bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒12‒06
twenty-five papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology


  1. Mol Cancer. 2020 Dec 01. 19(1): 168
    Ju S, Wang F, Wang Y, Ju S.
      Hypoxic stress plays a pivotal role in cancer progression; however, how hypoxia drives tumors to become more aggressive or metastatic and adaptive to adverse environmental stress is still poorly understood. In this study, we revealed that CSN8 might be a key regulatory switch controlling hypoxia-induced malignant tumor progression. We demonstrated that the expression of CSN8 increased significantly in colorectal cancerous tissues, which was correlated with lymph node metastasis and predicted poor patient survival. CSN8 overexpression induces the epithelial-mesenchymal transition (EMT) process in colorectal cancer cells, increasing migration and invasion. CSN8 overexpression arrested cell proliferation, upregulated key dormancy marker (NR2F1, DEC2, p27) and hypoxia response genes (HIF-1α, GLUT1), and dramatically enhanced survival under hypoxia, serum deprivation, or chemo-drug 5-fluorouracil treatment conditions. In particular, silenced CSN8 blocks the EMT and dormancy processes induced by the hypoxia of 1% O2 in vitro and undermines the adaptive capacity of colorectal cancer cells in vivo. The further study showed that CSN8 regulated EMT and dormancy partly by activating the HIF-1α signaling pathway, which increased HIF-1α mRNA expression by activating NF-κB and stabilized the HIF-1α protein via HIF-1α de-ubiquitination. Taken together, CSN8 endows primary colorectal cancer cells with highly aggressive/metastatic and adaptive capacities through regulating both EMT and dormancy induced by hypoxia. CSN8 could serve as a novel prognostic biomarker for colorectal cancer and would be an ideal target of disseminated dormant cell elimination and tumor metastasis, recurrence, and chemoresistance prevention.
    Keywords:  CSN8; Colorectal cancer; Dormancy; Epithelial–mesenchymal transition; Hypoxia
    DOI:  https://doi.org/10.1186/s12943-020-01285-4
  2. Trends Cancer. 2020 Nov 28. pii: S2405-8033(20)30302-2. [Epub ahead of print]
    Gensbittel V, Busnelli I, Osmani N, Goetz JG.
      Clustering of tumor cells is known to grant superior metastatic efficiency compared with single cells. However, the mechanisms involved remain elusive. Reporting in Cell, Wrenn et al. describe how sealed intercellular compartments, nanolumina, are used as growth factor reservoirs within tumor cell clusters to regulate tumor cell proliferation.
    DOI:  https://doi.org/10.1016/j.trecan.2020.11.003
  3. Cancer Res. 2020 Dec 04. pii: canres.1965.2020. [Epub ahead of print]
    Gao L, Zhang W, Zhang J, Liu J, Sun F, Liu H, Hu J, Wang X, Wang X, Su P, Chen S, Qu S, Shi B, Xiong X, Chen W, Dong X, Han B.
      The new generation androgen receptor (AR) pathway inhibitor enzalutamide can prolong the survival of patients with metastatic prostate cancer (PCa). However, resistance to enzalutamide inevitably develops in these patients, and the underlying mechanisms this resistance are not fully defined. Here we demonstrate that the kinesin family member 15 (KIF15) contributes to enzalutamide resistance by enhancing the AR signaling in prostate cancer (PCa) cells. KIF15 directly bound the N-terminus of AR/AR-V7 and prevented AR/AR-V7 proteins from degradation by increasing the protein association of ubiquitin-specific protease 14 (USP14) with AR/AR-V7. In turn, the transcriptionally active AR stimulated KIF15 expression. KIF15 inhibitors alone or in combination with enzalutamide significantly suppressed enzalutamide-resistant PCa cell growth and xenograft progression. These findings highlight a key role of KIF15 in enabling PCa cells to develop therapy resistance to enzalutamide and rationalize KIF15 as a potential therapeutic target.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1965
  4. Clin Cancer Res. 2020 Dec 01. pii: clincanres.0232.2020. [Epub ahead of print]
    Bernat-Peguera A, Navarro-Ventura J, Lorenzo-Sanz L, da Silva-Diz V, Bosio M, Palomero L, Penin RM, Pérez Sidelnikova D, Bermejo Segú JO, Taberna M, Vilariño N, Piulats JM, Mesia R, Viñals JM, González-Suárez E, Capella-Gutierrez S, Villanueva A, Viñals F, Muñoz P.
