bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2022‒06‒05
23 papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology
  1. Stromal changes in the aged lung induce an emergence from melanoma dormancy.
  2. A pro-metastatic tRNA fragment drives Nucleolin oligomerization and stabilization of its bound metabolic mRNAs.
  3. YAP inhibits ERα and ER+ breast cancer growth by disrupting a TEAD-ERα signaling axis.
  4. A stromal Integrated Stress Response activates perivascular cancer-associated fibroblasts to drive angiogenesis and tumour progression.
  5. Circulating extracellular vesicles and tumor cells: sticky partners in metastasis.
  6. The microRNA-183/96/182 cluster inhibits lung cancer progression and metastasis by inducing an interleukin-2-mediated antitumor CD8+ cytotoxic T-cell response.
  7. Enhancing PD-L1 Degradation by ITCH during MAPK Inhibitor Therapy Suppresses Acquired Resistance.
  8. Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability.
  9. SIK2 inhibition enhances PARP inhibitor activity synergistically in ovarian and triple-negative breast cancers.
  10. Glioma progression is shaped by genetic evolution and microenvironment interactions.
  11. Fatty acid oxidation protects cancer cells from apoptosis by increasing mitochondrial membrane lipids.
  12. STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer.
  13. EWS-FLI1 and HOXD13 control tumor cell plasticity in Ewing sarcoma.
  14. Landscape of cancer cell therapies: trends and real-world data.
  15. Comparative single-cell RNA-sequencing profiling of BMP4-treated primary glioma cultures reveals therapeutic markers.
  16. Integrated DNA and RNA Sequencing Reveals Drivers of Endocrine Resistance in Estrogen Receptor-Positive Breast Cancer.
  17. Precancer Atlases Could Help Intercept Malignancies.
  18. A Genome-wide screen identifies PDPK1 as a target to enhance the efficacy of MEK1/2 inhibitors in NRAS mutant melanoma.
  19. Hypoxia-inducible factors: cancer progression and clinical translation.
  20. In vivo gain-of-function cDNA library screening for colonization genes in a mouse model of pulmonary metastasis.
  21. ZBP1-Driven Necroptosis Potentiates Immunotherapy and Is Blocked by ADAR1.
  22. Integration of Genomic Biology Into Therapeutic Strategies of Gastric Cancer Peritoneal Metastasis.
  23. Persister state-directed transitioning and vulnerability in melanoma.
  1. Nature. 2022 Jun 01.
    Stromal changes in the aged lung induce an emergence from melanoma dormancy.
    Mitchell E Fane, Yash Chhabra, Gretchen M Alicea, Devon A Maranto, Stephen M Douglass, Marie R Webster, Vito W Rebecca, Gloria E Marino, Filipe Almeida, Brett L Ecker, Daniel J Zabransky, Laura Hüser, Thomas Beer, Hsin-Yao Tang, Andrew Kossenkov, Meenhard Herlyn, David W Speicher, Wei Xu, Xiaowei Xu, Elizabeth M Jaffee, Julio A Aguirre-Ghiso, Ashani T Weeraratna.
      Disseminated cancer cells from primary tumours can seed in distal tissues, but may take several years to form overt metastases, a phenomenon that is termed tumour dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully characterize dormancy within melanoma. Here we show that the aged lung microenvironment facilitates a permissive niche for efficient outgrowth of dormant disseminated cancer cells-in contrast to the aged skin, in which age-related changes suppress melanoma growth but drive dissemination. These microenvironmental complexities can be explained by the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state1-3. It was previously shown that dermal fibroblasts promote phenotype switching in melanoma during ageing4-8. We now identify WNT5A as an activator of dormancy in melanoma disseminated cancer cells within the lung, which initially enables the efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble WNT antagonist sFRP1, which inhibits WNT5A in melanoma cells and thereby enables efficient metastatic outgrowth. We also identify the tyrosine kinase receptors AXL and MER as promoting a dormancy-to-reactivation axis within melanoma cells. Overall, we find that age-induced changes in distal metastatic microenvironments promote the efficient reactivation of dormant melanoma cells in the lung.
