bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021–06–13
twenty-one papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. PELP1/SRC-3-dependent regulation of metabolic PFKFB kinases drives therapy resistant ER+ breast cancer.
  2. Single-cell lineage tracing of metastatic cancer reveals selection of hybrid EMT states.
  3. αSMA+ fibroblasts suppress Lgr5+ cancer stem cells and restrain colorectal cancer progression.
  4. The circACTN4 interacts with FUBP1 to promote tumorigenesis and progression of breast cancer by regulating the expression of proto-oncogene MYC.
  5. Dual covalent inhibition of PKM and IMPDH targets metabolism in cutaneous metastatic melanoma.
  6. Hypoxia-inducible exosomes facilitate liver-tropic pre-metastatic niche in colorectal cancer.
  7. Pharmacological inhibition of noncanonical EED-EZH2 signaling overcomes chemoresistance in prostate cancer.
  8. Identification of lymphocyte cell-specific protein-tyrosine kinase (LCK) as a driver for invasion and migration of oral cancer by tumor heterogeneity exploitation.
  9. Cancer stem cell-immune cell crosstalk in tumour progression.
  10. Resistance Mechanisms to CDK Inhibition plus Endocrine Therapy Identified.
  11. Analysis of the genomic landscape of yolk sac tumors reveals mechanisms of evolution and chemoresistance.
  12. A Wnt-Independent LGR4-EGFR Signaling Axis in Cancer Metastasis.
  13. MET amplification attenuates lung tumor response to immunotherapy by inhibiting STING.
  14. Targeting the tetraspanin CD81 reduces cancer invasion and metastasis.
  15. Cellular Stress Responses and Metabolic Reprogramming in Cancer Progression and Dormancy.
  16. Dynamic monitoring of circulating tumor DNA to predict prognosis and efficacy of adjuvant chemotherapy after resection of colorectal liver metastases.
  17. Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2.
  18. MPDZ as a novel epigenetic silenced tumor suppressor inhibits growth and progression of lung cancer through the Hippo-YAP pathway.
  19. Mechano-induced cell metabolism promotes microtubule glutamylation to force metastasis.
  20. The biological underpinnings of therapeutic resistance in pancreatic cancer.
  21. Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response.
  1. Oncogene. 2021 Jun 08.
    PELP1/SRC-3-dependent regulation of metabolic PFKFB kinases drives therapy resistant ER+ breast cancer.
    Thu H Truong, Elizabeth A Benner, Kyla M Hagen, Nuri A Temiz, Carlos Perez Kerkvliet, Ying Wang, Emilio Cortes-Sanchez, Chieh-Hsiang Yang, Marygrace C Trousdell, Thomas Pengo, Katrin P Guillen, Bryan E Welm, Camila O Dos Santos, Sucheta Telang, Carol A Lange, Julie H Ostrander.
      Recurrence of metastatic breast cancer stemming from acquired endocrine and chemotherapy resistance remains a health burden for women with luminal (ER+) breast cancer. Disseminated ER+ tumor cells can remain viable but quiescent for years to decades. Contributing factors to metastatic spread include the maintenance and expansion of breast cancer stem cells (CSCs). Breast CSCs frequently exist as a minority population in therapy resistant tumors. In this study, we show that cytoplasmic complexes composed of steroid receptor (SR) co-activators, PELP1 and SRC-3, modulate breast CSC expansion through upregulation of the HIF-activated metabolic target genes PFKFB3 and PFKFB4. Seahorse metabolic assays demonstrated that cytoplasmic PELP1 influences cellular metabolism by increasing both glycolysis and mitochondrial respiration. PELP1 interacts with PFKFB3 and PFKFB4 proteins, and inhibition of PFKFB3 and PFKFB4 kinase activity blocks PELP1-induced tumorspheres and protein-protein interactions with SRC-3. PFKFB4 knockdown inhibited in vivo emergence of circulating tumor cell (CTC) populations in mammary intraductal (MIND) models. Application of PFKFB inhibitors in combination with ER targeted therapies blocked tumorsphere formation in multiple models of advanced breast cancer including tamoxifen (TamR) and paclitaxel (TaxR) resistant models, murine tumor cells, and ER+ patient-derived organoids (PDxO). Together, our data suggest that PELP1, SRC-3, and PFKFBs cooperate to drive ER+ tumor cell populations that include CSCs and CTCs. Identifying non-ER pharmacological targets offers a useful approach to blocking metastatic escape from standard of care ER/estrogen (E2)-targeted strategies to overcome endocrine and chemotherapy resistance.
    DOI:  https://doi.org/10.1038/s41388-021-01871-w
  2. Cancer Cell. 2021 May 28. pii: S1535-6108(21)00271-3. [Epub ahead of print]
    Single-cell lineage tracing of metastatic cancer reveals selection of hybrid EMT states.