      PURPOSE: Recurrent and/or metastatic unresectable cutaneous squamous cell carcinomas (cSCCs) are treated with chemotherapy or radiotherapy but have poor clinical responses. A limited response (up to 45% of cases) to EGFR-targeted therapies was observed in clinical trials with advanced and metastatic cSCC patients. Here, we analyze the molecular traits underlying the response to EGFR inhibitors, and the mechanisms responsible for cSCC resistance to EGFR-targeted therapy.EXPERIMENTAL DESIGN: We generated primary cell cultures and patient cSCC-derived xenografts (cSCC-PDXs) that recapitulate the histopathological and molecular features of patient tumors. Response to gefitinib treatment was tested and gefitinib-resistant (GefR) cSCC-PDXs were developed. RNA sequence analysis was performed in matched untreated and GefR cSCC-PDXs to determine the mechanisms driving gefitinib resistance.
    RESULTS: cSCCs conserving epithelial traits exhibited strong activation of EGFR signaling, which promoted tumor cell proliferation, in contrast to mesenchymal-like cSCCs. Gefitinib treatment strongly blocked epithelial-like cSCC-PDX growth in the absence of EGFR and RAS mutations, whereas tumors carrying the E545K PIK3CA-activating mutation were resistant to treatment. A subset of initially responding tumors acquired resistance after long-term treatment, which was induced by the bypass from EGFR to FGFR signaling to allow tumor cell proliferation and survival upon gefitinib treatment. Pharmacological inhibition of FGFR signaling overcame resistance to EGFR inhibitor, even in PIK3CA-mutated tumors.
    CONCLUSIONS: EGFR-targeted therapy may be appropriate for treating many epithelial-like cSCCs without PIK3CA-activating mutations. Combined EGFR- and FGFR-targeted therapy may be used to treat cSCCs that show intrinsic or acquired resistance to EGFR inhibitors.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-0232
  5. Mol Cancer Res. 2020 Nov 30. pii: molcanres.0708.2020. [Epub ahead of print]
    Agostini LC, Jain A, Shupp A, Nevler A, McCarthy G, Bussard KM, Yeo CJ, Brody JR.
      The DNA damage response (DDR) pathway sets the stage for tumorigenesis and provides both an opportunity for drug efficacy and resistance. Therapeutic approaches to target the DDR pathway include aiming to increase the efficacy of cytotoxic chemotherapies and synergistic drug strategies to enhance DNA damage, and hence cell death. Here, we report the first preclinical evaluation of a novel synergistic approach by using both genetic and small molecule inhibition methods of silencing the DDR related protein, PARG (poly (ADP) ribose glycohydrolase) and the checkpoint kinase inhibitor, Wee1, in pancreatic ductal adenocarcinoma (PDAC) and colorectal carcinoma (CRC) cells in vitro and in vivo. Mechanistically, we demonstrate that co-inhibition of PARG and Wee1 synergistically decreased cell survival and increased DNA damage in an S-phase dependent manner. Implications: In pre-clinical models, we demonstrate the efficacy and mechanism of action of targeting both PARG and Wee1 in PDAC and CRC cells.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-20-0708
  6. Blood. 2020 Dec 03. pii: blood.2020005710. [Epub ahead of print]
    Feinauer MJ, Schneider SW, Berghoff AS, Robador JR, Tehranian C, Karreman MA, Venkataramani V, Solecki G, Grosch JK, Gunkel K, Kovalchuk B, Mayer FT, Fischer M, O Breckwoldt M, Brune M, Schwab Y, Wick W, Bauer AT, Winkler F.
      Clinically relevant brain metastases (BM) frequently form in cancer patients, with limited options for effective treatment. Circulating cancer cells must first permanently arrest in brain microvessels to colonize the brain, but the critical factors are not well understood. Here, in vivo multiphoton laser-scanning microscopy (MPLSM) of the entire brain metastatic cascade allowed unprecedented insights into how blood clot formation and von Willebrand factor (VWF) deposition determine the arrest of circulating cancer cells and subsequent brain colonization in mice. Clot formation in brain microvessels occurred frequently (>95%) and specifically at intravascularly arrested cancer cells, allowing their long-time arrest. An extensive clot embedded approximately 20% of brain-arrested cancer cells, and those were more likely to successfully extravasate and form a macrometastasis. Mechanistically, tissue factor-mediated thrombin generation by cancer cells accounted for local activation of plasmatic coagulation in the brain. Thrombin inhibition by treatment with low-molecular weight heparin or dabigatran and an anti-VWF antibody prevented clot formation, cancer cell arrest, extravasation, and brain macrometastasis formation. In contrast, tumor cells were not able to directly activate platelets, and antiplatelet treatments did reduce platelet dispositions at intravascular cancer cells but did not reduce overall BM formation. In conclusion, our data shows that plasmatic coagulation is activated early by intravascular tumor cells in the brain, with subsequent clot formation, discovering a novel and specific mechanism that is crucial for brain colonization. Direct or indirect thrombin and VWF inhibitors emerge as promising drug candidates for BM prevention trials.
