bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021‒01‒03
twenty-one papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Cancer Discov. 2020 Dec 28. pii: CD-20-0387. [Epub ahead of print]
    Li J, Duran MA, Dhanota N, Chatila WK, Bettigole SE, Kwon J, Sriram RK, Humphries MP, Salto-Tellez M, James JA, Hanna MG, Melms JC, Vallabhaneni S, Litchfield K, Usaite I, Biswas D, Bareja R, Li HW, Martin ML, Dorsaint P, Cavallo JA, Li P, Pauli C, Gottesdiener L, DiPardo BJ, Hollmann TJ, Merghoub T, Wen HY, Reis-Filho JS, Riaz N, Su SM, Kalbasi A, Vasan N, Powell SN, Wolchok JD, Elemento O, Swanton C, Shoushtari AN, Parkes EE, Izar B, Bakhoum SF.
      Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS-STING innate immune pathway. How tumors co-opt inflammatory signaling while evading immune surveillance remains unknown. Here we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune stimulatory metabolite whose breakdown products include the immune suppressor, adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wildtype ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part, through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti-PD1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune suppressive pathway.
  2. Cancers (Basel). 2020 Dec 21. pii: E3863. [Epub ahead of print]12(12):
    Fico F, Santamaria-Martínez A.
      Tumor progression involves the co-evolution of transformed cells and the milieu in which they live and expand. Breast cancer stem cells (BCSCs) are a specialized subset of cells that sustain tumor growth and drive metastatic colonization. However, the cellular hierarchy in breast tumors is rather plastic, and the capacity to transition from one cell state to another depends not only on the intrinsic properties of transformed cells, but also on the interplay with their niches. It has become evident that the tumor microenvironment (TME) is a major player in regulating the BCSC phenotype and metastasis. The complexity of the TME is reflected in its number of players and in the interactions that they establish with each other. Multiple types of immune cells, stromal cells, and the extracellular matrix (ECM) form an intricate communication network with cancer cells, exert a highly selective pressure on the tumor, and provide supportive niches for BCSC expansion. A better understanding of the mechanisms regulating these interactions is crucial to develop strategies aimed at interfering with key BCSC niche factors, which may help reducing tumor heterogeneity and impair metastasis.
    Keywords:  breast cancer; cancer stem cells; extracellular matrix; immune cells; stromal cells; tumor microenvironment
  3. Cancers (Basel). 2020 Dec 18. pii: E3823. [Epub ahead of print]12(12):
    Liu RZ, Godbout R.
      Treatment for early stage and localized prostate cancer (PCa) is highly effective. Patient survival, however, drops dramatically upon metastasis due to drug resistance and cancer recurrence. The molecular mechanisms underlying PCa metastasis are complex and remain unclear. It is therefore crucial to decipher the key genetic alterations and relevant molecular pathways driving PCa metastatic progression so that predictive biomarkers and precise therapeutic targets can be developed. Through PCa cohort analysis, we found that a fatty acid-binding protein (FABP) gene cluster (containing five FABP family members) is preferentially amplified and overexpressed in metastatic PCa. All five FABP genes reside on chromosome 8 at 8q21.13, a chromosomal region frequently amplified in PCa. There is emerging evidence that these FABPs promote metastasis through distinct biological actions and molecular pathways. In this review, we discuss how these FABPs may serve as drivers/promoters for PCa metastatic transformation using patient cohort analysis combined with a review of the literature.
    Keywords:  fatty acid-binding protein; gene amplification; lipid metabolism; metastasis; prostate cancer
  4. Cancers (Basel). 2020 Dec 11. pii: E3736. [Epub ahead of print]12(12):
    Knebel FH, Barber LJ, Newey A, Kleftogiannis D, Woolston A, Griffiths B, Fenwick K, Bettoni F, Ribeiro MFSA, da Fonseca L, Costa F, Capareli FC, Hoff PM, Sabbaga J, Camargo AA, Gerlinger M.