    DOI:  https://doi.org/10.1038/s41586-022-04774-2
  2. Mol Cell. 2022 May 26. pii: S1097-2765(22)00442-7. [Epub ahead of print]
    A pro-metastatic tRNA fragment drives Nucleolin oligomerization and stabilization of its bound metabolic mRNAs.
    Xuhang Liu, Wenbin Mei, Veena Padmanaban, Hanan Alwaseem, Henrik Molina, Maria C Passarelli, Bernardo Tavora, Sohail F Tavazoie.
      Stress-induced cleavage of transfer RNAs (tRNAs) into tRNA-derived fragments (tRFs) occurs across organisms from yeast to humans; yet, its mechanistic underpinnings and pathological consequences remain poorly defined. Small RNA profiling revealed increased abundance of a cysteine tRNA fragment (5'-tRFCys) during breast cancer metastatic progression. 5'-tRFCys was required for efficient breast cancer metastatic lung colonization and cancer cell survival. We identified Nucleolin as the direct binding partner of 5'-tRFCys. 5'-tRFCys promoted the oligomerization of Nucleolin and its bound metabolic transcripts Mthfd1l and Pafah1b1 into a higher-order transcript stabilizing ribonucleoprotein complex, which protected these transcripts from exonucleolytic degradation. Consistent with this, Mthfd1l and Pafah1b1 mediated pro-metastatic and metabolic effects downstream of 5'-tRFCys-impacting folate, one-carbon, and phosphatidylcholine metabolism. Our findings reveal that a tRF can promote oligomerization of an RNA-binding protein into a transcript stabilizing ribonucleoprotein complex, thereby driving specific metabolic pathways underlying cancer progression.
    Keywords:  Mthfd1l; Pafah1b1; breast cancer; metastasis; nucleolin; oligomerization; post-transcriptional; tRF; tRNA fragment; transcript stability
    DOI:  https://doi.org/10.1016/j.molcel.2022.05.008
  3. Nat Commun. 2022 Jun 02. 13(1): 3075
    YAP inhibits ERα and ER+ breast cancer growth by disrupting a TEAD-ERα signaling axis.
    Xu Li, Shu Zhuo, Ting Zhuang, Yong Suk Cho, Guojin Wu, Yuchen Liu, Kun Mu, Kai Zhang, Peng Su, Yingzi Yang, Cheng Cheng Zhang, Jian Zhu, Jin Jiang.
      Hippo signaling restricts tissue growth by inhibiting the transcriptional effector YAP. Here we uncover a role of Hippo signaling and a tumor suppressor function of YAP in estrogen receptor positive (ER+) breast cancer. We find that inhibition of Hippo/MST1/2 or activation of YAP blocks the ERα transcriptional program and ER+ breast cancer growth. Mechanistically, the Hippo pathway transcription factor TEAD physically interacts with ERα to increase its promoter/enhancer occupancy whereas YAP inhibits ERα/TEAD interaction, decreases ERα occupancy on its target promoters/enhancers, and promotes ERα degradation by the proteasome. Furthermore, YAP inhibits hormone-independent transcription of ERα gene (ESR1). Consistently, high levels of YAP correlate with good prognosis of ER+ breast cancer patients. Finally, we find that pharmacological inhibition of Hippo/MST1/2 impeded tumor growth driven by hormone therapy resistant ERα mutants, suggesting that targeting the Hippo-YAP-TEAD signaling axis could be a potential therapeutical strategy to overcome endocrine therapy resistance conferred by ERα mutants.
    DOI:  https://doi.org/10.1038/s41467-022-30831-5
  4. Nat Cell Biol. 2022 Jun 02.
    A stromal Integrated Stress Response activates perivascular cancer-associated fibroblasts to drive angiogenesis and tumour progression.