    DOI:  https://doi.org/10.1182/blood.2020005710
  7. Nat Mater. 2020 Nov 30.
    Maller O, Drain AP, Barrett AS, Borgquist S, Ruffell B, Zakharevich I, Pham TT, Gruosso T, Kuasne H, Lakins JN, Acerbi I, Barnes JM, Nemkov T, Chauhan A, Gruenberg J, Nasir A, Bjarnadottir O, Werb Z, Kabos P, Chen YY, Hwang ES, Park M, Coussens LM, Nelson AC, Hansen KC, Weaver VM.
      Stromal stiffening accompanies malignancy, compromises treatment and promotes tumour aggression. Clarifying the molecular nature and the factors that regulate stromal stiffening in tumours should identify biomarkers to stratify patients for therapy and interventions to improve outcome. We profiled lysyl hydroxylase-mediated and lysyl oxidase-mediated collagen crosslinks and quantified the greatest abundance of total and complex collagen crosslinks in aggressive human breast cancer subtypes with the stiffest stroma. These tissues harbour the highest number of tumour-associated macrophages, whose therapeutic ablation in experimental models reduced metastasis, and decreased collagen crosslinks and stromal stiffening. Epithelial-targeted expression of the crosslinking enzyme, lysyl oxidase, had no impact on collagen crosslinking in PyMT mammary tumours, whereas stromal cell targeting did. Stromal cells in microdissected human tumours expressed the highest level of collagen crosslinking enzymes. Immunohistochemical analysis of biopsies from a cohort of patients with breast cancer revealed that stromal expression of lysyl hydroxylase 2, an enzyme that induces hydroxylysine aldehyde-derived collagen crosslinks and stromal stiffening, correlated significantly with disease specific mortality. The findings link tissue inflammation, stromal cell-mediated collagen crosslinking and stiffening to tumour aggression and identify lysyl hydroxylase 2 as a stromal biomarker.
    DOI:  https://doi.org/10.1038/s41563-020-00849-5
  8. Cell Rep. 2020 Dec 01. pii: S2211-1247(20)31433-9. [Epub ahead of print]33(9): 108444
    Wohlhieter CA, Richards AL, Uddin F, Hulton CH, Quintanal-Villalonga À, Martin A, de Stanchina E, Bhanot U, Asher M, Shah NS, Hayatt O, Buonocore DJ, Rekhtman N, Shen R, Arbour KC, Donoghue M, Poirier JT, Sen T, Rudin CM.
      Concurrent loss-of-function mutations in STK11 and KEAP1 in lung adenocarcinoma (LUAD) are associated with aggressive tumor growth, resistance to available therapies, and early death. We investigated the effects of coordinate STK11 and KEAP1 loss by comparing co-mutant with single mutant and wild-type isogenic counterparts in multiple LUAD models. STK11/KEAP1 co-mutation results in significantly elevated expression of ferroptosis-protective genes, including SCD and AKR1C1/2/3, and resistance to pharmacologically induced ferroptosis. CRISPR screening further nominates SCD (SCD1) as selectively essential in STK11/KEAP1 co-mutant LUAD. Genetic and pharmacological inhibition of SCD1 confirms the essentiality of this gene and augments the effects of ferroptosis induction by erastin and RSL3. Together these data identify SCD1 as a selective vulnerability and a promising candidate for targeted drug development in STK11/KEAP1 co-mutant LUAD.
    Keywords:  AKR1C1; CRISPR; KEAP1; LKB1; NSCLC; SCD1; STK11; ferroptosis
    DOI:  https://doi.org/10.1016/j.celrep.2020.108444
  9. Cancer Discov. 2020 Dec;10(12): 1791-1793
    Marando L, Huntly BJP.
