bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒04‒12
23 papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology


  1. Autophagy. 2020 Apr 08.
    Marsh T, Debnath J.
      Macroautophagy/autophagy plays complex, context-dependent roles in cancer. How autophagy governs the emergence of metastatic disease has been incompletely understood. We recently uncovered that genetic autophagy inhibition strongly attenuates primary tumor growth in mammary cancer models, yet paradoxically promotes spontaneous metastasis to the lung and enables the outgrowth of disseminated tumor cells (DTCs) into overt macro-metastases. Furthermore, at both primary and metastatic sites, genetic autophagy inhibition leads to the marked expansion of tumor cells exhibiting aggressive and pro-metastatic basal epithelial differentiation. These pro-metastatic effects of autophagy inhibition are due to the cytosolic accumulation of the autophagy cargo receptor NBR1 in autophagy-deficient tumor cells.
    Keywords:  Autophagy; Keratin14; NBR1; Rubicon; TP63; chloroquine; metastasis
    DOI:  https://doi.org/10.1080/15548627.2020.1753001
  2. Cancers (Basel). 2020 Apr 03. pii: E868. [Epub ahead of print]12(4):
    Drescher F, Juárez P, Arellano DL, Serafín-Higuera N, Olvera-Rodriguez F, Jiménez S, Licea-Navarro AF, Fournier PG.
      Breast cancer (BCa) cells disseminating to the bone can remain dormant and resistant to treatments for many years until relapsing as bone metastases. The tyrosine kinase receptor TIE2 induces the dormancy of hematopoietic stem cells, and could also induce the dormancy of BCa cells. However, TIE2 is also a target for anti-angiogenic treatments in ongoing clinical trials, and its inhibition could then restart the proliferation of dormant BCa cells in bone. In this study, we used a combination of patient data, in vitro, and in vivo models to investigate the effect of TIE2 in the dormancy of bone metastases. In BCa patients, we found that a higher TIE2 expression is associated with an increased time to metastases and survival. In vitro, TIE2 decreased cell proliferation as it increased the expression of cyclin-dependent kinase inhibitors CDKN1A and CDKN1B and arrested cells in the G0/G1 phase. Expression of TIE2 also increased the resistance to the chemotherapeutic 5-Fluorouracil. In mice, TIE2 expression reduced tumor growth and the formation of osteolytic bone metastasis. Together, these results show that TIE2 is sufficient to induce dormancy in vitro and in vivo, and could be a useful prognostic marker for patients. Our data also suggest being cautious when using TIE2 inhibitors in the clinic, as they could awaken dormant disseminated tumor cells.
    Keywords:  TIE2; bone metastasis; breast cancer; cancer relapse; chemotherapy resistance; dormancy
    DOI:  https://doi.org/10.3390/cancers12040868
  3. Front Mol Biosci. 2020 ;7 36
    Drápela S, Bouchal J, Jolly MK, Culig Z, Souček K.
      The predominant way in which conventional chemotherapy kills rapidly proliferating cancer cells is the induction of DNA damage. However, chemoresistance remains the main obstacle to therapy effectivity. An increasing number of studies suggest that epithelial-to-mesenchymal transition (EMT) represents a critical process affecting the sensitivity of cancer cells to chemotherapy. Zinc finger E-box binding homeobox 1 (ZEB1) is a prime element of a network of transcription factors controlling EMT and has been identified as an important molecule in the regulation of DNA damage, cancer cell differentiation, and metastasis. Recent studies have considered upregulation of ZEB1 as a potential modulator of chemoresistance. It has been hypothesized that cancer cells undergoing EMT acquire unique properties that resemble those of cancer stem cells (CSCs). These stem-like cells manifest enhanced DNA damage response (DDR) and DNA repair capacity, self-renewal, or chemoresistance. In contrast, functional experiments have shown that ZEB1 induces chemoresistance regardless of whether other EMT-related changes occur. ZEB1 has also been identified as an important regulator of DDR by the formation of a ZEB1/p300/PCAF complex and direct interaction with ATM kinase, which has been linked to radioresistance. Moreover, ATM can directly phosphorylate ZEB1 and enhance its stability. Downregulation of ZEB1 has also been shown to reduce the abundance of CHK1, an effector kinase of DDR activated by ATR, and to induce its ubiquitin-dependent degradation. In this perspective, we focus on the role of ZEB1 in the regulation of DDR and describe the mechanisms of ZEB1-dependent chemoresistance.
