bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2022–04–24
twenty papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. Oxidative Stress in Skeletal Muscle Hinders Metastatic Colonization.
  2. Functional lineage tracing to study the clonal evolution of therapy resistance.
  3. Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer.
  4. Intratumor Microbes Promote Murine Breast Cancer Cell Invasion.
  5. CDK6-PI3K signaling axis is an efficient target for attenuating ABCB1/P-gp mediated multi-drug resistance (MDR) in cancer cells.
  6. TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis.
  7. KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming.
  8. USP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer.
  9. Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche.
  10. Therapeutic targeting of the mevalonate-geranylgeranyl diphosphate pathway with statins overcomes chemotherapy resistance in small cell lung cancer.
  11. KMT5A-methylated SNIP1 promotes triple-negative breast cancer metastasis by activating YAP signaling.
  12. Cooperative interaction between ERα and the EMT-inducer ZEB1 reprograms breast cancer cells for bone metastasis.
  13. Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors.
  14. Interferon-γ increases sensitivity to chemotherapy and provides immunotherapy targets in models of metastatic castration-resistant prostate cancer.
  15. The role of extracellular vesicles in the transfer of drug resistance competences to cancer cells.
  16. Integrated profiling of human pancreatic cancer organoids reveals chromatin accessibility features associated with drug sensitivity.
  17. Heterogeneity of neuroendocrine transcriptional states in metastatic small cell lung cancers and patient-derived models.
  18. DUB to the rescue.
  19. Ceramide-induced integrated stress response overcomes Bcl-2 inhibitor resistance in acute myeloid leukemia.
  20. AKT mutant allele-specific activation dictates pharmacologic sensitivities.
  1. Cancer Discov. 2022 Apr 22. OF1
    Oxidative Stress in Skeletal Muscle Hinders Metastatic Colonization.
      Elevated oxidative stress in skeletal muscle prevents outgrowth of disseminated tumor cells (DTC).
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-071
  2. Nat Rev Cancer. 2022 Apr 22.
    Functional lineage tracing to study the clonal evolution of therapy resistance.
    Christian Umkehrer.
      
    DOI:  https://doi.org/10.1038/s41568-022-00479-w
  3. Nat Commun. 2022 Apr 21. 13(1): 2177
    Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer.
    Martina Troiani, Manuel Colucci, Mariantonietta D'Ambrosio, Ilaria Guccini, Emiliano Pasquini, Angelica Varesi, Aurora Valdata, Simone Mosole, Ajinkya Revandkar, Giuseppe Attanasio, Andrea Rinaldi, Anna Rinaldi, Marco Bolis, Pietro Cippà, Andrea Alimonti.
      Cells subjected to treatment with anti-cancer therapies can evade apoptosis through cellular senescence. Persistent senescent tumor cells remain metabolically active, possess a secretory phenotype, and can promote tumor proliferation and metastatic dissemination. Removal of senescent tumor cells (senolytic therapy) has therefore emerged as a promising therapeutic strategy. Here, using single-cell RNA-sequencing, we find that senescent tumor cells rely on the anti-apoptotic gene Mcl-1 for their survival. Mcl-1 is upregulated in senescent tumor cells, including cells expressing low levels of Bcl-2, an established target for senolytic therapy. While treatment with the Bcl-2 inhibitor Navitoclax results in the reduction of metastases in tumor bearing mice, treatment with the Mcl-1 inhibitor S63845 leads to complete elimination of senescent tumor cells and metastases. These findings provide insights on the mechanism by which senescent tumor cells survive and reveal a vulnerability that can be exploited for cancer therapy.
    DOI:  https://doi.org/10.1038/s41467-022-29824-1
  4. Cancer Discov. 2022 Apr 22. OF1
    Intratumor Microbes Promote Murine Breast Cancer Cell Invasion.
      Intracellular bacteria in a spontaneous breast cancer model promote metastatic colonization.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-067
  5. Mol Cancer. 2022 Apr 22. 21(1): 103
    CDK6-PI3K signaling axis is an efficient target for attenuating ABCB1/P-gp mediated multi-drug resistance (MDR) in cancer cells.