      Recently, small-molecule inhibitors of general transcriptional regulators such as BET proteins and the RNA-PolII-regulating kinase CDK7 have been shown to have efficacy in multiple solid and liquid tumors. An article in this issue of Cancer Discovery identifies a nongenetic mechanism of resistance related to deficiency of folate that leads, via increased S-adenosylhomocysteine and reduced repressive histone methylation, to reactivation of a transcriptional program which promotes AML cell survival under the pressure of BET inhibition.See related article by Su et al., p. 1894.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1333
  10. Gastric Cancer. 2020 Dec 04.
    Busuttil RA, George J, House CM, Lade S, Mitchell C, Di Costanzo NS, Pattison S, Huang YK, Tan P, Cheong JH, Rha SY, Boussioutas A.
      OBJECTIVE: Gastric cancer patients generally have a poor outcome, particularly those with advanced-stage disease which is defined by the increased invasion of cancer locally and is associated with higher metastatic potential. This study aimed to identify genes that were functional in the most fundamental hallmark of cancer, namely invasion. We then wanted to assess their value as biomarkers of gastric cancer progression and recurrence.DESIGN: Data from a cohort of patients profiled on cDNA expression arrays was interrogated using K-means analysis. This genomic approach classified the data based on patterns of gene expression allowing the identification of the genes most correlated with the invasion of GC. We evaluated the functional role of a key protein from this analysis in invasion and as a biomarker of recurrence after curative resection.
    RESULTS: Expression of secreted frizzled-related protein 4 (SFRP4) was identified as directly proportional to gastric cancer invasion. This finding was validated in multiple, independent datasets and its functional role in invasion was also confirmed using invasion assays. A change in serum levels of SFRP4 after curative resection, when coupled with AJCC stage, can accurately predict the risk of disease recurrence after curative therapy in an assay we termed PredictR.
    CONCLUSIONS: This simple ELISA-based assay can help predict recurrence of disease after curative gastric cancer surgery irrespective of adjuvant therapy. The results require further evaluation in a prospective trial but would help in the rational prescription of cancer therapies and surveillance to prevent under or over treatment of patients after curative resection.
    Keywords:  Biomarker; Gastric cancer; Invasion; Recurrence; SFRP4
    DOI:  https://doi.org/10.1007/s10120-020-01143-8
  11. Cancers (Basel). 2020 Dec 02. pii: E3609. [Epub ahead of print]12(12):
    Robertson H, Dinkova-Kostova AT, Hayes JD.
      NF-E2 p45-related factor 2 (NRF2, encoded in the human by NFE2L2) mediates short-term adaptation to thiol-reactive stressors. In normal cells, activation of NRF2 by a thiol-reactive stressor helps prevent, for a limited period of time, the initiation of cancer by chemical carcinogens through induction of genes encoding drug-metabolising enzymes. However, in many tumour types, NRF2 is permanently upregulated. In such cases, its overexpressed target genes support the promotion and progression of cancer by suppressing oxidative stress, because they constitutively increase the capacity to scavenge reactive oxygen species (ROS), and they support cell proliferation by increasing ribonucleotide synthesis, serine biosynthesis and autophagy. Herein, we describe cancer chemoprevention and the discovery of the essential role played by NRF2 in orchestrating protection against chemical carcinogenesis. We similarly describe the discoveries of somatic mutations in NFE2L2 and the gene encoding the principal NRF2 repressor, Kelch-like ECH-associated protein 1 (KEAP1) along with that encoding a component of the E3 ubiquitin-ligase complex Cullin 3 (CUL3), which result in permanent activation of NRF2, and the recognition that such mutations occur frequently in many types of cancer. Notably, mutations in NFE2L2, KEAP1 and CUL3 that cause persistent upregulation of NRF2 often co-exist with mutations that activate KRAS and the PI3K-PKB/Akt pathway, suggesting NRF2 supports growth of tumours in which KRAS or PKB/Akt are hyperactive. Besides somatic mutations, NRF2 activation in human tumours can occur by other means, such as alternative splicing that results in a NRF2 protein which lacks the KEAP1-binding domain or overexpression of other KEAP1-binding partners that compete with NRF2. Lastly, as NRF2 upregulation is associated with resistance to cancer chemotherapy and radiotherapy, we describe strategies that might be employed to suppress growth and overcome drug resistance in tumours with overactive NRF2.