    Ioannis I Verginadis, Harris Avgousti, James Monslow, Giorgos Skoufos, Frank Chinga, Kyle Kim, Nektaria Maria Leli, Ilias V Karagounis, Brett I Bell, Anastasia Velalopoulou, Carlo Salas Salinas, Victoria S Wu, Yang Li, Jiangbin Ye, David A Scott, Andrei L Osterman, Arjun Sengupta, Aalim Weljie, Menggui Huang, Duo Zhang, Yi Fan, Enrico Radaelli, John W Tobias, Florian Rambow, Panagiotis Karras, Jean-Christophe Marine, Xiaowei Xu, Artemis G Hatzigeorgiou, Sandra Ryeom, J Alan Diehl, Serge Y Fuchs, Ellen Puré, Constantinos Koumenis.
      Bidirectional signalling between the tumour and stroma shapes tumour aggressiveness and metastasis. ATF4 is a major effector of the Integrated Stress Response, a homeostatic mechanism that couples cell growth and survival to bioenergetic demands. Using conditional knockout ATF4 mice, we show that global, or fibroblast-specific loss of host ATF4, results in deficient vascularization and a pronounced growth delay of syngeneic melanoma and pancreatic tumours. Single-cell transcriptomics of tumours grown in Atf4Δ/Δ mice uncovered a reduction in activation markers in perivascular cancer-associated fibroblasts (CAFs). Atf4Δ/Δ fibroblasts displayed significant defects in collagen biosynthesis and deposition and a reduced ability to support angiogenesis. Mechanistically, ATF4 regulates the expression of the Col1a1 gene and levels of glycine and proline, the major amino acids of collagen. Analyses of human melanoma and pancreatic tumours revealed a strong correlation between ATF4 and collagen levels. Our findings establish stromal ATF4 as a key driver of CAF functionality, malignant progression and metastasis.
    DOI:  https://doi.org/10.1038/s41556-022-00918-8
  5. Trends Cancer. 2022 May 26. pii: S2405-8033(22)00113-3. [Epub ahead of print]
    Circulating extracellular vesicles and tumor cells: sticky partners in metastasis.
    Katerina Jerabkova-Roda, Amandine Dupas, Naël Osmani, Vincent Hyenne, Jacky G Goetz.
      The intravascular behavior of tumor-derived extracellular vesicles (EVs) and circulating tumor cells (CTCs) lies at the heart of the metastatic cascade. Their capacity to disseminate and stop at specific vascular regions precedes and determines the formation of metastatic foci. We discuss in detail the central role of cellular adhesion molecules (CAMs) that are present on EV/CTC surface, as well as their endothelial ligands, in dictating their arrest site and their capacity to exit the vasculature. We focus on the differences and similarities between CAMs on CTCs and EVs, and speculate about their role in the organotropism of different cancer types. Better understanding of the binding mechanisms might pinpoint potential targets for novel therapies.
    Keywords:  cancer cell extravasation; cell adhesion; circulating tumor cells; endothelium; extracellular vesicles; metastasis
    DOI:  https://doi.org/10.1016/j.trecan.2022.05.002
  6. Genes Dev. 2022 Jun 02.
    The microRNA-183/96/182 cluster inhibits lung cancer progression and metastasis by inducing an interleukin-2-mediated antitumor CD8+ cytotoxic T-cell response.
    Samrat T Kundu, B Leticia Rodriguez, Laura A Gibson, Amanda N Warner, Mabel G Perez, Rakhee Bajaj, Jared J Fradette, Caleb A Class, Luisa M Solis, Frank R Rojas Alvarez, Ignacio I Wistuba, Lixia Diao, Fengju Chen, Mohit Sachdeva, Jing Wang, David G Kirsch, Chad J Creighton, Don L Gibbons.