    Keywords:  DNA damage response; EMT-epithelial to mesenchymal transition; ZEB1; plasticity; therapy resistance
    DOI:  https://doi.org/10.3389/fmolb.2020.00036
  4. Cancer Res. 2020 Apr 07. pii: canres.3428.2019. [Epub ahead of print]
    Park Y, Pang K, Park J, Hong E, Lee J, Ooshima A, Kim HS, Cho JH, Han Y, Lee C, Song YS, Park KS, Yang KM, Kim SJ.
      The adaptor protein TNF receptor-associated factor 6 (TRAF6) is a key mediator in inflammation. However, the molecular mechanisms controlling its activity and stability in cancer progression remain unclear. Here we show that death-associated protein kinase-related apoptosis-inducing kinase 1 (DRAK1) inhibits the proinflammatory signaling pathway by targeting TRAF6 for degradation, thereby suppressing inflammatory signaling-mediated tumor growth and metastasis in advanced cervical cancer cells. DRAK1 bound directly to the TRAF domain of TRAF6, preventing its autoubiquitination by interfering with homo-oligomerization, eventually leading to autophagy-mediated degradation of TRAF6. Depletion of DRAK1 in cervical cancer cells resulted in markedly increased levels of TRAF6 protein, promoting activation of the IL-1β signaling-associated pathway and proinflammatory cytokine production. DRAK1 was specifically underexpressed in metastatic cervical cancers and inversely correlated with TRAF6 expression in mouse xenograft model tumor tissues and human cervical tumor tissues. Collectively, our findings highlight DRAK1 as a novel antagonist of inflammation targeting TRAF6 for degradation that limits inflammatory signaling-mediated progression of advanced cervical cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-3428
  5. Blood. 2020 Apr 08. pii: blood.2019003636. [Epub ahead of print]
    Lin H, Rothe K, Chen M, Wu A, Babaian A, Yen R, Zeng J, Ruschmann J, Petriv OI, O'Neill K, Maetzig T, Knapp DJHF, Nakamichi N, Brinkman R, Birol I, Forrest DL, Hansen C, Humphries KK, Eaves CJ, Jiang X.
      Overcoming drug resistance and targeting cancer stem cells remain challenges for curative cancer treatment. To investigate the role of miRNAs in regulating drug resistance and leukemic stem cell (LSCs) fate, we performed global transcriptome profiling in treatment-naïve chronic myeloid leukemia (CML) stem/progenitor cells and identified that miR-185 levels anticipate their response to ABL tyrosine kinase inhibitors (TKIs). miR-185 functions as a tumor suppressor; its restored expression impaired survival of drug-resistant cells, sensitized them to TKIs in vitro, and markedly eliminated long-term repopulating LSCs and infiltrating blast cells, conferring a survival advantage in pre-clinical xenotransplantation models. Integrative analysis with mRNA profiles uncovered PAK6 as a crucial target of miR-185 and pharmacological inhibition of PAK6 perturbed the RAS/MAPK pathway and mitochondrial activity, sensitizing therapy-resistant cells to TKIs. Thus, miR-185 presents as a potential predictive biomarker, and dual targeting of miR-185-mediated PAK6 activity and BCR-ABL may provide a valuable strategy for overcoming drug resistance in patients.
    DOI:  https://doi.org/10.1182/blood.2019003636
  6. Cancer Discov. 2020 Apr 08. pii: CD-19-0532. [Epub ahead of print]
    Kato S, Weng QY, Insco ML, Chen KY, Muralidhar S, Pozniak J, Diaz JMS, Drier Y, Nguyen N, Lo JA, van Rooijen E, Kemeny LV, Zhan Y, Feng Y, Silkworth W, Powell CT, Liau BB, Xiong Y, Jin J, Newton-Bishop J, Zon LI, Bernstein BE, Fisher DE.