    Lei Zhang, Yidong Li, Chaohua Hu, Yangmin Chen, Zhuo Chen, Zhe-Sheng Chen, Jian-Ye Zhang, Shuo Fang.
       BACKGROUND: Multidrug resistance (MDR) mediated by ATP binding cassette subfamily B member 1 (ABCB1/P-gp) is a major cause of cancer chemotherapy failure, but the regulation mechanisms are largely unknown.
    METHODS: Based on single gene knockout, we studied the regulation of CDK6-PI3K axis on ABCB1-mediated MDR in human cancer cells. CRISPR/Cas9 technique was performed in KB-C2 cells to knockout cdk6 or cdk4 gene. Western blot, RT-PCR and transcriptome analysis were performed to investigate target gene deletion and expression of critical signaling factors. The effect of cdk4 or cdk6 deficiency on cell apoptosis and the cell cycle was analyzed using flow cytometry. In vivo studies were performed to study the sensitivity of KB-C2 tumors to doxorubicin, tumor growth and metastasis.
    RESULTS: Deficiency of cdk6 led to remarkable downregulation of ABCB1 expression and reversal of ABCB1-mediated MDR. Transcriptomic analysis revealed that CDK6 knockout regulated a series of signaling factors, among them, PI3K 110α and 110β, KRAS and MAPK10 were downregulated, and FOS-promoting cell autophagy and CXCL1-regulating multiple factors were upregulated. Notably, PI3K 110α/110β deficiency in-return downregulated CDK6 and the CDK6-PI3K axis synergizes in regulating ABCB1 expression, which strengthened the regulation of ABCB1 over single regulation by either CDK6 or PI3K 110α/110β. High frequency of alternative splicing (AS) of premature ABCB1 mRNA induced by CDK6, CDK4 or PI3K 110α/110β level change was confirmed to alter the ABCB1 level, among them 10 common skipped exon (SE) events were found. In vivo experiments demonstrated that loss of cdk6 remarkably increased the sensitivity of KB-C2 tumors to doxorubicin by increasing drug accumulation of the tumors, resulting in remarkable inhibition of tumor growth and metastasis, as well as KB-C2 survival in the nude mice.
    CONCLUSIONS: CDK6-PI3K as a new target signaling axis to reverse ABCB1-mediated MDR is reported for the first time in cancers. Pathways leading to inhibition of cancer cell proliferation were revealed to be accompanied by CDK6 deficiency.
    Keywords:  ATP-binding cassette (ABC) transporter ABCB1/P-gp; Cyclin dependent kinase 6 (CDK6); Multidrug resistance (MDR); PI3K 110α/110β; Signaling axis; Transcriptome sequencing; cancer
    DOI:  https://doi.org/10.1186/s12943-022-01524-w
  6. EMBO J. 2022 Apr 22. e110324
    TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis.
    Qichao Huang, Dan Wu, Jing Zhao, Zeyu Yan, Lin Chen, Shanshan Guo, Dalin Wang, Chong Yuan, Yinping Wang, Xiaoli Liu, Jinliang Xing.
      The mechanisms underlying cancer metastasis remain poorly understood. Here, we report that TFAM deficiency rapidly and stably induced spontaneous lung metastasis in mice with liver cancer. Interestingly, unexpected polymerization of nuclear actin was observed in TFAM-knockdown HCC cells when cytoskeleton was examined. Polymerization of nuclear actin is causally linked to the high-metastatic ability of HCC cells by modulating chromatin accessibility and coordinating the expression of genes associated with extracellular matrix remodeling, angiogenesis, and cell migration. Mechanistically, TFAM deficiency blocked the TCA cycle and increased the intracellular malonyl-CoA levels. Malonylation of mDia2, which drives actin assembly, promotes its nuclear translocation. Importantly, inhibition of malonyl-CoA production or nuclear actin polymerization significantly impeded the spread of HCC cells in mice. Moreover, TFAM was significantly downregulated in metastatic HCC tissues and was associated with overall survival and time to tumor recurrence of HCC patients. Taken together, our study connects mitochondria to the metastasis of human cancer via uncovered mitochondria-to-nucleus retrograde signaling, indicating that TFAM may serve as an effective target to block HCC metastasis.