      One of the mechanisms by which cancer cells acquire hyperinvasive and migratory properties with progressive loss of epithelial markers is the epithelial-to-mesenchymal transition (EMT). We have previously reported that in different cancer types, including nonsmall cell lung cancer (NSCLC), the microRNA-183/96/182 cluster (m96cl) is highly repressed in cells that have undergone EMT. In the present study, we used a novel conditional m96cl mouse to establish that loss of m96cl accelerated the growth of Kras mutant autochthonous lung adenocarcinomas. In contrast, ectopic expression of the m96cl in NSCLC cells results in a robust suppression of migration and invasion in vitro, and tumor growth and metastasis in vivo. Detailed immune profiling of the tumors revealed a significant enrichment of activated CD8+ cytotoxic T lymphocytes (CD8+ CTLs) in m96cl-expressing tumors, and m96cl-mediated suppression of tumor growth and metastasis was CD8+ CTL-dependent. Using coculture assays with naïve immune cells, we show that m96cl expression drives paracrine stimulation of CD8+ CTL proliferation and function. Using tumor microenvironment-associated gene expression profiling, we identified that m96cl elevates the interleukin-2 (IL2) signaling pathway and results in increased IL2-mediated paracrine stimulation of CD8+ CTLs. Furthermore, we identified that the m96cl modulates the expression of IL2 in cancer cells by regulating the expression of transcriptional repressors Foxf2 and Zeb1, and thereby alters the levels of secreted IL2 in the tumor microenvironment. Last, we show that in vivo depletion of IL2 abrogates m96cl-mediated activation of CD8+ CTLs and results in loss of metastatic suppression. Therefore, we have identified a novel mechanistic role of the m96cl in the suppression of lung cancer growth and metastasis by inducing an IL2-mediated systemic CD8+ CTL immune response.
    Keywords:  CD8+ T lymphocytes; CTL; EMT; Foxf2; Zeb1; antitumor immune response; interleukin-2; lung cancer; microRNA-183/96/182; tumor immune microenvironment
    DOI:  https://doi.org/10.1101/gad.349321.121
  7. Cancer Discov. 2022 Jun 02. pii: candisc.1463.2021-11-2 01:32:02.600. [Epub ahead of print]
    Enhancing PD-L1 Degradation by ITCH during MAPK Inhibitor Therapy Suppresses Acquired Resistance.
    Zhentao Yang, Yan Wang, Sixue Liu, Weixian Deng, Shirley H Lomeli, Gatien Moriceau, James Wohlschlegel, Marco Piva, Roger S Lo.
      MAPK inhibitor (MAPKi) therapy in melanoma leads to accumulation of tumor-surface PD-L1/2, which may evade antitumor immunity and accelerate acquired resistance. Here, we discover that the E3 ligase ITCH binds, ubiquitinates, and down-regulates tumor-surface PD-L1/L2 in MAPKi-treated human melanoma cells, thereby promoting T-cell activation. During MAPKi therapy in vivo, melanoma cell-intrinsic ITCH knockdown induced tumor-surface PD-L1, reduced intratumoral cytolytic CD8+ T cells, and accelerated acquired resistance only in immune-competent mice. Conversely, tumor cell-intrinsic ITCH over-expression reduced MAPKi-elicited PD-L1 accumulation, augmented intratumoral cytolytic CD8+ T cells, and suppressed acquired resistance in BrafV600MUT, NrasMUT, or Nf1MUT melanoma and KrasMUT-driven cancers. CD8+ T-cell depletion and tumor cell-intrinsic PD-L1 over-expression nullified the phenotype of ITCH over-expression, thereby supporting an in vivo ITCH-PD-L1-T-cell regulatory axis. Moreover, we identify a small-molecular ITCH activator which suppresses acquired MAPKi-resistance in vivo. Thus, MAPKi-induced PD-L1 accelerates resistance, and a PD-L1-degrading ITCH activator prolongs antitumor response.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-1463
  8. Nat Chem Biol. 2022 May 30.
    Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability.
    Zhipeng Li, Lucas Ferguson, Kirandeep K Deol, Melissa A Roberts, Leslie Magtanong, Joseph M Hendricks, Gergey Alzaem Mousa, Seda Kilinc, Kaitlin Schaefer, James A Wells, Michael C Bassik, Andrei Goga, Scott J Dixon, Nicholas T Ingolia, James A Olzmann.