      Epidermal growth factor receptor antibodies (EGFR-Abs) confer a survival benefit in patients with RAS wild-type metastatic colorectal cancer (mCRC), but resistance invariably occurs. Previous data showed that only a minority of cancer cells harboured known genetic resistance drivers when clinical resistance to single-agent EGFR-Abs had evolved, supporting the activity of non-genetic resistance mechanisms. Here, we used error-corrected ctDNA-sequencing (ctDNA-Seq) of 40 cancer genes to identify drivers of resistance and whether a genetic resistance-gap (a lack of detectable genetic resistance mechanisms in a large fraction of the cancer cell population) also occurs in RAS wild-type mCRCs treated with a combination of EGFR-Abs and chemotherapy. We detected one MAP2K1/MEK1 mutation and one ERBB2 amplification in 2/3 patients with primary resistance and KRAS, NRAS, MAP2K1/MEK1 mutations and ERBB2 aberrations in 6/7 patients with acquired resistance. In vitro testing identified MAP2K1/MEK1 P124S as a novel driver of EGFR-Ab resistance. Mutation subclonality analyses confirmed a genetic resistance-gap in mCRCs treated with EGFR-Abs and chemotherapy, with only 13.42% of cancer cells harboring identifiable resistance drivers. Our results support the utility of ctDNA-Seq to guide treatment allocation for patients with resistance and the importance of investigating further non-canonical EGFR-Ab resistance mechanisms, such as microenvironmentally-mediated resistance. The detection of MAP2K1 mutations could inform trials of MEK-inhibitors in these tumours.
    Keywords:  EGFR-antibodies; acquired resistance; colorectal cancer; ctDNA-Sequencing; ctDNA-ddPCR; genetic resistance-gap
  5. Clin Cancer Res. 2020 Dec 22. pii: clincanres.2839.2020. [Epub ahead of print]
    Fontana F, Scott MJ, Allen JS, Yang X, Cui G, Pan D, Yanaba N, Fiala MA, O'Neal J, Schmieder-Atteberry AH, Ritchey J, Rettig M, Simons K, Fletcher S, Vij R, DiPersio J, Lanza G.
      BACKGROUND: In multiple myeloma (MM), drug resistant cells underlie relapse or progression following chemotherapy. Cell adhesion mediated-drug resistance (CAM-DR) is an established mechanism used by MMC to survive chemotherapy and its markers are upregulated in residual disease. The integrin VLA4 (a4b1) is a key mediator of CAM-DR and its expression affects drug sensitivity of MMC. Rather than trying to inhibit its function, we here hypothesized that up-regulation of VLA4 by resistant MMC could be exploited for targeted delivery of drugs, which would improve safety and efficacy of treatments.METHODS: We synthetized 20 nm VLA4-targeted micellar nanoparticles (V-NP) carrying DiI for tracing or a novel camptothecin prodrug (V-CP). Human or murine MMC, alone or with stroma, and immunocompetent mice with orthotopic MM were used to track delivery of NP and response to treatments.
    RESULTS: V-NP selectively delivered their payload to MMC in vitro and in vivo, and chemotherapy increased their uptake by surviving MMC. V-CP, alone or in combination with melphalan, were well tolerated and prolonged survival in myeloma-bearing mice. V-CP also reduced the dose requirement for melphalan, reducing tumor burden in association to sub-optimal dosing without increasing overall toxicity.
    CONCLUSIONS: V-CP may be a safe and effective strategy to prevent or treat relapsing or refractory myeloma. V-NP targeting of resistant cells may suggest a new approach to environment-induced resistance in cancer.
    CONCLUSIONS: V-CP may be a safe and effective strategy to prevent or treat relapsing or refractory myeloma. V-NP targeting of resistant cells may suggest a new approach to environment-induced resistance in cancer.
  6. Physiol Rev. 2020 Dec 24.
    Clezardin P, Coleman R, Puppo M, Ottewell P, Bonnelye E, Paycha F, Confavreux CB, Holen I.