    Keywords:  ATF4; Cullin 3; KEAP1; NADPH generation; NRF2; adaptation; antioxidant; autophagy; bioactivation; bladder; chemoprevention; chemotherapy; colon; drug metabolism; drug resistance; glutathione; head and neck; initiation; liver; lung; metastasis; oesophagus; oncogene; oxidative stress; pentose phosphate pathway; progression; proteasome; quinone-containing drugs; reactive oxygen species; rectum; recurrent disease; stomach; thioredoxin; tumour suppressor
    DOI:  https://doi.org/10.3390/cancers12123609
  12. Genes Dev. 2020 Dec 01. 34(23-24): 1577-1598
    Shen M, Kang Y.
      Metastasis is the ultimate "survival of the fittest" test for cancer cells, as only a small fraction of disseminated tumor cells can overcome the numerous hurdles they encounter during the transition from the site of origin to a distinctly different distant organ in the face of immune and therapeutic attacks and various other stresses. During cancer progression, tumor cells develop a variety of mechanisms to cope with the stresses they encounter, and acquire the ability to form metastases. Restraining these stress-releasing pathways could serve as potentially effective strategies to prevent or reduce metastasis and improve the survival of cancer patients. Here, we provide an overview of the tumor-intrinsic, microenvironment- and treatment-induced stresses that tumor cells encounter in the metastatic cascade and the molecular pathways they develop to relieve these stresses. We also summarize the preclinical and clinical studies that evaluate the potential therapeutic benefit of targeting these stress-relieving pathways.
    Keywords:  cancer therapeutics; metastasis; stress; tumor microenvironment
    DOI:  https://doi.org/10.1101/gad.343251.120
  13. Oncogene. 2020 Dec 01.
    Song Y, Zeng S, Zheng G, Chen D, Li P, Yang M, Luo K, Yin J, Gu Y, Zhang Z, Jia X, Qiu N, He Z, Li H, Liu H.
      Metastasis remains the major obstacle to improved survival for breast cancer patients. Downregulation of FOXO3a transcription factor in breast cancer is causally associated with the development of metastasis through poorly understood mechanisms. Here, we report that FOXO3a is functionally related to the inhibition of VEGF-A/NRP1 signaling and to the consequent suppression of breast cancer metastasis. We show that FOXO3a directly induces miR-29b-2 and miR-338 expression. Ectopic expression of miR-29b-2/miR-338 significantly suppresses EMT, migration/invasion, and in vivo metastasis of breast cancer. Moreover, we demonstrate that miR-29b-2 directly targets VEGF-A while miR-338 directly targets NRP1, and show that regulation of miR-29b-2 and miR-338 mediates the ability of FOXO3a to suppress VEGF-A/NRP1 signaling and breast cancer metastasis. Clinically, our results show that the FOXO3a-miR-29b-2/miR-338-VEGF-A/NRP1 axis is dysregulated and plays a critical role in disease progression in breast cancer. Collectively, our findings propose that FOXO3a functions as a metastasis suppressor, and define a novel signaling axis of FOXO3a-miRNA-VEGF-A/NRP1 in breast cancer, which might be potential therapeutic targets for breast cancer.
    DOI:  https://doi.org/10.1038/s41388-020-01562-y
  14. Cell Death Differ. 2020 Dec 02.
    Moreno R, Banerjee S, Jackson AW, Quinn J, Baillie G, Dixon JE, Dinkova-Kostova AT, Edwards J, de la Vega L.
      To survive proteotoxic stress, cancer cells activate the proteotoxic-stress response pathway, which is controlled by the transcription factor heat shock factor 1 (HSF1). This pathway supports cancer initiation, cancer progression and chemoresistance and thus is an attractive therapeutic target. As developing inhibitors against transcriptional regulators, such as HSF1 is challenging, the identification and targeting of upstream regulators of HSF1 present a tractable alternative strategy. Here we demonstrate that in triple-negative breast cancer (TNBC) cells, the dual specificity tyrosine-regulated kinase 2 (DYRK2) phosphorylates HSF1, promoting its nuclear stability and transcriptional activity. DYRK2 depletion reduces HSF1 activity and sensitises TNBC cells to proteotoxic stress. Importantly, in tumours from TNBC patients, DYRK2 levels positively correlate with active HSF1 and associates with poor prognosis, suggesting that DYRK2 could be promoting TNBC. These findings identify DYRK2 as a key modulator of the HSF1 transcriptional programme and a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41418-020-00686-8
  15. Front Oncol. 2020 ;10 594514
    Ombrato L, Montagner M.