    Keywords:  HCC; metastasis; mitochondrial transcription factor A; nuclear F-actin
    DOI:  https://doi.org/10.15252/embj.2021110324
  7. Nat Cancer. 2022 Apr 21.
    KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming.
    Feifei Na, Xiangyu Pan, Jingyao Chen, Xuelan Chen, Manli Wang, Pengliang Chi, Liting You, Lanxin Zhang, Ailing Zhong, Lei Zhao, Siqi Dai, Mengsha Zhang, Yiyun Wang, Bo Wang, Jianan Zheng, Yuying Wang, Jing Xu, Jian Wang, Baohong Wu, Mei Chen, Hongyu Liu, Jianxin Xue, Meijuan Huang, Youling Gong, Jiang Zhu, Lin Zhou, Yan Zhang, Min Yu, Panwen Tian, Mingyu Fan, Zhenghao Lu, Zhihong Xue, Yinglan Zhao, Hanshuo Yang, Chengjian Zhao, Yuan Wang, Junhong Han, Shengyong Yang, Dan Xie, Lu Chen, Qian Zhong, Musheng Zeng, Scott W Lowe, You Lu, Yu Liu, Yuquan Wei, Chong Chen.
      Small cell lung cancer (SCLC) is notorious for its early and frequent metastases, which contribute to it as a recalcitrant malignancy. To understand the molecular mechanisms underlying SCLC metastasis, we generated SCLC mouse models with orthotopically transplanted genome-edited lung organoids and performed multiomics analyses. We found that a deficiency of KMT2C, a histone H3 lysine 4 methyltransferase frequently mutated in extensive-stage SCLC, promoted multiple-organ metastases in mice. Metastatic and KMT2C-deficient SCLC displayed both histone and DNA hypomethylation. Mechanistically, KMT2C directly regulated the expression of DNMT3A, a de novo DNA methyltransferase, through histone methylation. Forced DNMT3A expression restrained metastasis of KMT2C-deficient SCLC through repressing metastasis-promoting MEIS/HOX genes. Further, S-(5'-adenosyl)-L-methionine, the common cofactor of histone and DNA methyltransferases, inhibited SCLC metastasis. Thus, our study revealed a concerted epigenetic reprogramming of KMT2C- and DNMT3A-mediated histone and DNA hypomethylation underlying SCLC metastasis, which suggested a potential epigenetic therapeutic vulnerability.
    DOI:  https://doi.org/10.1038/s43018-022-00361-6
  8. Nat Commun. 2022 Apr 19. 13(1): 2070
    USP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer.
    Jessica K Nelson, May Zaw Thin, Theodore Evan, Steven Howell, Mary Wu, Bruna Almeida, Nathalie Legrave, Duco S Koenis, Gabriela Koifman, Yoichiro Sugimoto, Miriam Llorian Sopena, James MacRae, Emma Nye, Michael Howell, Ambrosius P Snijders, Andreas Prachalias, Yoh Zen, Debashis Sarker, Axel Behrens.
      Deubiquitylating enzymes (DUBs) play an essential role in targeted protein degradation and represent an emerging therapeutic paradigm in cancer. However, their therapeutic potential in pancreatic ductal adenocarcinoma (PDAC) has not been explored. Here, we develop a DUB discovery pipeline, combining activity-based proteomics with a loss-of-function genetic screen in patient-derived PDAC organoids and murine genetic models. This approach identifies USP25 as a master regulator of PDAC growth and maintenance. Genetic and pharmacological USP25 inhibition results in potent growth impairment in PDAC organoids, while normal pancreatic organoids are insensitive, and causes dramatic regression of patient-derived xenografts. Mechanistically, USP25 deubiquitinates and stabilizes the HIF-1α transcription factor. PDAC is characterized by a severely hypoxic microenvironment, and USP25 depletion abrogates HIF-1α transcriptional activity and impairs glycolysis, inducing PDAC cell death in the tumor hypoxic core. Thus, the USP25/HIF-1α axis is an essential mechanism of metabolic reprogramming and survival in PDAC, which can be therapeutically exploited.