      Epigenetic regulators, when genomically altered, may become driver oncogenes that mediate otherwise unexplained pro-oncogenic changes lacking a clear genetic stimulus, such as activation of the WNT/B-catenin pathway in melanoma. This study identifies previously unrecognized recurrent activating mutations in the G9a histone methyltransferase gene, as well as G9a genomic copy gains in ~26% of human melanomas, which collectively drive tumor growth and an immunologically sterile microenvironment beyond melanoma. Furthermore, the WNT pathway is identified as a key tumorigenic target of G9a gain-of-function, via suppression of the WNT antagonist DKK1. Importantly, genetic or pharmacologic suppression of mutated or amplified G9a using multiple in vitro and in vivo models demonstrate that G9a is a druggable target for therapeutic intervention in melanoma and other cancers harboring G9a genomic aberrations.
    DOI:  https://doi.org/10.1158/2159-8290.CD-19-0532
  7. J Clin Invest. 2020 Apr 06. pii: 131133. [Epub ahead of print]
    Alajati A, D'Ambrosio M, Troiani M, Mosole S, Pellegrini L, Chen J, Revandkar A, Bolis M, Theurillat JP, Guccini I, Losa M, Calcinotto A, De Bernardis G, Pasquini E, D'Antuono R, Sharp A, Figueiredo I, Nava Rodrigues D, Welti J, Gil V, Yuan W, Vlajnic T, Bubendorf L, Chiorino G, Gnetti L, Torrano V, Carracedo A, Camplese L, Hirabayashi S, Canato E, Pasut G, Montopoli M, Rüschoff JH, Wild P, Moch H, De Bono J, Alimonti A.
      The mechanisms by which prostate cancer shifts from an indolent castration-sensitive phenotype to lethal castration-resistant prostate cancer (CRPC) are poorly understood. Identification of clinically relevant genetic alterations leading to CRPC may reveal potential vulnerabilities for cancer therapy. Here we find that CUB domain-containing protein 1 (CDCP1), a transmembrane protein that acts as a substrate for SRC family kinases (SFKs), is overexpressed in a subset of CRPC. Notably, CDCP1 cooperates with the loss of the tumor suppressor gene PTEN to promote the emergence of metastatic prostate cancer. Mechanistically, we find that androgens suppress CDCP1 expression and that androgen deprivation in combination with loss of PTEN promotes the upregulation of CDCP1 and the subsequent activation of the SRC/MAPK pathway. Moreover, we demonstrate that anti-CDCP1 immunoliposomes (anti-CDCP1 ILs) loaded with chemotherapy suppress prostate cancer growth when administered in combination with enzalutamide. Thus, our study identifies CDCP1 as a powerful driver of prostate cancer progression and uncovers different potential therapeutic strategies for the treatment of metastatic prostate tumors.
    Keywords:  Oncology; Prostate cancer
    DOI:  https://doi.org/10.1172/JCI131133
  8. Gastroenterology. 2020 Apr 07. pii: S0016-5085(20)30461-3. [Epub ahead of print]
    Kung-Chun Chiu D, Wai-Hin Yuen V, Wing-Sum Cheu J, Wei LL, Ting V, Fehlings M, Sumatoh H, Nardin A, Newell EW, Oi-Lin Ng I, Chung-Cheung Yau T, Wong CM, Chak-Lui Wong C.
      BACKGROUND & AIMS: Immune checkpoint inhibitors are effective in treatment of some hepatocellular carcinomas (HCCs), but these tumors do not always respond to inhibitors of programmed cell death 1 (PDCD1, also called PD1). We investigated mechanisms of resistance of liver tumors in mice to infiltrating T cells.METHODS: Mice were given hydrodynamic tail vein injections of CRISPR-Cas9 and transposon vectors to disrupt Trp53 and overexpress Myc (Trp53KO/C-MycOE mice). PVRL1 and PVRL3 were knocked down in Hepa1-6 cells using short hairpin RNAs. Hepa1-6 cells were injected into livers of C57BL/6 mice; some mice were given intraperitoneal injections of antibodies against PD1, TIGIT, or CD8 before the cancer cells were injected. Liver tissues were collected from mice and analyzed by histology, immunohistochemistry, and quantitative real-time PCR; tumors were analyzed by mass cytometry using markers to detect T cells and other lymphocytes. We obtained HCC and non-tumor liver tissues and clinical data from patients who underwent surgery in Hong Kong and analyzed the tissues by immunohistochemistry.