      Metastases are a major cause of cancer-related death and despite the fact that they have been focus of intense research over the last two decades, effective therapies for patients with distant secondary lesions are still very limited. In addition, in some tumor types metastases can grow years after the patients have been declared clinically cured, indicating that disseminated cancer cells (DCCs) persist undetected for years, even decades in a quiescent state. Clinical and experimental data highlight the importance of the immune system in shaping the fitness and behaviour of DCCs. Here, we review mechanisms of survival, quiescence and outgrowth of DCCs with a special focus on immune-regulation and we highlight the latest cutting-edge techniques for modelling the biology of DCCs in vitro and for studying the metastatic niche in vivo. We believe that a wide dissemination of those techniques will boost scientific findings towards new therapies to defeat metastatic relapses in cancer patients.
    Keywords:  dormancy; immune cells; labeling techniques; metastasis; tumor microenviroment (TME)
    DOI:  https://doi.org/10.3389/fonc.2020.594514
  16. Blood. 2020 Dec 01. pii: blood.2020008528. [Epub ahead of print]
    Boiko S, Proia TA, San Martin M, Gregory G, Wu MM, Aryal NK, Hattersley MM, Shao W, Saeh JC, Fawell S, Johnstone RW, Drew L, Cidado J.
      BH3 mimetics like Venetoclax target pro-survival Bcl-2 family proteins and are important therapeutics in the treatment of hematological malignancies. We demonstrate endogenous Bfl-1 expression can render preclinical lymphoma tumor models insensitive to Mcl-1 and Bcl-2-inhibitors. However, suppression of Bfl-1 alone was insufficient to fully induce apoptosis in Bfl-1-expressing lymphomas, highlighting the need for targeting additional pro-survival proteins in this context. Importantly, we demonstrated that CDK9 inhibitors rapidly downregulate both Bfl-1 and Mcl-1, inducing apoptosis in BH3 mimetic resistant lymphoma cell lines in vitro and driving in vivo tumor regressions in DLBCL PDX models expressing Bfl-1. This data underscores the need to clinically develop CDK9 inhibitors, like AZD4573, for the treatment of lymphomas using Bfl-1 as a selection biomarker.
    DOI:  https://doi.org/10.1182/blood.2020008528
  17. Cell. 2020 Dec 01. pii: S0092-8674(20)31445-8. [Epub ahead of print]
    Donovan KA, Ferguson FM, Bushman JW, Eleuteri NA, Bhunia D, Ryu S, Tan L, Shi K, Yue H, Liu X, Dobrovolsky D, Jiang B, Wang J, Hao M, You I, Teng M, Liang Y, Hatcher J, Li Z, Manz TD, Groendyke B, Hu W, Nam Y, Sengupta S, Cho H, Shin I, Agius MP, Ghobrial IM, Ma MW, Che J, Buhrlage SJ, Sim T, Gray NS, Fischer ES.
      Targeted protein degradation (TPD) refers to the use of small molecules to induce ubiquitin-dependent degradation of proteins. TPD is of interest in drug development, as it can address previously inaccessible targets. However, degrader discovery and optimization remains an inefficient process due to a lack of understanding of the relative importance of the key molecular events required to induce target degradation. Here, we use chemo-proteomics to annotate the degradable kinome. Our expansive dataset provides chemical leads for ∼200 kinases and demonstrates that the current practice of starting from the highest potency binder is an ineffective method for discovering active compounds. We develop multitargeted degraders to answer fundamental questions about the ubiquitin proteasome system, uncovering that kinase degradation is p97 dependent. This work will not only fuel kinase degrader discovery, but also provides a blueprint for evaluating targeted degradation across entire gene families to accelerate understanding of TPD beyond the kinome.
    Keywords:  E3 ligase; IMiD; PROTAC; degrader; kinase; targeted degradation; ubiquitin; ubiquitin proteasome system
    DOI:  https://doi.org/10.1016/j.cell.2020.10.038
  18. Cancers (Basel). 2020 Nov 29. pii: E3566. [Epub ahead of print]12(12):
    Pandey K, Park N, Park KS, Hur J, Cho YB, Kang M, An HJ, Kim S, Hwang S, Moon YW.