    Kamen P Simeonov, China N Byrns, Megan L Clark, Robert J Norgard, Beth Martin, Ben Z Stanger, Jay Shendure, Aaron McKenna, Christopher J Lengner.
      The underpinnings of cancer metastasis remain poorly understood, in part due to a lack of tools for probing their emergence at high resolution. Here we present macsGESTALT, an inducible CRISPR-Cas9-based lineage recorder with highly efficient single-cell capture of both transcriptional and phylogenetic information. Applying macsGESTALT to a mouse model of metastatic pancreatic cancer, we recover ∼380,000 CRISPR target sites and reconstruct dissemination of ∼28,000 single cells across multiple metastatic sites. We find that cells occupy a continuum of epithelial-to-mesenchymal transition (EMT) states. Metastatic potential peaks in rare, late-hybrid EMT states, which are aggressively selected from a predominately epithelial ancestral pool. The gene signatures of these late-hybrid EMT states are predictive of reduced survival in both human pancreatic and lung cancer patients, highlighting their relevance to clinical disease progression. Finally, we observe evidence for in vivo propagation of S100 family gene expression across clonally distinct metastatic subpopulations.
    Keywords:  CRISPR; EMT; S100; barcoding; epithelial-to-mesenchymal transition; evolving barcodes; ineage tracing; metastasis; phylogenetics; single cell
    DOI:  https://doi.org/10.1016/j.ccell.2021.05.005
  3. Oncogene. 2021 Jun 09.
    αSMA+ fibroblasts suppress Lgr5+ cancer stem cells and restrain colorectal cancer progression.
    Kathleen M McAndrews, Karina Vázquez-Arreguín, Changsoo Kwak, Hikaru Sugimoto, Xiaofeng Zheng, Bingrui Li, Michelle L Kirtley, Valerie S LeBleu, Raghu Kalluri.
      The development and progression of solid tumors is dependent on cancer cell autonomous drivers and the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) in the TME possess both tumor-promoting and tumor-restraining functions. In the current study, we interrogated the role of αSMA+ CAFs in a genetic mouse model of metastatic colorectal cancer (CRC). Selective depletion of αSMA+ CAFs resulted in increased tumor invasiveness, lymph node metastasis, and reduced overall survival. Depletion of αSMA+ CAFs reduced BMP4 and increased TGFβ1 secretion from stromal cells, and was associated with increased Lgr5+ cancer stem-like cells (CSCs) and the generation of an immunosuppressive TME with increased frequency of Foxp3+ regulatory T cells and suppression of CD8+ T cells. This study demonstrates that αSMA+ CAFs in CRC exert tumor-restraining functions via BMP4/TGFβ1 paracrine signaling that serves to suppress Lgr5+ CSCs and promote anti-tumor immunity, ultimately limiting CRC progression.
    DOI:  https://doi.org/10.1038/s41388-021-01866-7
  4. Mol Cancer. 2021 Jun 11. 20(1): 91
    The circACTN4 interacts with FUBP1 to promote tumorigenesis and progression of breast cancer by regulating the expression of proto-oncogene MYC.
    Xiaosong Wang, Lei Xing, Rui Yang, Hang Chen, Min Wang, Rong Jiang, Luyu Zhang, Junxia Chen.
       BACKGROUND: Recent studies have revealed that circular RNAs (circRNAs) play significant roles in the occurrence and development of many kinds of cancers including breast cancer (BC). However, the potential functions of most circRNAs and the molecular mechanisms underlying progression of BC remain elusive.
    METHOD: Here, Circular RNA microarray was executed in 4 pairs of breast cancer tissues and para-cancer tissues. The expression and prognostic significance of circACTN4 in BC cells and tissues were determined by qRT-PCR and in situ hybridization. Gain-and loss-of-function experiments were implemented to observe the impacts of circACTN4 on the growth, invasion, and metastasis of BC cells in vitro and in vivo. Mechanistically, chromatin immunoprecipitation, luciferase reporter, RNA pulldown, mass spectrum, RNA immunoprecipitation, fluorescence in situ hybridization and co-immunoprecipitation assays were executed.
    RESULTS: CircACTN4 was significantly upregulated in breast cancer tissues and cells, its expression was correlated with clinical stage and poor prognosis of patients with BC. Ectopic expression of circACTN4 strikingly facilitated the growth, invasion, and metastasis of breast cancer cells in vitro and in vivo. Whereas knockdown of circACTN4 revealed opposite roles. CircACTN4 was mainly distributed in the nucleus. Further mechanistic research proved that circACTN4 could competitively bind to far upstream element binding protein 1 (FUBP1) to prevent the combination between FUBP1 and FIR, thereby activating MYC transcription and facilitating tumor progression of breast cancer. Furthermore, we found that upstream transcription factor 2 (USF2) might promote the biogenesis of circACTN4.