    RESULTS: Trp53KO/C-MycOE mice developed liver tumors in 3-5 weeks; injections of anti-PD1 did not slow tumor development. Tumors from mice given anti-PD1 had larger numbers of memory CD8+ T cells (CD44+CD62L-KLRGint) and T cells that expressed PD1, LAG3, and TIGIT, compared with mice not given the antibody. HCC tissues from patients had higher levels of PVRL1 mRNA and protein than non-tumor tissues. Increased PVRL1 associated with shorter times of disease-free survival. Knockdown of PVRL1 in Hepa1-6 cells caused them to form smaller tumors in mice, infiltrated by higher numbers of CD8+ T cells that expressed the inhibitory protein TIGIT; these effects were not observed in mice with depletion of CD8+ T cells. In Hepa1-6 cells, PVRL1 stabilized cell surface PVR, which interacted with TIGIT on CD8+ T cells; knockdown of PVRL1 reduced cell-surface levels of PVR but not levels of Pvr mRNA. In Trp53KO/C-MycOE mice and mice with tumors grown from Hepa1-6 cells, injection of the combination of anti-PD1 and anti-TIGIT significantly reduced tumor growth, increased the ratio of cytotoxic to regulatory T cells in tumors, and prolonged survival.
    CONCLUSIONS: PVRL1, which is upregulated by HCC cells, stabilizes cell surface PVR, which interacts with TIGIT, an inhibitory molecule on CD8+ effector memory T cells. This suppresses the anti-tumor immune response. Inhibitors of PVRL1, along with anti-PD1 and anti-TIGIT, might be developed for treatment of HCC.
    Keywords:  immune regulation; immunotherapy; liver cancer; mouse model
    DOI:  https://doi.org/10.1053/j.gastro.2020.03.074
  9. Nat Commun. 2020 Apr 06. 11(1): 1720
    Ge MK, Zhang N, Xia L, Zhang C, Dong SS, Li ZM, Ji Y, Zheng MH, Sun J, Chen GQ, Shen SM.
      Nuclear localization of PTEN is essential for its tumor suppressive role, and loss of nuclear PTEN is more prominent than cytoplasmic PTEN in many kinds of cancers. However, nuclear PTEN-specific regulatory mechanisms were rarely reported. Based on the finding that nuclear PTEN is more unstable than cytoplasmic PTEN, here we identify that F-box only protein 22 (FBXO22) induces ubiquitylation of nuclear but not cytoplasmic PTEN at lysine 221, which is responsible for the degradation of nuclear PTEN. FBXO22 plays a tumor-promoting role by ubiquitylating and degrading nuclear PTEN. In accordance, FBXO22 is overexpressed in various cancer types, and contributes to nuclear PTEN downregulation in colorectal cancer tissues. Cumulatively, our study reports the mechanism to specifically regulate the stability of nuclear PTEN, which would provide the opportunity for developing therapeutic strategies aiming to achieve complete reactivation of PTEN as a tumor suppressor.
    DOI:  https://doi.org/10.1038/s41467-020-15578-1
  10. Clin Cancer Res. 2020 Apr 06. pii: clincanres.3809.2019. [Epub ahead of print]
    Morris VK, Bekaii-Saab T.