      The selenoprotein glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid peroxides into nontoxic lipid alcohols. GPX4 has emerged as a promising therapeutic target for cancer treatment, but some cancer cells are resistant to ferroptosis triggered by GPX4 inhibition. Using a chemical-genetic screen, we identify LRP8 (also known as ApoER2) as a ferroptosis resistance factor that is upregulated in cancer. Loss of LRP8 decreases cellular selenium levels and the expression of a subset of selenoproteins. Counter to the canonical hierarchical selenoprotein regulatory program, GPX4 levels are strongly reduced due to impaired translation. Mechanistically, low selenium levels result in ribosome stalling at the inefficiently decoded GPX4 selenocysteine UGA codon, leading to ribosome collisions, early translation termination and proteasomal clearance of the N-terminal GPX4 fragment. These findings reveal rewiring of the selenoprotein hierarchy in cancer cells and identify ribosome stalling and collisions during GPX4 translation as ferroptosis vulnerabilities in cancer.
    DOI:  https://doi.org/10.1038/s41589-022-01033-3
  9. J Clin Invest. 2022 Jun 01. pii: e146471. [Epub ahead of print]132(11):
    SIK2 inhibition enhances PARP inhibitor activity synergistically in ovarian and triple-negative breast cancers.
    Zhen Lu, Weiqun Mao, Hailing Yang, Janice M Santiago-O'Farrill, Philip J Rask, Jayanta Mondal, Hu Chen, Cristina Ivan, Xiuping Liu, Chang-Gong Liu, Yuanxin Xi, Kenta Masuda, Eli M Carrami, Meng Chen, Yitao Tang, Lan Pang, David S Lakomy, George A Calin, Han Liang, Ahmed A Ahmed, Hariprasad Vankayalapati, Robert C Bast.
      Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) have had an increasing role in the treatment of ovarian and breast cancers. PARP inhibitors are selectively active in cells with homologous recombination DNA repair deficiency caused by mutations in BRCA1/2 and other DNA repair pathway genes. Cancers with homologous recombination DNA repair proficiency respond poorly to PARP inhibitors. Cancers that initially respond to PARP inhibitors eventually develop drug resistance. We have identified salt-inducible kinase 2 (SIK2) inhibitors, ARN3236 and ARN3261, which decreased DNA double-strand break (DSB) repair functions and produced synthetic lethality with multiple PARP inhibitors in both homologous recombination DNA repair deficiency and proficiency cancer cells. SIK2 is required for centrosome splitting and PI3K activation and regulates cancer cell proliferation, metastasis, and sensitivity to chemotherapy. Here, we showed that SIK2 inhibitors sensitized ovarian and triple-negative breast cancer (TNBC) cells and xenografts to PARP inhibitors. SIK2 inhibitors decreased PARP enzyme activity and phosphorylation of class-IIa histone deacetylases (HDAC4/5/7). Furthermore, SIK2 inhibitors abolished class-IIa HDAC4/5/7-associated transcriptional activity of myocyte enhancer factor-2D (MEF2D), decreasing MEF2D binding to regulatory regions with high chromatin accessibility in FANCD2, EXO1, and XRCC4 genes, resulting in repression of their functions in the DNA DSB repair pathway. The combination of PARP inhibitors and SIK2 inhibitors provides a therapeutic strategy to enhance PARP inhibitor sensitivity for ovarian cancer and TNBC.
    Keywords:  Apoptosis; Cancer; Cell Biology; DNA repair; Therapeutics
    DOI:  https://doi.org/10.1172/JCI146471
  10. Cell. 2022 May 24. pii: S0092-8674(22)00536-0. [Epub ahead of print]
    Glioma progression is shaped by genetic evolution and microenvironment interactions.
    GLASS Consortium
      The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.
    Keywords:  genomics; glioblastoma; glioma; hypermutation; macrophages; microenvironment; neurons; single-cell; spatial imaging; treatment resistance
    DOI:  https://doi.org/10.1016/j.cell.2022.04.038
  11. Cell Rep. 2022 May 31. pii: S2211-1247(22)00645-3. [Epub ahead of print]39(9): 110870
    Fatty acid oxidation protects cancer cells from apoptosis by increasing mitochondrial membrane lipids.
    Yi-Jia Li, Johannes Francois Fahrmann, Maryam Aftabizadeh, Qianqian Zhao, Satyendra C Tripathi, Chunyan Zhang, Yuan Yuan, David Ann, Samir Hanash, Hua Yu.