    CONCLUSION: Our findings uncover a pivotal mechanism that circACTN4 mediated by USF2 might interact with FUBP1 to promote the occurrence and development of breast cancer via enhancing the expression of MYC. CircACTN4 could be a novel potential target for diagnosis and treatment of breast cancer.
    Keywords:  Breast cancer; FUBP1; MYC; The RNA-binding protein; circactn4
    DOI:  https://doi.org/10.1186/s12943-021-01383-x
  5. Cancer Res. 2021 Jun 07. pii: canres.2114.2020. [Epub ahead of print]
    Dual covalent inhibition of PKM and IMPDH targets metabolism in cutaneous metastatic melanoma.
    Marwa Zerhouni, Anthony R Martin, Nathan Furstoss, Vincent S Gutierrez, Emilie Jaune, Nedra Tekaya, Guillaume E Beranger, Patricia Abbe, Claire Regazzetti, Hella Amdouni, Mohsine Driowya, Patrice Dubreuil, Frédéric Luciano, Arnaud Jacquel, Meri K Tulic, Thomas Cluzeau, Brendan P O'Hara, Issam Ben-Sahra, Thierry Passeron, Rachid Benhida, Guillaume Robert, Patrick Auberger, Stéphane Rocchi.
      Overcoming acquired drug resistance is a primary challenge in cancer treatment. Notably, more than 50% of BRAFV600E cutaneous metastatic melanoma (CMM) patients eventually develop resistance to BRAF inhibitors. Resistant cells undergo metabolic reprogramming which profoundly influences therapeutic response and promotes tumor progression. Uncovering metabolic vulnerabilities could help suppress CMM tumor growth and overcome drug resistance. Here we identified a drug, HA344, that concomitantly targets two distinct metabolic hubs in cancer cells. HA344 inhibited the final and rate-limiting step of glycolysis through its covalent binding to the pyruvate kinase M2 (PKM2) enzyme, and it concurrently blocked the activity of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme of de novo guanylate synthesis. As a consequence, HA344 efficiently targeted vemurafemib-sensitive and -resistant CMM cells and impaired CMM xenograft tumor growth in mice. In addition, HA344 acted synergistically with BRAF inhibitors on CMM cell lines in vitro. Thus, the mechanism of action of HA344 provides potential therapeutic avenues for patients with CMM and a broad range of different cancers.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-2114
  6. Hepatology. 2021 Jun 10.
    Hypoxia-inducible exosomes facilitate liver-tropic pre-metastatic niche in colorectal cancer.
    Hao Sun, Qingtao Meng, Chengyu Shi, Hongbao Yang, Xiaobo Li, Shenshen Wu, Giuseppe Familiari, Michela Relucenti, Michael Aschner, Xuehao Wang, Rui Chen.
       BACKGROUND & AIMS: Liver metastasis is a frequent occurrences in patients with colorectal cancer (CRC), 15%-25% of CRC patients have liver metastases at the time of initial diagnosis (1). Specifically, some regional-stage patients with mild symptoms (stage Ⅰ or II) will also advance to liver metastases rapidly, even CRC lesion in situ is resected in time. Nevertheless, the precise mechanism of liver metastasis is still unclear.
    APPROACH & RESULTS: Fresh tumor tissues from CRC patients, adjacent noncancerous tissues (ANT) and colorectal adenoma tissues (ADE) were subjected to microarray analysis to identify differentially expressed miRNA. Exosomes from human serum and cell culture medium were separated, quantitated and verified by transmission electronic microscopy and Zetasizer Nano. Luciferase reporter assay, real-time qPCR, western blot, immunoprecipitation, chromatin and re-chromatin immunoprecipitation, migration and invasion assay, PDX mice model, flow cytometry, immunohistochemistry and immunofluorescence staining were employed to explore the regulation among CRC liver metastases, immunosuppression and cell adhesion. In this study, we demonstrated that the hypoxic microenvironment in primary CRC lesions boosted exosome release, selectively initiated a favorable pre-metastatic niche formation in the hepar, but not in other organs. Mechanistically, Kupffer cells (KCs) can phagocytose exosomes contained highly expressed miR-135a-5p from blood circulation into the liver. The exosomal miR-135a-5p initiated LATS2-YAP-MMP7 axis to promote the occurrences of CRC liver metastasis, and CD30-TRAF2-p65-mediated immunosuppression signaling also contributed to this process.
    CONCLUSIONS: Hypoxia-induced exosomal miR-135a-5p correlates with the development, clinical severity and prognosis of CRC liver metastases through the pre-metastatic niche, and our findings revealed that miR-135a-5p might be a promising target in halting CRC liver metastases.
    Keywords:  Colorectal Cancer; Exosome; Liver Metastasis; Pre-Metastatic Niche
    DOI:  https://doi.org/10.1002/hep.32009
  7. Theranostics. 2021 ;11(14): 6873-6890
    Pharmacological inhibition of noncanonical EED-EZH2 signaling overcomes chemoresistance in prostate cancer.