      Breast cancer represents the number one global cancer burden in women and the hormone receptor (HR)-positive subtype comprises approximately 70% of breast cancers. Unfortunately, acquired resistance ultimately occurs in almost all cases, even though cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are a highly effective therapy for HR-positive/human epidermal growth factor receptor 2-negative subtype. Here, we investigated mechanisms of resistance to CDK4/6 inhibitor and potential therapeutic strategies using our palbociclib-resistant preclinical model. We observed that cyclin E was significantly overexpressed in palbociclib-resistant cells, and similar association was also confirmed in pleural effusion samples collected from HR-positive breast cancer patients. After confirmation of cyclin E-CDK2 interaction by co-immunoprecipitation, we demonstrated CDK2 inhibition combined with palbociclib synergistically suppressed proliferation of palbociclib-resistant cells and growth of palbociclib-resistant xenograft in mice. We also proved that enhancing C-MYC-mediated senescence is a novel mechanism behind the synergism created by targeting both CDK2 and CDK4/6. Furthermore, the clinical relevance of cyclin E as a therapeutic target was supported by significant association between CCNE1 overexpression and poor prognosis based on large-scale public gene expression data sets in HR-positive breast cancer patients. Therefore, we propose cyclin E-CDK2 signaling as a promising therapeutic target for overcoming cyclin E-associated resistance to CDK4/6 inhibitor.
    Keywords:  C-MYC; CDK2; CDK4/6; drug resistance; hormone receptor-positive breast cancer
    DOI:  https://doi.org/10.3390/cancers12123566
  19. Trends Cancer. 2020 Oct 23. pii: S2405-8033(20)30262-4. [Epub ahead of print]
    Furesi G, Rauner M, Hofbauer LC.
      Patients with advanced prostate cancer (PCa) frequently develop skeletal metastases that are associated with fractures, disability, and increased mortality. Within the bone metastatic niche, mutual interactions between tumor cells and osteoblasts have been proposed as major contributors of osteotropism by PCa. Here, we highlight the emerging role of PCa-derived extracellular vesicles (EVs) in reprogramming osteoblasts and support of premetastatic niche formation. We also develop the concept of cancer-associated osteoblasts (CAOs) and outline the potential of PCa cells to acquire an osteoblastic phenotype, termed osteomimicry, as two strategies that PCa utilizes to create a favorable protected niche. Finally, we delineate future research that may help to deconstruct the complexity of PCa osteotropism.
    Keywords:  bone metastasis; cancer-associated osteoblasts; osteomimicry; prostate cancer; tumor-derived extracellular vesicles; tumor-educated osteoblasts
    DOI:  https://doi.org/10.1016/j.trecan.2020.09.006
  20. Nat Rev Genet. 2020 Nov 30.
    Persi E, Wolf YI, Horn D, Ruppin E, Demichelis F, Gatenby RA, Gillies RJ, Koonin EV.
      Intratumour heterogeneity and phenotypic plasticity, sustained by a range of somatic aberrations, as well as epigenetic and metabolic adaptations, are the principal mechanisms that enable cancers to resist treatment and survive under environmental stress. A comprehensive picture of the interplay between different somatic aberrations, from point mutations to whole-genome duplications, in tumour initiation and progression is lacking. We posit that different genomic aberrations generally exhibit a temporal order, shaped by a balance between the levels of mutations and selective pressures. Repeat instability emerges first, followed by larger aberrations, with compensatory effects leading to robust tumour fitness maintained throughout the tumour progression. A better understanding of the interplay between genetic aberrations, the microenvironment, and epigenetic and metabolic cellular states is essential for early detection and prevention of cancer as well as development of efficient therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41576-020-00299-4
  21. Nat Commun. 2020 12 02. 11(1): 6175
    Park YH, Lal S, Lee JE, Choi YL, Wen J, Ram S, Ding Y, Lee SH, Powell E, Lee SK, Yu JH, Ching KA, Nam JY, Kim SW, Nam SJ, Kim JY, Cho SY, Park S, Kim J, Hwang S, Kim YJ, Bonato V, Fernandez D, Deng S, Wang S, Shin H, Kang ES, Park WY, Rejto PA, Bienkowska J, Kan Z.
      To elucidate the effects of neoadjuvant chemotherapy (NAC), we conduct whole transcriptome profiling coupled with histopathology analyses of a longitudinal breast cancer cohort of 146 patients including 110 pairs of serial tumor biopsies collected before treatment, after the first cycle of treatment and at the time of surgery. Here, we show that cytotoxic chemotherapies induce dynamic changes in the tumor immune microenvironment that vary by subtype and pathologic response. Just one cycle of treatment induces an immune stimulatory microenvironment harboring more tumor infiltrating lymphocytes (TILs) and up-regulation of inflammatory signatures predictive of response to anti-PD1 therapies while residual tumors are immune suppressed at end-of-treatment compared to the baseline. Increases in TILs and CD8+ T cell proportions in response to NAC are independently associated with pathologic complete response. Further, on-treatment immune response is more predictive of treatment outcome than immune features in paired baseline samples although these are strongly correlated.