      Overcoming resistance to chemotherapies remains a major unmet need for cancers, such as triple-negative breast cancer (TNBC). Therefore, mechanistic studies to provide insight for drug development are urgently needed to overcome TNBC therapy resistance. Recently, an important role of fatty acid β-oxidation (FAO) in chemoresistance has been shown. But how FAO might mitigate tumor cell apoptosis by chemotherapy is unclear. Here, we show that elevated FAO activates STAT3 by acetylation via elevated acetyl-coenzyme A (CoA). Acetylated STAT3 upregulates expression of long-chain acyl-CoA synthetase 4 (ACSL4), resulting in increased phospholipid synthesis. Elevating phospholipids in mitochondrial membranes leads to heightened mitochondrial integrity, which in turn overcomes chemotherapy-induced tumor cell apoptosis. Conversely, in both cultured tumor cells and xenograft tumors, enhanced cancer cell apoptosis by inhibiting ASCL4 or specifically targeting acetylated-STAT3 is associated with a reduction in phospholipids within mitochondrial membranes. This study demonstrates a critical mechanism underlying tumor cell chemoresistance.
    Keywords:  ACSL; CP: Cancer; CP: Metabolism; STAT3 acetylation; anti-apoptosis; chemoresistance; fatty acid oxidation; mitochondrial membrane potential; phospholipids
    DOI:  https://doi.org/10.1016/j.celrep.2022.110870
  12. Nat Commun. 2022 May 31. 13(1): 3022
    STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer.
    Qiwei Wang, Johann S Bergholz, Liya Ding, Ziying Lin, Sheheryar K Kabraji, Melissa E Hughes, Xiadi He, Shaozhen Xie, Tao Jiang, Weihua Wang, Jason J Zoeller, Hye-Jung Kim, Thomas M Roberts, Panagiotis A Konstantinopoulos, Ursula A Matulonis, Deborah A Dillon, Eric P Winer, Nancy U Lin, Jean J Zhao.
      PARP inhibitors (PARPi) have drastically changed the treatment landscape of advanced ovarian tumors with BRCA mutations. However, the impact of this class of inhibitors in patients with advanced BRCA-mutant breast cancer is relatively modest. Using a syngeneic genetically-engineered mouse model of breast tumor driven by Brca1 deficiency, we show that tumor-associated macrophages (TAMs) blunt PARPi efficacy both in vivo and in vitro. Mechanistically, BRCA1-deficient breast tumor cells induce pro-tumor polarization of TAMs, which in turn suppress PARPi-elicited DNA damage in tumor cells, leading to reduced production of dsDNA fragments and synthetic lethality, hence impairing STING-dependent anti-tumor immunity. STING agonists reprogram M2-like pro-tumor macrophages into an M1-like anti-tumor state in a macrophage STING-dependent manner. Systemic administration of a STING agonist breaches multiple layers of tumor cell-mediated suppression of immune cells, and synergizes with PARPi to suppress tumor growth. The therapeutic benefits of this combination require host STING and are mediated by a type I IFN response and CD8+ T cells, but do not rely on tumor cell-intrinsic STING. Our data illustrate the importance of targeting innate immune suppression to facilitate PARPi-mediated engagement of anti-tumor immunity in breast cancer.
    DOI:  https://doi.org/10.1038/s41467-022-30568-1
  13. Clin Cancer Res. 2022 Jun 02. pii: clincanres.0384.2022-2-5 13:20:00.280. [Epub ahead of print]
    EWS-FLI1 and HOXD13 control tumor cell plasticity in Ewing sarcoma.
    April A Apfelbaum, Feinan Wu, Allegra G Hawkins, Brian Magnuson, Jennifer A Jimenez, Sean D Taylor, Emma D Wrenn, Olivia Waltner, Elise R Pfaltzgraff, Jane Y Song, Cody Hall, Deneen M Wellik, Mats Ljungman, Scott N Furlan, Russell J H Ryan, Jay F Sarthy, Elizabeth R Lawlor.