    Xin Li, Lajos Gera, Shumin Zhang, Yanhua Chen, Lei Lou, Lauren Marie Wilson, Zhong-Ru Xie, Giuseppe Sautto, Degang Liu, Alira Danaher, Kenza Mamouni, Yang Yang, Yuhong Du, Haian Fu, Omer Kucuk, Adeboye O Osunkoya, Jia Zhou, Daqing Wu.
      Rationale: Chemoresistance is a major obstacle in prostate cancer (PCa) treatment. We sought to understand the underlying mechanism of PCa chemoresistance and discover new treatments to overcome docetaxel resistance. Methods: We developed a novel phenotypic screening platform for the discovery of specific inhibitors of chemoresistant PCa cells. The mechanism of action of the lead compound was investigated using computational, molecular and cellular approaches. The in vivo toxicity and efficacy of the lead compound were evaluated in clinically-relevant animal models. Results: We identified LG1980 as a lead compound that demonstrates high selectivity and potency against chemoresistant PCa cells. Mechanistically, LG1980 binds embryonic ectoderm development (EED), disrupts the interaction between EED and enhancer of zeste homolog 2 (EZH2), thereby inducing the protein degradation of EZH2 and inhibiting the phosphorylation and activity of EZH2. Consequently, LG1980 targets a survival signaling cascade consisting of signal transducer and activator of transcription 3 (Stat3), S-phase kinase-associated protein 2 (SKP2), ATP binding cassette B 1 (ABCB1) and survivin. As a lead compound, LG1980 is well tolerated in mice and effectively suppresses the in vivo growth of chemoresistant PCa and synergistically enhances the efficacy of docetaxel in xenograft models. Conclusions: These results indicate that pharmacological inhibition of EED-EZH2 interaction is a novel strategy for the treatment of chemoresistant PCa. LG1980 and its analogues have the potential to be integrated into standard of care to improve clinical outcomes in PCa patients.
    Keywords:  EED inhibitor; EZH2 signaling; chemoresistance; drug discovery; prostate cancer
    DOI:  https://doi.org/10.7150/thno.49235
  8. Mol Cancer. 2021 Jun 11. 20(1): 88
    Identification of lymphocyte cell-specific protein-tyrosine kinase (LCK) as a driver for invasion and migration of oral cancer by tumor heterogeneity exploitation.
    Jonas Weiße, Julia Rosemann, Lisa Müller, Matthias Kappler, Alexander W Eckert, Markus Glaß, Danny Misiak, Stefan Hüttelmaier, Wolfgang G Ballhausen, Mechthild Hatzfeld, Monika Haemmerle, Tony Gutschner.
       BACKGROUND: Cancer metastases are the main cause of lethality. The five-year survival rate for patients diagnosed with advanced stage oral cancer is 30%. Hence, the identification of novel therapeutic targets is an urgent need. However, tumors are comprised of a heterogeneous collection of cells with distinct genetic and molecular profiles that can differentially promote metastasis making therapy development a challenging task. Here, we leveraged intratumoral heterogeneity in order to identify drivers of cancer cell motility that might be druggable targets for anti-metastasis therapy.
    METHODS: We used 2D migration and 3D matrigel-based invasion assays to characterize the invasive heterogeneity among and within four human oral cancer cell lines in vitro. Subsequently, we applied mRNA-sequencing to map the transcriptomes of poorly and strongly invasive subclones as well as primary tumors and matched metastasis.
    RESULTS: We identified SAS cells as a highly invasive oral cancer cell line. Clonal analysis of SAS yielded a panel of 20 subclones with different invasive capacities. Integrative gene expression analysis identified the Lymphocyte cell-specific protein-tyrosine kinase (LCK) as a druggable target gene associated with cancer cell invasion and metastasis. Inhibition of LCK using A-770041 or dasatinib blocked invasion of highly aggressive SAS cells. Interestingly, reduction of LCK activity increased the formation of adherens junctions and induced cell differentiation.
    CONCLUSION: Analysis of invasive heterogeneity led to the discovery of LCK as an important regulator of motility in oral cancer cells. Hence, small molecule mediated inhibition of LCK could be a promising anti-metastasis therapy option for oral cancer patients.
    Keywords:  Clonal heterogeneity; Dasatinib; EMT; HNSCC; ITH; Invasion; Metastasis; OSCC; Src
    DOI:  https://doi.org/10.1186/s12943-021-01384-w
  9. Nat Rev Cancer. 2021 Jun 08.
    Cancer stem cell-immune cell crosstalk in tumour progression.
    Defne Bayik, Justin D Lathia.