    DOI:  https://doi.org/10.1038/s41467-022-29684-9
  9. Cell. 2022 Apr 15. pii: S0092-8674(22)00343-9. [Epub ahead of print]
    Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche.
    Pilar Baldominos, Alex Barbera-Mourelle, Olga Barreiro, Yu Huang, Andrew Wight, Jae-Won Cho, Xi Zhao, Guillem Estivill, Isam Adam, Xavier Sanchez, Shannon McCarthy, Julien Schaller, Zara Khan, Albert Ruzo, Ricardo Pastorello, Edward T Richardson, Deborah Dillon, Paula Montero-Llopis, Romualdo Barroso-Sousa, Juliet Forman, Sachet A Shukla, Sara M Tolaney, Elizabeth A Mittendorf, Ulrich H von Andrian, Kai W Wucherpfennig, Martin Hemberg, Judith Agudo.
      Immunotherapy is a promising treatment for triple-negative breast cancer (TNBC), but patients relapse, highlighting the need to understand the mechanisms of resistance. We discovered that in primary breast cancer, tumor cells that resist T cell attack are quiescent. Quiescent cancer cells (QCCs) form clusters with reduced immune infiltration. They also display superior tumorigenic capacity and higher expression of chemotherapy resistance and stemness genes. We adapted single-cell RNA-sequencing with precise spatial resolution to profile infiltrating cells inside and outside the QCC niche. This transcriptomic analysis revealed hypoxia-induced programs and identified more exhausted T cells, tumor-protective fibroblasts, and dysfunctional dendritic cells inside clusters of QCCs. This uncovered differential phenotypes in infiltrating cells based on their intra-tumor location. Thus, QCCs constitute immunotherapy-resistant reservoirs by orchestrating a local hypoxic immune-suppressive milieu that blocks T cell function. Eliminating QCCs holds the promise to counteract immunotherapy resistance and prevent disease recurrence in TNBC.
    Keywords:  T cells; TME; breast cancer; cancer-associated fibroblasts; dendritic cells; immunotherapy; resistance to therapy; single-cell RNA-sequencing; tumor dormancy; tumor immunology; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cell.2022.03.033
  10. Nat Cancer. 2022 Apr 21.
    Therapeutic targeting of the mevalonate-geranylgeranyl diphosphate pathway with statins overcomes chemotherapy resistance in small cell lung cancer.
    Chenchen Guo, Ruijie Wan, Yayi He, Shu-Hai Lin, Jiayu Cao, Ying Qiu, Tengfei Zhang, Qiqi Zhao, Yujia Niu, Yujuan Jin, Hsin-Yi Huang, Xue Wang, Li Tan, Roman K Thomas, Hua Zhang, Luonan Chen, Kwok-Kin Wong, Liang Hu, Hongbin Ji.
      Small cell lung cancer (SCLC) lacks effective treatments to overcome chemoresistance. Here we established multiple human chemoresistant xenograft models through long-term intermittent chemotherapy, mimicking clinically relevant therapeutic settings. We show that chemoresistant SCLC undergoes metabolic reprogramming relying on the mevalonate (MVA)-geranylgeranyl diphosphate (GGPP) pathway, which can be targeted using clinically approved statins. Mechanistically, statins induce oxidative stress accumulation and apoptosis through the GGPP synthase 1 (GGPS1)-RAB7A-autophagy axis. Statin treatment overcomes both intrinsic and acquired SCLC chemoresistance in vivo across different SCLC PDX models bearing high GGPS1 levels. Moreover, we show that GGPS1 expression is negatively associated with survival in patients with SCLC. Finally, we demonstrate that combined statin and chemotherapy treatment resulted in durable responses in three patients with SCLC who relapsed from first-line chemotherapy. Collectively, these data uncover the MVA-GGPP pathway as a metabolic vulnerability in SCLC and identify statins as a potentially effective treatment to overcome chemoresistance.
    DOI:  https://doi.org/10.1038/s43018-022-00358-1
  11. Nat Commun. 2022 Apr 21. 13(1): 2192
    KMT5A-methylated SNIP1 promotes triple-negative breast cancer metastasis by activating YAP signaling.