      Although the last two decades have seen a broad improvement in overall survival, colorectal cancer (CRC) is still the second leading cause of cancer deaths worldwide. Patient populations continue to face poor disease prognoses due to the challenges of early detection and the molecular subtypes driving their CRC. Consequently, many patients present with metastatic CRC, which often limits options and shifts treatment focus away from curative interventions. BRAFV600E mutations are present in approximately 10% of CRC tumors and are associated with uninhibited cell proliferation, reduced apoptosis and resistance to standard therapeutic options. In CRC, BRAFV600E mutations are associated with decreased overall survival, poor treatment responses, and different patterns of metastatic spread compared to tumors with wildtype BRAF. Success in treating other BRAFV600E-mutant cancers with BRAF inhibitors as monotherapy has not translated into efficacious treatment of metastatic CRC. Consequently, combination therapy with inhibitors of BRAF, MEK, and epidermal growth factor receptor, which overcomes the innate treatment-resistant characteristics of BRAFV600E-mutant CRC, is now recommended by treatment guidelines.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-19-3809
  11. Cancers (Basel). 2020 Apr 03. pii: E867. [Epub ahead of print]12(4):
    Dianat-Moghadam H, Azizi M, Eslami-S Z, Cortés-Hernández LE, Heidarifard M, Nouri M, Alix-Panabières C.
      Metastases and cancer recurrence are the main causes of cancer death. Circulating Tumor Cells (CTCs) and disseminated tumor cells are the drivers of cancer cell dissemination. The assessment of CTCs' clinical role in early metastasis prediction, diagnosis, and treatment requires more information about their biology, their roles in cancer dormancy, and immune evasion as well as in therapy resistance. Indeed, CTC functional and biochemical phenotypes have been only partially characterized using murine metastasis models and liquid biopsy in human patients. CTC detection, characterization, and enumeration represent a promising tool for tailoring the management of each patient with cancer. The comprehensive understanding of CTCs will provide more opportunities to determine their clinical utility. This review provides much-needed insights into this dynamic field of translational cancer research.
    Keywords:  cancer stem cells; circulating tumor cells; dormancy; immune escape; liquid biopsy; metastasis; therapy resistance
    DOI:  https://doi.org/10.3390/cancers12040867
  12. Cancer Res. 2020 Apr 07. pii: canres.3339.2019. [Epub ahead of print]
    Yang L, So JY, Skrypek N, Yang HH, Merchant AS, Nelson GW, Chen WD, Ishii H, Chen JM, Hu G, Achyut BR, Yoon EC, Han L, Huang C, Cam MC, Zhao K, Lee MP.
      Current cancer treatments are largely based on the genetic characterization of primary tumors and are ineffective for metastatic disease. Here we report that DNA methyltransferase 3B (DNMT3B) is induced at distant metastatic sites and mediates epigenetic reprogramming of metastatic tumor cells. Multi-omics analysis and spontaneous metastatic mouse models revealed that DNMT3B alters multiple pathways including STAT3, NFκB, PI3K/Akt, β-catenin, and Notch signaling, which are critical for cancer cell survival, apoptosis, proliferation, invasion, and colonization. PGE2 and IL-6 were identified as critical inflammatory mediators in DNMT3B induction. DNMT3B expression levels positively correlated with human metastatic progression. Targeting IL-6 or COX-2 reduced DNMT3B induction and improved chemo- or PD1- therapy. We propose a novel mechanism linking the metastatic microenvironment with epigenetic alterations that occur at distant sites. These results caution against the "Achilles' heel" in cancer therapies based on primary tumor characterization and suggests targeting DNMT3B induction as new option for treating metastatic disease.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-3339
  13. J Vis Exp. 2020 Mar 20.
    Cheng RYS, Patel NL, Back T, Basudhar D, Somasundaram V, Kalen JD, Wink DA, Ridnour LA.
      Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited therapeutic options. When compared to patients with less aggressive breast tumors, the 5-year survival rate of TNBC patients is 77% due to their characteristic drug-resistant phenotype and metastatic burden. Toward this end, murine models have been established aimed at identifying novel therapeutic strategies limiting TNBC tumor growth and metastatic spread. This work describes a practical guide for the TNBC orthotopic model where MDA-MB-231 breast cancer cells suspended in a basement membrane matrix are implanted in the fourth mammary fat pad, which closely mimics the cancer cell behavior in humans. Measurement of tumors by caliper, lung metastasis assessment via in vivo and ex vivo imaging, and molecular detection are discussed. This model provides an excellent platform to study therapeutic efficacy and is especially suitable for the study of the interaction between the primary tumor and distal metastatic sites.