      Cellular heterogeneity and an immunosuppressive tumour microenvironment are independent yet synergistic drivers of tumour progression and underlie therapeutic resistance. Recent studies have highlighted the complex interaction between these cell-intrinsic and cell-extrinsic mechanisms. The reciprocal communication between cancer stem cells (CSCs) and infiltrating immune cell populations in the tumour microenvironment is a paradigm for these interactions. In this Perspective, we discuss the signalling programmes that simultaneously induce CSCs and reprogramme the immune response to facilitate tumour immune evasion, metastasis and recurrence. We further highlight biological factors that can impact the nature of CSC-immune cell communication. Finally, we discuss targeting opportunities for simultaneous regulation of the CSC niche and immunosurveillance.
    DOI:  https://doi.org/10.1038/s41568-021-00366-w
  10. Cancer Discov. 2021 Jun 11.
    Resistance Mechanisms to CDK Inhibition plus Endocrine Therapy Identified.
      In early-stage breast cancer, ribociclib plus letrozole led to estrogen-independent resistance pathways.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2021-083
  11. Nat Commun. 2021 Jun 11. 12(1): 3579
    Analysis of the genomic landscape of yolk sac tumors reveals mechanisms of evolution and chemoresistance.
    Xuan Zong, Ying Zhang, Xinxin Peng, Dongyan Cao, Mei Yu, Jinhui Wang, Hongyue Li, Xuejiao Guo, Han Liang, Jiaxin Yang.
      Yolk sac tumors (YSTs) are a major histological subtype of malignant ovarian germ cell tumors with a relatively poor prognosis. The molecular basis of this disease has not been thoroughly characterized at the genomic level. Here we perform whole-exome and RNA sequencing on 41 clinical tumor samples from 30 YST patients, with distinct responses to cisplatin-based chemotherapy. We show that microsatellite instability status and mutational signatures are informative of chemoresistance. We identify somatic driver candidates, including significantly mutated genes KRAS and KIT and copy-number alteration drivers, including deleted ARID1A and PARK2, and amplified ZNF217, CDKN1B, and KRAS. YSTs have very infrequent TP53 mutations, whereas the tumors from patients with abnormal gonadal development contain both KRAS and TP53 mutations. We further reveal a role of OVOL2 overexpression in YST resistance to cisplatin. This study lays a critical foundation for understanding key molecular aberrations in YSTs and developing related therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-021-23681-0
  12. Cancer Res. 2021 Jun 07. pii: canres.1112.2021. [Epub ahead of print]
    A Wnt-Independent LGR4-EGFR Signaling Axis in Cancer Metastasis.
    Fei Yue, Weiyu Jiang, Amy T Ku, Adelaide I J Young, Weijie Zhang, Eric P Souto, Yankun Gao, Zihan Yu, Yi Wang, Chad J Creighton, Chandandeep Nagi, Tao Wang, Susan G Hilsenbeck, Xin-Hua Feng, Shixia Huang, Cristian Coarfa, Xiang H-F Zhang, Qingyun Liu, Xia Lin, Yi Li.
      Leucine-rich repeat-containing G protein-coupled receptors 4, 5, and 6 (LGR4/5/6) play critical roles in development and cancer. The widely accepted mechanism is that these proteins, together with their R-spondin ligands, stabilize Wnt receptors, thus potentiating Wnt signaling. Here we show that LGR4 enhanced breast cancer cell metastasis even when Wnt signaling was deactivated pharmacologically or genetically. Furthermore, LGR4 mutants that cannot potentiate Wnt signaling nevertheless promoted breast cancer cell migration and invasion in vitro and breast cancer metastasis in vivo. Multi-omic screening identified EGFR as a crucial mediator of LGR4 activity in cancer progression. Mechanistically, LGR4 interacted with EGFR and blocked EGFR ubiquitination and degradation, resulting in persistent EGFR activation. Together, these data uncover a Wnt-independent LGR4-EGFR signaling axis with broad implications for cancer progression and targeted therapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-1112
  13. Cancer Discov. 2021 Jun 07. pii: candisc.1500.2020. [Epub ahead of print]
    MET amplification attenuates lung tumor response to immunotherapy by inhibiting STING.
    Yong Zhang, Qifan Yang, Xiangyu Zeng, Manxiang Wang, Shuang Dong, Bin Yang, Xinyi Tu, Ting Wei, Wenzhuan Xie, Chao Zhang, Qiang Guo, Jake A Kloeber, Yueyu Cao, Guijie Guo, Qin Zhou, Fei Zhao, Jinzhou Huang, Li Liu, Kai Zhang, Mingwei Wang, Ping Yin, Kuntian Luo, Min Deng, Wootae Kim, Jing Hou, Yu Shi, Qian Zhu, Lifeng Chen, Sheng Hu, Junqiu Yue, Guoliang Pi, Zhenkun Lou.