      Skeletal metastases are frequent complications of many cancers, causing bone complications (fractures, bone pain, disability), which negatively affect the patient's quality of life. Here, we first discuss the burden of skeletal complications in cancer bone metastasis. We then describe the pathophysiology of bone metastasis. Bone metastasis is a multistage process; long before the development of clinically detectable metastases, circulating tumor cells settle and enter a dormant state in normal vascular and endosteal niches present in the bone marrow, which provide immediate attachment and shelter, and only become active years later as they proliferate and alter the functions of bone-resorbing (osteoclasts) and bone-forming (osteoblasts) cells, promoting skeletal destruction. The molecular mechanisms involved in mediating each of these steps are described and we also explain how tumor cells interact with a myriad of interconnected cell populations in the bone marrow, including a rich vascular network, immune cells, adipocytes and nerves. We discuss metabolic programs that tumor cells could engage with to specifically grow in bone. We also describe the progress and future directions of existing bone-targeted agents and report emerging therapies that have arisen from recent advances in our understanding of the pathophysiology of bone metastases. Finally, we discuss the value of bone turnover biomarkers in detection and monitoring of progression and therapeutic effects in patients with bone metastasis.
    Keywords:  bone resorption; immune surveillance; metastatic niche; osteomimicry; tumor cell dormancy
  7. Cancer Res. 2020 Dec 15. pii: canres.2275.2020. [Epub ahead of print]
    Kumarasamy V, Vail P, Nambiar R, Witkiewicz AK, Knudsen ES.
      Intrinsic or acquired resistance to clinically approved CDK4/6 inhibitors has emerged as a major obstacle that hinders their utility beyond ER+ breast cancer. In this study, CDK4/6-dependent and -resistant models were employed to identify functional determinants of response to pharmacological CDK4/6 inhibitors. In all models tested, the activation of RB and inhibition of CDK2 activity emerged as determinants of sensitivity. While depleting CDK4 and 6 was sufficient to limit proliferation in specific resistance settings, RB loss rendered cells completely independent of these kinases. The main downstream target in this context was the activation status of CDK2, which was suppressed with CDK4/6 inhibition in an RB-dependent fashion. Protein levels of p27 were associated with plasticity/rigidity of the cell cycle and correlated with sensitivity to CDK4/6 inhibition. Exogenous overexpression and pharmacological induction of p27 via inhibition of SKP2 and targeting the MEK/ERK pathway enhanced the cytostatic effect of CDK4/6 inhibitors. Mice bearing ER+ xenografts displayed a durable ani-tumor response to palbociclib; however, over the course of treatment, few cells retained RB phosphorylation, which is associated with limited p27 protein levels as determined by multi-spectral imaging. Similarly, combination treatment of palbociclib with a MEK inhibitor in pancreatic cancer PDX models upregulated p27 and further enhanced the in vivo tumor response to palbociclib. Collectively, these results suggest that the cell cycle plasticity that enables tumor models to evade palbociclib-mediated activation of RB could be targeted using a clinically applicable CDK2 inhibitor.
  8. Clin Cancer Res. 2020 Dec 29. pii: clincanres.1319.2020. [Epub ahead of print]
    Teijeira A, Garasa S, Ochoa MC, Villalba Esparza M, Olivera I, Cirella A, Eguren-Santamaria I, Berraondo P, Schalper KA, de Andrea CE, Sanmamed MF, Melero I.
      One of the most important mechanisms by which cancer fosters its own development is the generation of an immune microenvironment that inhibits or impairs antitumor immune responses. A cancer permissive immune microenvironment is present in an important proportion of the cancer patients who do not respond to immunotherapy approaches intended to unleash pre-existing antitumor immune responses, for instance, immune checkpoint blockade. High circulating levels of interleukin-8 (IL-8) in cancer patients quite accurately predict those patients who will not benefit from checkpoint-based immunotherapy. IL-8 has been reported to favor cancer progression and metastases via different mechanisms, including pro-angiogenesis and maintenance of cancer stem cells, but its ability to attract and functionally modulate neutrophils and macrophages arguably may be the most important factors. IL-8 does not only recruit neutrophils to tumor lesions but also triggers the extrusion of neutrophil extracellular traps (NETs). The relevance and mechanisms underlying the contribution of both neutrophils and NETs to cancer development and progression are starting to be uncovered and include both direct effects on cancer cells and changes in the tumor microenvironment, such as facilitating metastasis, awakening micrometastases from dormancy, and facilitating escape from cytotoxic immune cells. Blockade of IL-8 or its receptors (CXCR1 and CXCR2) is being pursued in drug development, and clinical trials alone or in combination with anti-PD-(L)1 checkpoint inhibitors are already ongoing.