    DOI:  https://doi.org/10.1038/s41467-020-19933-0
  22. Proc Natl Acad Sci U S A. 2020 Dec 01. pii: 202013595. [Epub ahead of print]
    Kim O, Park EY, Kwon SY, Shin S, Emerson RE, Shin YH, DeMayo FJ, Lydon JP, Coffey DM, Hawkins SM, Quilliam LA, Cheon DJ, Fernández FM, Nephew KP, Karpf AR, Widschwendter M, Sood AK, Bast RC, Godwin AK, Miller KD, Cho CH, Kim J.
      Effective cancer prevention requires the discovery and intervention of a factor critical to cancer development. Here we show that ovarian progesterone is a crucial endogenous factor inducing the development of primary tumors progressing to metastatic ovarian cancer in a mouse model of high-grade serous carcinoma (HGSC), the most common and deadliest ovarian cancer type. Blocking progesterone signaling by the pharmacologic inhibitor mifepristone or by genetic deletion of the progesterone receptor (PR) effectively suppressed HGSC development and its peritoneal metastases. Strikingly, mifepristone treatment profoundly improved mouse survival (∼18 human years). Hence, targeting progesterone/PR signaling could offer an effective chemopreventive strategy, particularly in high-risk populations of women carrying a deleterious mutation in the BRCA gene.
    Keywords:  BRCA; antiprogestins; hormone; ovarian cancer; progesterone
    DOI:  https://doi.org/10.1073/pnas.2013595117
  23. EMBO J. 2020 Dec 04. e106123
    Lv J, Liu Y, Cheng F, Li J, Zhou Y, Zhang T, Zhou N, Li C, Wang Z, Ma L, Liu M, Zhu Q, Liu X, Tang K, Ma J, Zhang H, Xie J, Fang Y, Zhang H, Wang N, Liu Y, Huang B.
      Identifying and sorting highly tumorigenic and metastatic tumor cells from a heterogeneous cell population is a daunting challenge. Here, we show that microfluidic devices can be used to sort marker-based heterogeneous cancer stem cells (CSC) into mechanically stiff and soft subpopulations. The isolated soft tumor cells (< 400 Pa) but not the stiff ones (> 700 Pa) can form a tumor in immunocompetent mice with 100 cells per inoculation. Notably, only the soft, but not the stiff cells, isolated from CD133+ , ALDH+ , or side population CSCs, are able to form a tumor with only 100 cells in NOD-SCID or immunocompetent mice. The Wnt signaling protein BCL9L is upregulated in soft tumor cells and regulates their stemness and tumorigenicity. Clinically, BCL9L expression is correlated with a worse prognosis. Our findings suggest that the intrinsic softness is a unique marker of highly tumorigenic and metastatic tumor cells.
    Keywords:  BCL9L; metastasis; microfluidic sorting; soft tumor cells; stemness
    DOI:  https://doi.org/10.15252/embj.2020106123
  24. Sci Transl Med. 2020 Dec 02. pii: eabb5817. [Epub ahead of print]12(572):
    Perego M, Tyurin VA, Tyurina YY, Yellets J, Nacarelli T, Lin C, Nefedova Y, Kossenkov A, Liu Q, Sreedhar S, Pass H, Roth J, Vogl T, Feldser D, Zhang R, Kagan VE, Gabrilovich DI.
      Tumor recurrence years after seemingly successful treatment of primary tumors is one of the major causes of mortality in patients with cancer. Reactivation of dormant tumor cells is largely responsible for this phenomenon. Using dormancy models of lung and ovarian cancer, we found a specific mechanism, mediated by stress and neutrophils, that may govern this process. Stress hormones cause rapid release of proinflammatory S100A8/A9 proteins by neutrophils. S100A8/A9 induce activation of myeloperoxidase, resulting in accumulation of oxidized lipids in these cells. Upon release from neutrophils, these lipids up-regulate the fibroblast growth factor pathway in tumor cells, causing tumor cell exit from the dormancy and formation of new tumor lesions. Higher serum concentrations of S100A8/A9 were associated with shorter time to recurrence in patients with lung cancer after complete tumor resection. Targeting of S100A8/A9 or β2-adrenergic receptors abrogated stress-induced reactivation of dormant tumor cells. These observations demonstrate a mechanism linking stress and specific neutrophil activation with early recurrence in cancer.
    DOI:  https://doi.org/10.1126/scitranslmed.abb5817