    DOI:  https://doi.org/10.3791/60316
  14. Science. 2020 Apr 10. pii: eaaw5473. [Epub ahead of print]368(6487):
    Faubert B, Solmonson A, DeBerardinis RJ.
      Metabolic reprogramming is a hallmark of malignancy. As our understanding of the complexity of tumor biology increases, so does our appreciation of the complexity of tumor metabolism. Metabolic heterogeneity among human tumors poses a challenge to developing therapies that exploit metabolic vulnerabilities. Recent work also demonstrates that the metabolic properties and preferences of a tumor change during cancer progression. This produces distinct sets of vulnerabilities between primary tumors and metastatic cancer, even in the same patient or experimental model. We review emerging concepts about metabolic reprogramming in cancer, with particular attention on why metabolic properties evolve during cancer progression and how this information might be used to develop better therapeutic strategies.
    DOI:  https://doi.org/10.1126/science.aaw5473
  15. JCI Insight. 2020 Apr 09. pii: 134564. [Epub ahead of print]5(7):
    Singla N, Xie Z, Zhang Z, Gao M, Yousuf Q, Onabolu O, McKenzie T, Tcheuyap VT, Ma Y, Choi J, McKay R, Christie A, Torras OR, Bowman IA, Margulis V, Pedrosa I, Przybycin C, Wang T, Kapur P, Rini B, Brugarolas J.
      Renal cell carcinoma (RCC) is characterized by a particularly broad metastatic swath, and, enigmatically, when the pancreas is a destination, the disease is associated with improved survival. Intrigued by this observation, we sought to characterize the clinical behavior, therapeutic implications, and underlying biology. While pancreatic metastases (PM) are infrequent, we identified 31 patients across 2 institutional cohorts and show that improved survival is independent of established prognostic variables, that these tumors are exquisitely sensitive to antiangiogenic agents and resistant to immune checkpoint inhibitors (ICIs), and that they are characterized by a distinctive biology. Primary tumors of patients with PM exhibited frequent PBRM1 mutations, 3p loss, and 5q amplification, along with a lower frequency of aggressive features such as BAP1 mutations and loss of 9p, 14q, and 4q. Gene expression analyses revealed constrained evolution with remarkable uniformity, reduced effector T cell gene signatures, and increased angiogenesis. Similar findings were observed histopathologically. Thus, RCC metastatic to the pancreas is characterized by indolent biology, heightened angiogenesis, and an uninflamed stroma, likely underlying its good prognosis, sensitivity to antiangiogenic therapies, and refractoriness to ICI. These data suggest that metastatic organotropism may be an indicator of a particular biology with prognostic and treatment implications for patients.
    Keywords:  Oncology; Urology
    DOI:  https://doi.org/10.1172/jci.insight.134564
  16. Nat Cell Biol. 2020 Apr 06.
    Martinez-Høyer S, Deng Y, Parker J, Jiang J, Mo A, Docking TR, Gharaee N, Li J, Umlandt P, Fuller M, Jädersten M, Kulasekararaj A, Malcovati L, List AF, Hellström-Lindberg E, Platzbecker U, Karsan A.
      Interstitial deletion of the long arm of chromosome 5 (del(5q)) is the most common structural genomic variant in myelodysplastic syndromes (MDS)1. Lenalidomide (LEN) is the treatment of choice for patients with del(5q) MDS, but half of the responding patients become resistant2 within 2 years. TP53 mutations are detected in ~20% of LEN-resistant patients3. Here we show that patients who become resistant to LEN harbour recurrent variants of TP53 or RUNX1. LEN upregulated RUNX1 protein and function in a CRBN- and TP53-dependent manner in del(5q) cells, and mutation or downregulation of RUNX1 rendered cells resistant to LEN. LEN induced megakaryocytic differentiation of del(5q) cells followed by cell death that was dependent on calpain activation and CSNK1A1 degradation4,5. We also identified GATA2 as a LEN-responsive gene that is required for LEN-induced megakaryocyte differentiation. Megakaryocytic gene-promoter analyses suggested that LEN-induced degradation of IKZF1 enables a RUNX1-GATA2 complex to drive megakaryocytic differentiation. Overexpression of GATA2 restored LEN sensitivity in the context of RUNX1 or TP53 mutations by enhancing LEN-induced megakaryocytic differentiation. Screening for mutations that block LEN-induced megakaryocytic differentiation should identify patients who are resistant to LEN.