      Immune checkpoint blockade (ICB) has revolutionized cancer therapy. However, the response of patients to ICB is difficult to predict. Here, we examined 81 lung cancer patients under ICB treatment and found that patients with MET amplification were resistant to ICB and had a poor progress-free survival. Tumors with MET amplifications had significantly decreased STING levels and antitumor T cell infiltration. Furthermore, we performed deep single-cell RNA sequencing on more than 20000 single immune cells and identified an immunosuppressive signature with increased subsets of XIST- and CD96-positive exhausted NK cells and decreased CD8+ T cell and NK cell populations in patients with MET-amplification. Mechanistically, we found that oncogenic MET signaling induces phosphorylation of UPF1 and downregulates tumor cell STING expression via modulation of the 3'-UTR length of STING by UPF1. Decreased efficiency of ICB by MET amplification can be overcome by inhibiting MET.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1500
  14. Proc Natl Acad Sci U S A. 2021 Jun 15. pii: e2018961118. [Epub ahead of print]118(24):
    Targeting the tetraspanin CD81 reduces cancer invasion and metastasis.
    Felipe Vences-Catalán, Ranjani Rajapaksa, Chiung-Chi Kuo, Caitlyn L Miller, Anderson Lee, Vishnu C Ramani, Stefanie S Jeffrey, Ronald Levy, Shoshana Levy.
      Tetraspanins are an evolutionary conserved family of proteins involved in multiple aspects of cell physiology, including proliferation, migration and invasion, protein trafficking, and signal transduction; yet their detailed mechanism of action is unknown. Tetraspanins have no known natural ligands, but their engagement by antibodies has begun to reveal their role in cell biology. Studies of tetraspanin knockout mice and of germline mutations in humans have highlighted their role under normal and pathological conditions. Previously, we have shown that mice deficient in the tetraspanin CD81 developed fewer breast cancer metastases compared to their wild-type (WT) counterparts. Here, we show that a unique anti-human CD81 antibody (5A6) effectively halts invasion of triple-negative breast cancer (TNBC) cell lines. We demonstrate that 5A6 induces CD81 clustering at the cell membrane and we implicate JAM-A protein in the ability of this antibody to inhibit tumor cell invasion and migration. Furthermore, in a series of in vivo studies we demonstrate that this antibody inhibits metastases in xenograft models, as well as in syngeneic mice bearing a mouse tumor into which we knocked in the human CD81 epitope recognized by the 5A6 antibody.
    Keywords:  JAM-A; immunotherapy; xenograft
    DOI:  https://doi.org/10.1073/pnas.2018961118
  15. Semin Cancer Biol. 2021 Jun 04. pii: S1044-579X(21)00172-3. [Epub ahead of print]
    Cellular Stress Responses and Metabolic Reprogramming in Cancer Progression and Dormancy.
    Kyle K Payne.
      Recurrent disease after prolonged tumor dormancy is a major cause of cancer associated mortality, yet many of the mechanisms that are engaged to initiate dormancy as well as later recurrence remain incompletely understood. It is known that cancer cells initiate adaptation mechanisms to adapt tightly regulated cellular processes to non-optimal growth environments; Recent investigations have begun to elucidate the contribution of these mechanisms to malignant progression, with intriguing studies now defining cellular stress as a key contributor to the development and maintenance of cancer dormancy. This review will discuss our current understanding of stress responses facilitating malignant cell adaptation and metabolic reprogramming to establish tumor dormancy.
    Keywords:  Cancer dormancy; Cancer recurrence; Endoplasmic Reticulum stress; Metabolism; Oxidative Stress
    DOI:  https://doi.org/10.1016/j.semcancer.2021.06.004
  16. Theranostics. 2021 ;11(14): 7018-7028
    Dynamic monitoring of circulating tumor DNA to predict prognosis and efficacy of adjuvant chemotherapy after resection of colorectal liver metastases.
    De-Shen Wang, Hui Yang, Xiao-Yun Liu, Zhi-Gang Chen, Yun Wang, William Pat Fong, Ming-Tao Hu, Yuan-Chao Zheng, Yun Zheng, Bin-Kui Li, Yun-Fei Yuan, Gong Chen, Zhi-Zhong Pan, Lele Song, Yu-Hong Li, Rui-Hua Xu.
