Park, Kibyeong Kim, Dahee Shim, Sang-Eun Park, Jing Yu Zhang, Du-Min Go, Dae-Yong Kim, Won Kee Yoon, Seung-Pyo Lee, Jongsuk Chung, Ki-Wook Kim, Jung Hwan Park, Seung Hyun Lee, Sak Lee, Soo-Jin Ann, Sang-Hak Lee, Hyo-Suk Ahn, Seong Cheol Jeong, Tae Kyeong Kim, Goo Taeg Oh, Woong-Yang Park, Hae-Ock Lee, Jae-Hoon Choi.
      Valvular inflammation triggered by hyperlipidemia has been considered as an important initial process of aortic valve disease; however, cellular and molecular evidence remains unclear. Here, we assess the relationship between plasma lipids and valvular inflammation, and identify association of low-density lipoprotein with increased valvular lipid and macrophage accumulation. Single-cell RNA sequencing analysis reveals the cellular heterogeneity of leukocytes, valvular interstitial cells, and valvular endothelial cells, and their phenotypic changes during hyperlipidemia leading to recruitment of monocyte-derived MHC-IIhi macrophages. Interestingly, we find activated PPARγ pathway in Cd36+ valvular endothelial cells increased in hyperlipidemic mice, and the conservation of PPARγ activation in non-calcified human aortic valves. While the PPARγ inhibition promotes inflammation, PPARγ activation using pioglitazone reduces valvular inflammation in hyperlipidemic mice. These results show that low-density lipoprotein is the main lipoprotein accumulated in the aortic valve during hyperlipidemia, leading to early-stage aortic valve disease, and PPARγ activation protects the aortic valve against inflammation.
    DOI:  https://doi.org/10.1038/s41467-022-33202-2
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