    DOI:  https://doi.org/10.1038/s41556-020-0497-9
  17. Proc Natl Acad Sci U S A. 2020 Apr 09. pii: 201914505. [Epub ahead of print]
    de Semir D, Bezrookove V, Nosrati M, Scanlon KR, Singer E, Judkins J, Rieken C, Wu C, Shen J, Schmudermayer C, Dar AA, Miller JR, Cobbs C, Yount G, Desprez PY, Debs RJ, Salomonis N, McAllister S, Cleaver JE, Soroceanu L, Kashani-Sabet M.
      The invasive behavior of glioblastoma is essential to its aggressive potential. Here, we show that pleckstrin homology domain interacting protein (PHIP), acting through effects on the force transduction layer of the focal adhesion complex, drives glioblastoma motility and invasion. Immunofluorescence analysis localized PHIP to the leading edge of glioblastoma cells, together with several focal adhesion proteins: vinculin (VCL), talin 1 (TLN1), integrin beta 1 (ITGB1), as well as phosphorylated forms of paxillin (pPXN) and focal adhesion kinase (pFAK). Confocal microscopy specifically localized PHIP to the force transduction layer, together with TLN1 and VCL. Immunoprecipitation revealed a physical interaction between PHIP and VCL. Targeted suppression of PHIP resulted in significant down-regulation of these focal adhesion proteins, along with zyxin (ZYX), and produced profoundly disorganized stress fibers. Live-cell imaging of glioblastoma cells overexpressing a ZYX-GFP construct demonstrated a role for PHIP in regulating focal adhesion dynamics. PHIP silencing significantly suppressed the migratory and invasive capacity of glioblastoma cells, partially restored following TLN1 or ZYX cDNA overexpression. PHIP knockdown produced substantial suppression of tumor growth upon intracranial implantation, as well as significantly reduced microvessel density and secreted VEGF levels. PHIP copy number was elevated in the classical glioblastoma subtype and correlated with elevated EGFR levels. These results demonstrate PHIP's role in regulating the actin cytoskeleton, focal adhesion dynamics, and tumor cell motility, and identify PHIP as a key driver of glioblastoma migration and invasion.
    Keywords:  PHIP; angiogenesis; glioblastoma; invasion; motility
    DOI:  https://doi.org/10.1073/pnas.1914505117
  18. Genes Dev. 2020 Apr 09.
    Qiao S, Koh SB, Vivekanandan V, Salunke D, Patra KC, Zaganjor E, Ross K, Mizukami Y, Jeanfavre S, Chen A, Mino-Kenudson M, Ramaswamy S, Clish C, Haigis M, Bardeesy N, Ellisen LW.
      Human cancers with activating RAS mutations are typically highly aggressive and treatment-refractory, yet RAS mutation itself is insufficient for tumorigenesis, due in part to profound metabolic stress induced by RAS activation. Here we show that loss of REDD1, a stress-induced metabolic regulator, is sufficient to reprogram lipid metabolism and drive progression of RAS mutant cancers. Redd1 deletion in genetically engineered mouse models (GEMMs) of KRAS-dependent pancreatic and lung adenocarcinomas converts preneoplastic lesions into invasive and metastatic carcinomas. Metabolic profiling reveals that REDD1-deficient/RAS mutant cells exhibit enhanced uptake of lysophospholipids and lipid storage, coupled to augmented fatty acid oxidation that sustains both ATP levels and ROS-detoxifying NADPH. Mechanistically, REDD1 loss triggers HIF-dependent activation of a lipid storage pathway involving PPARγ and the prometastatic factor CD36. Correspondingly, decreased REDD1 expression and a signature of REDD1 loss predict poor outcomes selectively in RAS mutant but not RAS wild-type human lung and pancreas carcinomas. Collectively, our findings reveal the REDD1-mediated stress response as a novel tumor suppressor whose loss defines a RAS mutant tumor subset characterized by reprogramming of lipid metabolism, invasive and metastatic progression, and poor prognosis. This work thus provides new mechanistic and clinically relevant insights into the phenotypic heterogeneity and metabolic rewiring that underlies these common cancers.