      Rationale: Hepatectomy and adjuvant chemotherapy after resection of colorectal liver metastases (CRLM) may improve survival, however, patients which may benefit cannot currently be identified. Postoperative circulating tumor DNA (ctDNA) analysis can detect minimal residual disease (MRD) and predict the prognosis and efficacy of adjuvant chemotherapy. Our study aims to determine the impact of serial ctDNA analysis to predict the outcome among patients undergoing resection of CRLM. Methods: Between May 2018 and October 2019, 91 CRLM patients were prospectively enrolled. Whole exome sequencing was performed in 50 primary and 48 metastatic liver tissues. Targeted sequencing of 451 cancer relevant genes was performed in 50 baseline plasma to determine plasma-tissue concordance. We prospectively investigated changes in the amount and constitution of ctDNA in 271 serial plasma samples taken at different time points (baseline, pre-operation, post-operation, post-operative adjuvant chemotherapy (post-ACT) and recurrence) during the treatment of CRLM. Results: Detected molecular alterations were highly consistent among baseline ctDNA, primary and liver metastases tissue. Patients with a higher variant allele frequency (VAF) level at baseline ctDNA represent a higher tumor burden, and decreased ctDNA during pre-operative chemotherapy predicted better tumor response. Patients with detectable post-operative and post-ACT ctDNA were associated with significantly shorter recurrence-free survival (RFS). ROC analysis showed that post-ACT ctDNA status was superior to post-operative ctDNA status in predicting RFS with an AUROC of 0.79. A significant difference in overall recurrence rate was observed in patients with detectable vs undetectable levels of ctDNA after resection of CRLM (79.4% vs 41.7%) and after completion of adjuvant chemotherapy (77.3% vs 40.7%). During adjuvant chemotherapy, patients with decreased ctDNA VAF after adjuvant chemotherapy had a recurrence rate of 63.6%, compared to 92.3% in patients with increased ctDNA VAF. Conclusions: We envision that dynamic ctDNA analysis, especially in a post-ACT setting, might be used to not only reflect MRD but also to determine rational personalized adjuvant therapy after the resection of CRLM.
    Keywords:  adjuvant chemotherapy; colorectal liver metastases; ctDNA; next-generation sequencing; prognosis
    DOI:  https://doi.org/10.7150/thno.59644
  17. Nat Commun. 2021 06 07. 12(1): 3356
    Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2.
    Lindsey R Pack, Leighton H Daigh, Mingyu Chung, Tobias Meyer.
      Since their discovery as drivers of proliferation, cyclin-dependent kinases (CDKs) have been considered therapeutic targets. Small molecule inhibitors of CDK4/6 are used and tested in clinical trials to treat multiple cancer types. Despite their clinical importance, little is known about how CDK4/6 inhibitors affect the stability of CDK4/6 complexes, which bind cyclins and inhibitory proteins such as p21. We develop an assay to monitor CDK complex stability inside the nucleus. Unexpectedly, treatment with CDK4/6 inhibitors-palbociclib, ribociclib, or abemaciclib-immediately dissociates p21 selectively from CDK4 but not CDK6 complexes. This effect mediates indirect inhibition of CDK2 activity by p21 but not p27 redistribution. Our work shows that CDK4/6 inhibitors have two roles: non-catalytic inhibition of CDK2 via p21 displacement from CDK4 complexes, and catalytic inhibition of CDK4/6 independent of p21. By broadening the non-catalytic displacement to p27 and CDK6 containing complexes, next-generation CDK4/6 inhibitors may have improved efficacy and overcome resistance mechanisms.
    DOI:  https://doi.org/10.1038/s41467-021-23612-z
  18. Oncogene. 2021 Jun 09.
    MPDZ as a novel epigenetic silenced tumor suppressor inhibits growth and progression of lung cancer through the Hippo-YAP pathway.
    Wenbin Liu, Yongsheng Huang, Dandan Wang, Fei Han, Hongqiang Chen, Jianping Chen, Xiao Jiang, Jia Cao, Jinyi Liu.
      MPDZ also named MUPP1 is involved in signal transduction mediated by the formation of protein complexes. However, the expression regulation, clinical significance, potential function, and mechanism of this gene in lung cancer remain unclear. Methylation status of MPDZ was measured by methylation-specific PCR and bisulfite genomic sequencing. Kaplan-Meier and Cox regression analyses were performed to identify the prognostic value of MPDZ. The tumor suppressing effects of MPDZ were determined in vitro and in vivo. The target molecules and signaling pathway that mediated the function of MPDZ were also identified. MPDZ methylation was identified in 61.2% of primary lung cancer tissues and most lung cancer cell lines but not in normal lung tissues. MPDZ expression was significantly downregulated in lung cancer tissues and negatively associated with DNA hypermethylation, and attenuated MPDZ expression predicted a poor outcome. Furthermore, MPDZ overexpression prominently dampened cell growth, migration, and invasion of tumor cells. Conversely, MPDZ knockdown promoted cell proliferation, migration, and invasion in vitro and in vivo. Moreover, MPDZ deficiency promotes tumor metastasis and reduces the survival of MPDZ knockout mice. Importantly, MPDZ promotes tumor suppressor ability that depends on the Hippo pathway-mediated repression of YAP. MPDZ activates the phosphorylation of YAP (Ser127) and inhibits YAP expression through stabilizing MST1 and interaction with LATS1. We first identified and validated that MPDZ methylation and expression could be a good diagnostic marker and independent prognostic factor for lung cancer. MPDZ functions as a tumor suppressor by inhibiting cell proliferation, migration, and invasion through regulating the Hippo-YAP signaling pathway.