    Bo Yu, Jun Su, Qiqi Shi, Qing Liu, Jun Ma, Guoqing Ru, Lei Zhang, Jian Zhang, Xichun Hu, Jianming Tang.
      Smad nuclear-interacting protein 1 (SNIP1) is a transcription repressor related to the TGF-β signaling pathway and associates with c-MYC, a key regulator of cell proliferation and tumor development. Currently, the mechanism by which SNIP1 regulates tumorigenesis and cancer metastasis is unknown. Here, we identify that SNIP1 is a non-histone substrate of lysine methyltransferase KMT5A, which undergoes KMT5A-mediated mono-methylation to promote breast cancer cell growth, invasion and lung metastasis. Mechanistically, we show KMT5A-mediated K301 methylation of SNIP1 represents a sensing signal to release histone acetyltransferase KAT2A and promotes the interaction of c-MYC and KAT2A, and the recruitment of c-MYC/KAT2A complex to promoter of c-MYC targets. This event ultimately inhibits the Hippo kinase cascade to enhance triple-negative breast cancer (TNBC) metastasis by transcriptionally activating MARK4. Co-inhibition of KMT5A catalytic activity and YAP in TNBC xenograft-bearing animals attenuates breast cancer metastasis and increases survival. Collectively, this study presents an KMT5A methylation-dependent regulatory mechanism governing oncogenic function of SNIP1.
    DOI:  https://doi.org/10.1038/s41467-022-29899-w
  12. Nat Commun. 2022 Apr 19. 13(1): 2104
    Cooperative interaction between ERα and the EMT-inducer ZEB1 reprograms breast cancer cells for bone metastasis.
    Nastaran Mohammadi Ghahhari, Magdalena K Sznurkowska, Nicolas Hulo, Lilia Bernasconi, Nicola Aceto, Didier Picard.
      The epithelial to mesenchymal transition (EMT) has been proposed to contribute to the metastatic spread of breast cancer cells. EMT-promoting transcription factors determine a continuum of different EMT states. In contrast, estrogen receptor α (ERα) helps to maintain the epithelial phenotype of breast cancer cells and its expression is crucial for effective endocrine therapies. Determining whether and how EMT-associated transcription factors such as ZEB1 modulate ERα signaling during early stages of EMT could promote the discovery of therapeutic approaches to suppress metastasis. Here we show that, shortly after induction of EMT and while cells are still epithelial, ZEB1 modulates ERα-mediated transcription induced by estrogen or cAMP signaling in breast cancer cells. Based on these findings and our ex vivo and xenograft results, we suggest that the functional interaction between ZEB1 and ERα may alter the tissue tropism of metastatic breast cancer cells towards bone.
    DOI:  https://doi.org/10.1038/s41467-022-29723-5
  13. Nat Commun. 2022 Apr 19. 13(1): 2057
    Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors.
    Kristin M Zimmerman Savill, Brian B Lee, Jason Oeh, Jie Lin, Eva Lin, Wei-Jen Chung, Amy Young, Wennie Chen, Monika Miś, Kathryn Mesh, Jeffrey Eastham, Florian Gnad, Zhaoshi Jiang, Eric W Stawiski, Benjamin Haley, Anneleen Daemen, Xiaojing Wang, Hartmut Koeppen, Zora Modrusan, Scott E Martin, Deepak Sampath, Kui Lin.
      The AKT kinases have emerged as promising therapeutic targets in oncology and both allosteric and ATP-competitive AKT inhibitors have entered clinical investigation. However, long-term efficacy of such inhibitors will likely be challenged by the development of resistance. We have established prostate cancer models of acquired resistance to the allosteric inhibitor MK-2206 or the ATP-competitive inhibitor ipatasertib following prolonged exposure. While alterations in AKT are associated with acquired resistance to MK-2206, ipatasertib resistance is driven by rewired compensatory activity of parallel signaling pathways. Importantly, MK-2206 resistance can be overcome by treatment with ipatasertib, while ipatasertib resistance can be reversed by co-treatment with inhibitors of pathways including PIM signaling. These findings demonstrate that distinct resistance mechanisms arise to the two classes of AKT inhibitors and that combination approaches may reverse resistance to ATP-competitive inhibition.