  9. Cancer Res. 2020 Dec 23. pii: canres.2480.2020. [Epub ahead of print]
    Zhou Q, Tian W, Jiang Z, Huang T, Ge C, Liu T, Zhao F, Chen T, Cui Y, Li H, Yao M, Li J, Tian H.
      AKR1C3 is an enzyme belonging to the aldo-ketoreductase family, the members of which catalyze redox transformations involved in biosynthesis, intermediary metabolism, and detoxification. AKR1C3 plays an important role in tumor progression and metastasis; however, little is known about the function and the molecular mechanism underlying the role of AKR1C3 in hepatocellular carcinoma (HCC). In the present study, we report that AKR1C3 is significantly upregulated in HCC and that increased AKR1C3 is associated with poor survival. AKR1C3 positively regulated HCC cell proliferation and metastasis in vitro and in vivo. AKR1C3 promoted tumor proliferation and metastasis by activating NF-κB signaling. Furthermore, AKR1C3 regulated NF-κB activity by modulating TRAF6 and inducing its autoubiquitination in HCC cells. Activation of NF-κB released proinflammatory factors that facilitated the phosphorylation of STAT3 and increased tumor cell proliferation and invasion. Gain- and loss-of-function experiments showed that AKR1C3 promoted tumor proliferation and invasion via the IL-6/STAT3 pathway. STAT3 also directly bound the AKR1C3 promoter and increased transcription of AKR1C3, thereby establishing a positive regulatory feedback loop. Treatment with the AKR1C3 inhibitors indocin and medroxyprogesterone acetate (MPA) inhibited tumor growth and invasion and promoted apoptosis in HCC cells. Collectively, these results indicate that a AKR1C3/NF-κB/STAT3 signaling loop results in HCC cell proliferation and metastasis and could be a promising therapeutic target in HCC.
  10. Cell. 2020 Dec 18. pii: S0092-8674(20)31614-7. [Epub ahead of print]
    Shen JZ, Qiu Z, Wu Q, Finlay D, Garcia G, Sun D, Rantala J, Barshop W, Hope JL, Gimple RC, Sangfelt O, Bradley LM, Wohlschlegel J, Rich JN, Spruck C.
      Repetitive elements (REs) compose ∼50% of the human genome and are normally transcriptionally silenced, although the mechanism has remained elusive. Through an RNAi screen, we identified FBXO44 as an essential repressor of REs in cancer cells. FBXO44 bound H3K9me3-modified nucleosomes at the replication fork and recruited SUV39H1, CRL4, and Mi-2/NuRD to transcriptionally silence REs post-DNA replication. FBXO44/SUV39H1 inhibition reactivated REs, leading to DNA replication stress and stimulation of MAVS/STING antiviral pathways and interferon (IFN) signaling in cancer cells to promote decreased tumorigenicity, increased immunogenicity, and enhanced immunotherapy response. FBXO44 expression inversely correlated with replication stress, antiviral pathways, IFN signaling, and cytotoxic T cell infiltration in human cancers, while a FBXO44-immune gene signature correlated with improved immunotherapy response in cancer patients. FBXO44/SUV39H1 were dispensable in normal cells. Collectively, FBXO44/SUV39H1 are crucial repressors of RE transcription, and their inhibition selectively induces DNA replication stress and viral mimicry in cancer cells.
    Keywords:  FBXO44; H3K9me3; SUV39H1; immunotherapy; repetitive elements
  11. Trends Cancer. 2020 Dec 23. pii: S2405-8033(20)30312-5. [Epub ahead of print]
    Shen YW, Zhou YD, Chen HZ, Luan X, Zhang WD.