    Keywords:  RAS; REDD1; energy stress; fatty acid oxidation; glycolysis; lipid metabolism; lysophospholipids; metastasis; oxidative stress
    DOI:  https://doi.org/10.1101/gad.335166.119
  19. Cancer Res. 2020 Apr 07. pii: canres.2400.2019. [Epub ahead of print]
    Zhao H, Iqbal NJ, Sukrithan V, Nicholas C, Xue Y, Yu C, Locker J, Zou J, Schwartz EL, Zhu L.
      The RB1 tumor suppressor gene is mutated in highly aggressive tumors including small cell lung cancer (SCLC), where its loss, along with TP53, is required and sufficient for tumorigenesis. While RB1 mutant cells fail to arrest at G1/S in response to cell cycle restriction point signals, this information has not led to effective strategies to treat RB1-deficient tumors, as it is challenging to develop targeted drugs for tumors that are driven by the loss of gene function. Our group previously identified Skp2, a substrate recruiting subunit of the SCF-Skp2 E3 ubiquitin ligase, as an early repression target of pRb whose knockout blocked tumorigenesis in Rb1-deficient prostate and pituitary tumors. Here we used genetic mouse models to demonstrate that deletion of Skp2 completely blocked the formation of SCLC in Rb1/p53-knockout mice (RP mice). Skp2 KO caused an increased accumulation of the Skp2-degradation target p27, a cyclin-dependent kinase inhibitor, which was confirmed as the mechanism of protection by using knock-in of a mutant p27 that was unable to bind to Skp2. Building on the observed synthetic lethality between Rb1 and Skp2, we found that small molecules that bind/inhibit Skp2 have in vivo antitumor activity in mouse tumors and human patient-derived xenograft models of SCLC. Using genetic and pharmacologic approaches, antitumor activity was seen with Skp2 loss or inhibition in established SCLC primary lung tumors, in liver metastases, and in chemotherapy-resistant tumors. Our data highlight a downstream actionable target in RB1-deficient cancers, for which there are currently no targeted therapies available.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-2400
  20. Elife. 2020 Apr 09. pii: e48963. [Epub ahead of print]9
    Tsang YH, Wang Y, Kong K, Grzeskowiak C, Zagorodna O, Dogruluk T, Lu H, Villafane N, Bhavana VH, Moreno D, Elsea SH, Liang H, Mills GB, Scott KL.
      The melanoma-associated antigen family A (MAGEA) antigens are expressed in a wide variety of malignant tumors but not in adult somatic cells, rendering them attractive targets for cancer immunotherapy. Here we show that a number of cancer-associated MAGEA mutants that undergo proteasome-dependent degradation in vitro could negatively impact their utility as immunotherapeutic targets. Importantly, in pancreatic ductal adenocarcinoma cell models, MAGEA6 suppresses macroautophagy (autophagy). The inhibition of autophagy is released upon MAGEA6 degradation, which can be induced by nutrient deficiency or by acquisition of cancer-associated mutations. Using xenograft mouse models, we demonstrated that inhibition of autophagy is critical for tumor initiation whereas reinstitution of autophagy as a consequence of MAGEA6 degradation contributes to tumor progression. These findings could inform cancer immunotherapeutic strategies for targeting MAGEA antigens and provide mechanistic insight into the divergent roles of MAGEA6 during pancreatic cancer initiation and progression.
    Keywords:  cancer biology; genetics; genomics; human
    DOI:  https://doi.org/10.7554/eLife.48963
  21. Cancer Discov. 2020 Apr 10.
      Lurbinectedin produced responses in 35.2% of 105 patients with relapsed small-cell lung cancer.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-053