    DOI:  https://doi.org/10.1038/s41467-022-29655-0
  14. Sci Rep. 2022 Apr 22. 12(1): 6657
    Interferon-γ increases sensitivity to chemotherapy and provides immunotherapy targets in models of metastatic castration-resistant prostate cancer.
    Dimitrios Korentzelos, Alan Wells, Amanda M Clark.
      Interferon-γ (IFNγ) is a cytokine with limited evidence of benefit in cancer clinical trials to date. However, it could potentially play a role in potentiating anti-tumor immunity in the immunologically "cold" metastatic castration-resistant prostate cancer (mCRPC) by inducing antigen presentation pathways and concurrently providing targets for immune checkpoint blockade therapy. Moreover, it could additionally increase sensitivity to chemotherapy based on its pleiotropic effects on cell phenotype. Here, we show that IFNγ treatment induced expression of major histocompatibility class-I (MHC-I) genes and PD-L1 in prostate cancer cells in vitro. Furthermore, IFNγ treatment led to a decrease in E-cadherin expression with a consequent increase in sensitivity to chemotherapy in vitro. In an in vivo murine tumor model of spontaneous metastatic prostate cancer, IFNγ systemic pretreatment upregulated the expression of HLA-A and decreased E-cadherin expression in the primary tumor, and more importantly in the metastatic site led to increased apoptosis and limited micrometastases in combination with paclitaxel treatment compared to diffuse metastatic disease in control and monotherapy treatment groups. These findings suggest that IFNγ may be useful in combinatorial regimens to induce sensitivity to immunotherapy and chemotherapy in hepatic metastases of mCRPC.
    DOI:  https://doi.org/10.1038/s41598-022-10724-9
  15. Drug Resist Updat. 2022 Apr 05. pii: S1368-7646(22)00032-2. [Epub ahead of print]62 100833
    The role of extracellular vesicles in the transfer of drug resistance competences to cancer cells.
    Cristina P R Xavier, Dimas Carolina Belisario, Rita Rebelo, Yehuda G Assaraf, Elisa Giovannetti, Joanna Kopecka, M Helena Vasconcelos.
      Drug resistance remains a major hurdle to successful cancer treatment, being accountable for approximately 90% of cancer-related deaths. In the past years, increasing attention has been given to the role of extracellular vesicles (EVs) in the horizontal transfer of drug resistance in cancer. Indeed, many studies have described the dissemination of therapy resistance traits mediated by EVs, which may be transferred from drug resistant tumor cells to their drug sensitive counterparts. Importantly, different key players of drug resistance have been identified in the cargo of those EVs, such as drug efflux pumps, oncoproteins, antiapoptotic proteins, or microRNAs, among others. Interestingly, the EVs-mediated crosstalk between cells from the tumor microenvironment (TME) and tumor cells has emerged as another important mechanism that leads to cancer cells drug resistance. Recently, the cargo of the TME-derived EVs responsible for the transfer of drug resistance traits has also become a focus of attention. In addition, the possible mechanisms involved in drug sequestration by EVs, likely to contribute to cancer drug resistance, are also described and discussed herein. Despite the latest scientific advances in the field of EVs, this is still a challenging area of research, particularly in the clinical setting. Therefore, further investigation is needed to assess the relevance of EVs to the failure of cancer patients to drug treatment, to identify biomarkers of drug resistance in the EV's cargo, and to develop effective therapeutic strategies to surmount drug resistance. This up-to-date review summarizes relevant literature on the role of EVs in the transfer of drug resistance competences to cancer cells, and the relevance of tumor cells and of TME cells in this process. Finally, this knowledge is integrated with a discussion of possible future clinical applications of EVs as biomarkers of drug resistance.
    Keywords:  Cancer drug resistance; Extracellular vesicles; Intercellular transfer of drug resistance competences; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.drup.2022.100833
  16. Nat Commun. 2022 Apr 21. 13(1): 2169
    Integrated profiling of human pancreatic cancer organoids reveals chromatin accessibility features associated with drug sensitivity.