      Despite the dramatic advances in cancer research over the decades, effective therapeutic strategies are still urgently needed. Increasing evidence indicates that connective tissue growth factor (CTGF), a multifunctional signaling modulator, promotes cancer initiation, progression, and metastasis by regulating cell proliferation, migration, invasion, drug resistance, and epithelial-mesenchymal transition (EMT). CTGF is also involved in the tumor microenvironment in most of the nodes, including angiogenesis, inflammation, and cancer-associated fibroblast (CAF) activation. In this review, we comprehensively discuss the expression of CTGF and its regulation, oncogenic role, clinical relevance, targeting strategies, and therapeutic agents. Herein, we propose that CTGF is a promising cancer therapeutic target that could potentially improve the clinical outcomes of cancer patients.
    Keywords:  CTGF/CCN2; cancer; cellular function; connective tissue growth factor; targeted therapy; tumor microenvironment
  12. Cancer Discov. 2020 Dec 18.
      Injection of DNA-barcoded cancer cell lines into mice revealed their metastatic characteristics.
  13. Cancer Res. 2020 Dec 29. pii: canres.1377.2020. [Epub ahead of print]
    Gheghiani L, Wang L, Zhang Y, Moore XTR, Zhang J, Smith SC, Tian Y, Wang L, Turner K, Jackson-Cook CK, Mukhopadhyay ND, Fu Z.
      Polo-like kinase 1 (PLK1) is an essential cell cycle regulator that is frequently overexpressed in various human cancers. To determine whether Plk1 overexpression drives tumorigenesis, we established transgenic mouse lines that ubiquitously express increased levels of Plk1. High Plk1 levels were a driving force for different types of spontaneous tumors. Increased Plk1 levels resulted in multiple defects in mitosis and cytokinesis, supernumerary centrosomes, and compromised cell cycle checkpoints, allowing accumulation of chromosomal instability (CIN) which resulted in aneuploidy and tumor formation. Clinically, higher expression of PLK1 positively associated with an increase in genome-wide copy number alterations in multiple human cancers. This study provides in vivo evidence that aberrant expression of PLK1 triggers CIN and tumorigenesis and highlights potential therapeutic opportunities for CIN-positive cancers.
  14. Cancer Res. 2020 Dec 28. pii: canres.2121.2020. [Epub ahead of print]
    Dai M, Boudreault J, Wang N, Poulet S, Daliah G, Yan G, Moamer A, Burgos SA, Sabri S, Ali S, Lebrun JJ.
      Although the cyclin-dependent kinases CDK4 and CDK6 play fundamental roles in cancer, the specific pathways and downstream targets by which they exert their tumorigenic effects remain elusive. In this study, we uncover distinct and novel functions for these kinases in regulating tumor formation and metastatic colonization in various solid tumors, including those of the breast, prostate, and pancreas. Combining in vivo CRISPR-based CDK4 and CDK6 gene editing with pharmacological inhibition approaches in orthotopic transplantation and patient-derived xenograft preclinical models, we defined clear functions for CDK4 and CDK6 in facilitating tumor growth and progression in metastatic cancers. Transcriptomic profiling of CDK4/6 CRISPR knockouts in breast cancer revealed these two kinases to regulate cancer progression through distinct mechanisms. CDK4 regulated pro-metastatic inflammatory cytokine signaling whereas CDK6 mainly controlled DNA replication and repair processes. Inhibition of CDK6 but not CDK4 resulted in defective DNA repair and increased DNA damage. Multiple CDK6 DNA replication/repair genes were not only associated with cancer subtype, grades, and poor clinical outcomes, but also facilitated primary tumor growth and metastasis in vivo. CRISPR-based genomic deletion of CDK6 efficiently blocked tumor formation and progression in pre-established cell- and patient-derived xenograft preclinical models of breast cancer, providing a potential novel targeted therapy for these deadly tumors.