    DOI:  https://doi.org/10.1038/s41388-021-01857-8
  19. Cell Metab. 2021 May 31. pii: S1550-4131(21)00226-6. [Epub ahead of print]
    Mechano-induced cell metabolism promotes microtubule glutamylation to force metastasis.
    Stéphanie Torrino, Eloise M Grasset, Stephane Audebert, Ilyes Belhadj, Caroline Lacoux, Meagan Haynes, Sabrina Pisano, Sophie Abélanet, Frederic Brau, Stephen Y Chan, Bernard Mari, William M Oldham, Andrew J Ewald, Thomas Bertero.
      Mechanical signals from the tumor microenvironment modulate cell mechanics and influence cell metabolism to promote cancer aggressiveness. Cells withstand external forces by adjusting the stiffness of their cytoskeleton. Microtubules (MTs) act as compression-bearing elements. Yet how cancer cells regulate MT dynamic in response to the locally constrained environment has remained unclear. Using breast cancer as a model of a disease in which mechanical signaling promotes disease progression, we show that matrix stiffening rewires glutamine metabolism to promote MT glutamylation and force MT stabilization, thereby promoting cell invasion. Pharmacologic inhibition of glutamine metabolism decreased MT glutamylation and affected their mechanical stabilization. Similarly, decreased MT glutamylation by overexpressing tubulin mutants lacking glutamylation site(s) decreased MT stability, thereby hampering cancer aggressiveness in vitro and in vivo. Together, our results decipher part of the enigmatic tubulin code that coordinates the fine-tunable properties of MT and link cell metabolism to MT dynamics and cancer aggressiveness.
    Keywords:  breast cancer; cancer cell metabolism; glutamine metabolism; glutamylation; mechanobiology; microtubules; posttranslational modifications
    DOI:  https://doi.org/10.1016/j.cmet.2021.05.009
  20. Genes Dev. 2021 Jun 11.
    The biological underpinnings of therapeutic resistance in pancreatic cancer.
    Gregory L Beatty, Gregor Werba, Costas A Lyssiotis, Diane M Simeone.
      Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality in the United States and has only recently achieved a 5-yr survival rate of 10%. This dismal prognosis reflects the remarkable capacity of PDAC to effectively adapt to and resist therapeutic intervention. In this review, we discuss recent advances in our understanding of the biological underpinnings of PDAC and their implications as targetable vulnerabilities in this highly lethal disease.
    Keywords:  PDAC; genetics; metabolism; microbiome; pancreatic cancer; pancreatic tumor microenvironment; targeted therapy; therapeutic resistance
    DOI:  https://doi.org/10.1101/gad.348523.121
  21. Proc Natl Acad Sci U S A. 2021 Jun 15. pii: e2103240118. [Epub ahead of print]118(24):
    Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response.
    Yuping Zhang, Sathiya P Narayanan, Rahul Mannan, Gregory Raskind, Xiaoming Wang, Pankaj Vats, Fengyun Su, Noshad Hosseini, Xuhong Cao, Chandan Kumar-Sinha, Stephanie J Ellison, Thomas J Giordano, Todd M Morgan, Sethuramasundaram Pitchiaya, Ajjai Alva, Rohit Mehra, Marcin Cieslik, Saravana M Dhanasekaran, Arul M Chinnaiyan.
      Diverse subtypes of renal cell carcinomas (RCCs) display a wide spectrum of histomorphologies, proteogenomic alterations, immune cell infiltration patterns, and clinical behavior. Delineating the cells of origin for different RCC subtypes will provide mechanistic insights into their diverse pathobiology. Here, we employed single-cell RNA sequencing (scRNA-seq) to develop benign and malignant renal cell atlases. Using a random forest model trained on this cell atlas, we predicted the putative cell of origin for more than 10 RCC subtypes. scRNA-seq also revealed several attributes of the tumor microenvironment in the most common subtype of kidney cancer, clear cell RCC (ccRCC). We elucidated an active role for tumor epithelia in promoting immune cell infiltration, potentially explaining why ccRCC responds to immune checkpoint inhibitors, despite having a low neoantigen burden. In addition, we characterized an association between high endothelial cell types and lack of response to immunotherapy in ccRCC. Taken together, these single-cell analyses of benign kidney and RCC provide insight into the putative cell of origin for RCC subtypes and highlight the important role of the tumor microenvironment in influencing ccRCC biology and response to therapy.
    Keywords:  cell of origin; clear cell renal cell carcinoma; renal cell carcinoma; single-cell RNA sequencing; tumor microenvironment
    DOI:  https://doi.org/10.1073/pnas.2103240118
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