    Xiaohan Shi, Yunguang Li, Qiuyue Yuan, Shijie Tang, Shiwei Guo, Yehan Zhang, Juan He, Xiaoyu Zhang, Ming Han, Zhuang Liu, Yiqin Zhu, Suizhi Gao, Huan Wang, Xiongfei Xu, Kailian Zheng, Wei Jing, Luonan Chen, Yong Wang, Gang Jin, Dong Gao.
      Chromatin accessibility plays an essential role in controlling cellular identity and the therapeutic response of human cancers. However, the chromatin accessibility landscape and gene regulatory network of pancreatic cancer are largely uncharacterized. Here, we integrate the chromatin accessibility profiles of 84 pancreatic cancer organoid lines with whole-genome sequencing data, transcriptomic sequencing data and the results of drug sensitivity analysis of 283 epigenetic-related chemicals and 5 chemotherapeutic drugs. We identify distinct transcription factors that distinguish molecular subtypes of pancreatic cancer, predict numerous chromatin accessibility peaks associated with gene regulatory networks, discover regulatory noncoding mutations with potential as cancer drivers, and reveal the chromatin accessibility signatures associated with drug sensitivity. These results not only provide the chromatin accessibility atlas of pancreatic cancer but also suggest a systematic approach to comprehensively understand the gene regulatory network of pancreatic cancer in order to advance diagnosis and potential personalized medicine applications.
    DOI:  https://doi.org/10.1038/s41467-022-29857-6
  17. Nat Commun. 2022 Apr 19. 13(1): 2023
    Heterogeneity of neuroendocrine transcriptional states in metastatic small cell lung cancers and patient-derived models.
    Delphine Lissa, Nobuyuki Takahashi, Parth Desai, Irena Manukyan, Christopher W Schultz, Vinodh Rajapakse, Moises J Velez, Deborah Mulford, Nitin Roper, Samantha Nichols, Rasa Vilimas, Linda Sciuto, Yuanbin Chen, Udayan Guha, Arun Rajan, Devon Atkinson, Rajaa El Meskini, Zoe Weaver Ohler, Anish Thomas.
      Molecular subtypes of small cell lung cancer (SCLC) defined by the expression of key transcription regulators have recently been proposed in cell lines and limited number of primary tumors. The clinical and biological implications of neuroendocrine (NE) subtypes in metastatic SCLC, and the extent to which they vary within and between patient tumors and in patient-derived models is not known. We integrate histology, transcriptome, exome, and treatment outcomes of SCLC from a range of metastatic sites, revealing complex intra- and intertumoral heterogeneity of NE differentiation. Transcriptomic analysis confirms previously described subtypes based on ASCL1, NEUROD1, POU2F3, YAP1, and ATOH1 expression, and reveal a clinical subtype with hybrid NE and non-NE phenotypes, marked by chemotherapy-resistance and exceedingly poor outcomes. NE tumors are more likely to have RB1, NOTCH, and chromatin modifier gene mutations, upregulation of DNA damage response genes, and are more likely to respond to replication stress targeted therapies. In contrast, patients preferentially benefited from immunotherapy if their tumors were non-NE. Transcriptional phenotypes strongly skew towards the NE state in patient-derived model systems, an observation that was confirmed in paired patient-matched tumors and xenografts. We provide a framework that unifies transcriptomic and genomic dimensions of metastatic SCLC. The marked differences in transcriptional diversity between patient tumors and model systems are likely to have implications in development of novel therapeutic agents.
    DOI:  https://doi.org/10.1038/s41467-022-29517-9
  18. Mol Cell. 2022 Apr 21. pii: S1097-2765(22)00295-7. [Epub ahead of print]82(8): 1411-1413
    DUB to the rescue.
    Wei Pin Teh, He Zhu, Jarrod A Marto, Sara J Buhrlage.
      Henning et al. (2022) report development of a novel class of agents, bivalent deubiquitinase (DUB)-targeting chimeras (DUBTACs), that can selectively stabilize protein targets. These findings encourage further pursuit of targeted protein stabilization as a new paradigm in chemical biology and drug discovery.
    DOI:  https://doi.org/10.1016/j.molcel.2022.03.039
  19. Blood. 2022 Apr 20. pii: blood.2021013277. [Epub ahead of print]
    Ceramide-induced integrated stress response overcomes Bcl-2 inhibitor resistance in acute myeloid leukemia.