  15. Cell. 2020 Dec 17. pii: S0092-8674(20)31613-5. [Epub ahead of print]
    Sun Y, Wu L, Zhong Y, Zhou K, Hou Y, Wang Z, Zhang Z, Xie J, Wang C, Chen D, Huang Y, Wei X, Shi Y, Zhao Z, Li Y, Guo Z, Yu Q, Xu L, Volpe G, Qiu S, Zhou J, Ward C, Sun H, Yin Y, Xu X, Wang X, Esteban MA, Yang H, Wang J, Dean M, Zhang Y, Liu S, Yang X, Fan J.
      Hepatocellular carcinoma (HCC) has high relapse and low 5-year survival rates. Single-cell profiling in relapsed HCC may aid in the design of effective anticancer therapies, including immunotherapies. We profiled the transcriptomes of ∼17,000 cells from 18 primary or early-relapse HCC cases. Early-relapse tumors have reduced levels of regulatory T cells, increased dendritic cells (DCs), and increased infiltrated CD8+ T cells, compared with primary tumors, in two independent cohorts. Remarkably, CD8+ T cells in recurrent tumors overexpressed KLRB1 (CD161) and displayed an innate-like low cytotoxic state, with low clonal expansion, unlike the classical exhausted state observed in primary HCC. The enrichment of these cells was associated with a worse prognosis. Differential gene expression and interaction analyses revealed potential immune evasion mechanisms in recurrent tumor cells that dampen DC antigen presentation and recruit innate-like CD8+ T cells. Our comprehensive picture of the HCC ecosystem provides deeper insights into immune evasion mechanisms associated with tumor relapse.
    Keywords:  early-relapse tumor; hepatocellular carcinoma; immune microenvironment; immune therapy; single-cell RNA sequencing; tumor ecosystem
  16. Nat Commun. 2020 Dec 22. 11(1): 6438
    Chang KC, Diermeier SD, Yu AT, Brine LD, Russo S, Bhatia S, Alsudani H, Kostroff K, Bhuiya T, Brogi E, Pappin DJ, Bennett CF, Rigo F, Spector DL.
      Misregulation of long non-coding RNA (lncRNA) genes has been linked to a wide variety of cancer types. Here we report on Mammary Tumor Associated RNA 25 (MaTAR25), a nuclear enriched and chromatin associated lncRNA that plays a role in mammary tumor cell proliferation, migration, and invasion, both in vitro and in vivo. MaTAR25 functions by interacting with purine rich element binding protein B (PURB), and associating with a major downstream target gene Tensin1 (Tns1) to regulate its expression in trans. The Tns1 protein product is a critical component of focal adhesions linking signaling between the extracellular matrix and the actin cytoskeleton. Knockout of MaTAR25 results in down-regulation of Tns1 leading to a reorganization of the actin cytoskeleton, and a reduction of focal adhesions and microvilli. We identify LINC01271 as the human ortholog of MaTAR25, and importantly, increased expression of LINC01271 is associated with poor patient prognosis and metastasis. Our findings demonstrate that LINC01271 represents a potential therapeutic target to alter breast cancer progression.
  17. Cancer Cell. 2020 Dec 22. pii: S1535-6108(20)30661-9. [Epub ahead of print]
    Da Silva-Álvarez S, Collado M.
      Cellular senescence is a response with two faces in cancer: it restricts tumor proliferation, but it can also promote cancer progression and metastasis. In this issue of Cancer Cell, Guccini et al. uncover the role of TIMP1 in prostate cancer allowing a switch from tumor-controlling to tumor-promoting senescence.
  18. Cancer Res. 2020 Dec 23. pii: canres.1323.2020. [Epub ahead of print]
    Cai LY, Chen SJ, Xiao SH, Sun QJ, Ding CH, Zheng BN, Zhu XY, Liu SQ, Yang F, Yang YX, Zhou B, Luo C, Zhang X, Xie WF.