    Alexander C Lewis, Victoria S Pope, Melinda N Tea, Manjun Li, Gus O Nwosu, Thao M Nguyen, Craig Thomas Wallington-Beddoe, Paul A Moretti, Dovile Anderson, Darren J Creek, Maurizio Costabile, Saira R Ali, Chloe Al Thompson-Peach, B Kate Dredge, Andrew G Bert, Gregory J Goodall, Paul G Ekert, Anna L Brown, Richard J D'Andrea, Nirmal Robinson, Melissa R Pitman, Daniel Thomas, David M Ross, Briony L Gliddon, Jason A Powell, Stuart M Pitson.
      Inducing cell death by the sphingolipid ceramide is a potential anti-cancer strategy, but the underlying mechanisms remain poorly defined. Here, we show that triggering accumulation of ceramide in acute myeloid leukaemia (AML) cells by inhibition of sphingosine kinase induces an apoptotic integrated stress response (ISR) through protein kinase R-mediated activation of the master transcription factor ATF4. This leads to transcription of the BH3-only protein, Noxa, and degradation of the pro-survival Mcl-1 protein on which AML cells are highly dependent on for survival. Targeting this novel ISR pathway in combination with the Bcl-2 inhibitor venetoclax synergistically killed primary AML blasts, including those with venetoclax-resistant mutations, as well as immunophenotypic leukemic stem cells, and reduced leukemic engraftment in patient-derived AML xenografts. Collectively, these findings provide mechanistic insight into the anti-cancer effects of ceramide and pre-clinical evidence for new approaches to augment Bcl-2 inhibition in the therapy of AML and other cancers with high Mcl-1 dependency.
    DOI:  https://doi.org/10.1182/blood.2021013277
  20. Nat Commun. 2022 Apr 19. 13(1): 2111
    AKT mutant allele-specific activation dictates pharmacologic sensitivities.
    Tripti Shrestha Bhattarai, Tambudzai Shamu, Alexander N Gorelick, Matthew T Chang, Debyani Chakravarty, Elena I Gavrila, Mark T A Donoghue, JianJong Gao, Swati Patel, Sizhi Paul Gao, Margaret H Reynolds, Sarah M Phillips, Tara Soumerai, Wassim Abida, David M Hyman, Alison M Schram, David B Solit, Lillian M Smyth, Barry S Taylor.
      AKT- a key molecular regulator of PI-3K signaling pathway, is somatically mutated in diverse solid cancer types, and aberrant AKT activation promotes altered cancer cell growth, survival, and metabolism1-8. The most common of AKT mutations (AKT1 E17K) sensitizes affected solid tumors to AKT inhibitor therapy7,8. However, the pathway dependence and inhibitor sensitivity of the long tail of potentially activating mutations in AKT is poorly understood, limiting our ability to act clinically in prospectively characterized cancer patients. Here we show, through population-scale driver mutation discovery combined with functional, biological, and therapeutic studies that some but not all missense mutations activate downstream AKT effector pathways in a growth factor-independent manner and sensitize tumor cells to diverse AKT inhibitors. A distinct class of small in-frame duplications paralogous across AKT isoforms induce structural changes different than those of activating missense mutations, leading to a greater degree of membrane affinity, AKT activation, and cell proliferation as well as pathway dependence and hyper-sensitivity to ATP-competitive, but not allosteric AKT inhibitors. Assessing these mutations clinically, we conducted a phase II clinical trial testing the AKT inhibitor capivasertib (AZD5363) in patients with solid tumors harboring AKT alterations (NCT03310541). Twelve patients were enrolled, out of which six harbored AKT1-3 non-E17K mutations. The median progression free survival (PFS) of capivasertib therapy was 84 days (95% CI 50-not reached) with an objective response rate of 25% (n = 3 of 12) and clinical benefit rate of 42% (n = 5 of 12). Collectively, our data indicate that the degree and mechanism of activation of oncogenic AKT mutants vary, thereby dictating allele-specific pharmacological sensitivities to AKT inhibition.
    DOI:  https://doi.org/10.1038/s41467-022-29638-1
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