      Targeting epigenetics in cancer has emerged as a promising anticancer strategy. p300/CBP is a central regulator of epigenetics and plays an important role in hepatocellular carcinoma (HCC) progression. Tumor-associated metabolic alterations contribute to the establishment and maintenance of the tumorigenic state. In this study, we used a novel p300 inhibitor, B029-2, to investigate the effect of targeting p300/CBP in HCC and tumor metabolism. p300/CBP-mediated acetylation of H3K18 and H3K27 increased in HCC tissues compared to surrounding noncancerous tissues. Conversely, treatment with B029-2 specifically decreased H3K18Ac and H3K27Ac and displayed significant antitumor effects in HCC cells in vitro and in vivo. Importantly, ATAC-seq and RNA-seq integrated analysis revealed that B029-2 disturbed metabolic reprogramming in HCC cells. Moreover, B029-2 decreased glycolytic function and nucleotide synthesis in Huh-7 cells by reducing H3K18Ac and H3K27Ac levels at the promoter regions of amino acid metabolism and nucleotide synthesis enzyme genes, including PSPH, PSAT1, ALDH18A1, TALDO1, ATIC, and DTYMK. Overexpression of PSPH and DTYMK partially reversed the inhibitory effect of B029-2 on HCC cells. These findings suggested that p300/CBP epigenetically regulates the expression of glycolysis-related metabolic enzymes through modulation of histone acetylation in HCC and highlight the value of targeting the histone acetyltransferase activity of p300/CBP for HCC therapy.
  19. Cancer Res. 2020 Dec 21. pii: canres.1417.2020. [Epub ahead of print]
    Alpsoy A, Utturkar SM, Carter BC, Dhiman A, Torregrosa-Allen SE, Currie MP, Elzey BD, Dykhuizen EC.
      Switch/sucrose-non-fermentable (SWI/SNF) chromatin remodeling complexes are critical regulators of chromatin dynamics during transcription, DNA replication, and DNA repair. A recently identified SWI/SNF subcomplex termed GLTSCR1/1L-BAF (GBAF; or "non-canonical BAF", ncBAF) uniquely contains bromodomain-containing protein BRD9 and glioma tumor suppressor candidate region 1 (GLTSCR1) or its paralog GLTSCR1-like (GLTSCR1L). Recent studies have identified a unique dependency on GBAF (ncBAF) complexes in synovial sarcoma and malignant rhabdoid tumors, both of which possess aberrations in canonical BAF (cBAF) and Polybromo-BAF (PBAF) complexes. Dependencies on GBAF in malignancies without SWI/SNF aberrations, however, are less defined. Here, we show that GBAF, particularly its BRD9 subunit, is required for the viability of prostate cancer cell lines in vitro and for optimal xenograft tumor growth in vivo. BRD9 interacts with androgen receptor (AR) and CCCTC-binding factor (CTCF), and modulates AR-dependent gene expression. The GBAF complex exhibits overlapping genome localization and transcriptional targets as bromodomain and extraterminal domain containing (BET) proteins, which are established AR-coregulators. Our results demonstrate that GBAF is critical for coordinating SWI/SNF - BET cooperation and uncover a new druggable target for AR-positive prostate cancers, including those resistant to androgen deprivation or antiandrogen therapies.
  20. JCI Insight. 2020 Dec 22. pii: 130510. [Epub ahead of print]
    Hitomi M, Chumakova AP, Silver DJ, Knudsen AM, Pontius WD, Murphy S, Anand NS, Kristensen BW, Lathia J.
      Asymmetric cell division (ACD) enables the maintenance of a stem cell population while simultaneously generating differentiated progeny. Cancer stem cells (CSCs) undergo multiple modes of cell division during tumor expansion and in response to therapy, yet the functional consequences of these division modes remain to be determined. Using a fluorescent reporter for cell surface receptor distribution during mitosis, we found that ACD generated a daughter cell with enhanced therapeutic resistance and increased co-enrichment of epidermal growth factor receptor (EGFR) and neurotrophin receptor (p75NTR) from a glioblastoma CSC. Stimulation of both receptors antagonized differentiation induction and promoted self-renewal capacity. p75NTR knockdown enhanced the therapeutic efficacy of EGFR inhibition, indicating that co-inheritance of p75NTR and EGFR promotes resistance to EGFR inhibition through a redundant mechanism. These data demonstrate that ACD produces progeny with co-enriched growth factor receptors, which contributes to the generation of a more therapeutically resistant CSC population.
    Keywords:  Brain cancer; Cancer; Cell Biology; Stem cells