      PURPOSE: Propagation of Ewing sarcoma (EwS) requires precise regulation of EWS::FLI1 transcriptional activity. Determining the mechanisms of fusion regulation will advance our understanding of tumor progression. Here we investigated whether HOXD13, a developmental transcription factor that promotes EwS metastatic phenotypes, influences EWS::FLI1 transcriptional activity.EXPERIMENTAL DESIGN: Existing tumor and cell line datasets were used to define EWS::FLI1 binding sites and transcriptional targets. Chromatin immunoprecipitation and CRISPR-interference were employed to identify enhancers. CUT&RUN and RNA-seq defined binding sites and transcriptional targets of HOXD13. Transcriptional states were investigated using bulk and single-cell transcriptomic data from cell lines, patient-derived xenografts, and patient tumors. Mesenchymal phenotypes were assessed by geneset enrichment, flow cytometry, and migration assays.
    RESULTS: We found that EWS::FLI1 creates a de novo GGAA microsatellite enhancer in a developmentally conserved regulatory region of the HOXD locus. Knockdown of HOXD13 led to widespread changes in expression of developmental gene programs and EWS::FLI1 targets. HOXD13 binding was enriched at established EWS::FLI1 binding sites where it influenced expression of EWS::FLI1-activated genes. More strikingly, HOXD13 bound and activated EWS::FLI1-repressed genes, leading to adoption of mesenchymal and migratory cell states that are normally suppressed by the fusion. Single-cell analysis confirmed that direct transcriptional antagonism between HOXD13-mediated gene activation and EWS::FLI1-dependent gene repression defines the state of EwS cells along a mesenchymal axis.
    CONCLUSIONS: EwS tumors are comprised of tumor cells that exist along a mesenchymal transcriptional continuum. The identity of cells along this continuum is, in large part, determined by the competing activities of EWS::FLI1 and HOXD13.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-0384
  14. Nat Rev Drug Discov. 2022 Jun 01.
    Landscape of cancer cell therapies: trends and real-world data.
    Ana Rosa Saez-Ibañez, Samik Upadhaya, Tanya Partridge, Monica Shah, Diego Correa, Jay Campbell.
      
    DOI:  https://doi.org/10.1038/d41573-022-00095-1
  15. Neuro Oncol. 2022 May 26. pii: noac143. [Epub ahead of print]
    Comparative single-cell RNA-sequencing profiling of BMP4-treated primary glioma cultures reveals therapeutic markers.
    Iris S C Verploegh, Andrea Conidi, Rutger W W Brouwer, Hayri E Balcioglu, Panagiotis Karras, Samira Makhzami, Anne Korporaal, Jean-Christophe Marine, Martine Lamfers, Wilfred F J van IJcken, Sieger Leenstra, Danny Huylebroeck.
      BACKGROUND: Glioblastoma (GBM) is the most aggressive primary brain tumor. Its cellular composition is very heterogeneous, with cells exhibiting stem-cell characteristics (GSCs) that co-determine therapy resistance and tumor recurrence. Bone Morphogenetic Protein (BMP)-4 promotes astroglial and suppresses oligodendrocyte differentiation in GSCs, processes associated with superior patient prognosis. We characterized variability in cell viability of patient-derived GBM cultures in response to BMP4 and, based on single-cell transcriptome profiling, propose predictive positive and early-response markers for sensitivity to BMP4.METHODS: Cell viability was assessed in 17 BMP4-treated patient-derived GBM cultures. In two cultures, one highly sensitive to BMP4 (high therapeutic efficacy) and one with low sensitivity, response to treatment with BMP4 was characterized. We applied single-cell RNA-sequencing, analyzed the relative abundance of cell clusters, searched for and identified the aforementioned two marker types, and validated these results in all 17 cultures.
    RESULTS: High variation in cell viability was observed after treatment with BMP4. In three cultures with highest sensitivity for BMP4, a substantial new cell subpopulation formed. These cells displayed decreased cell proliferation and increased apoptosis. Neuronal differentiation was reduced most in cultures with little sensitivity for BMP4. OLIG1/2 levels were found predictive for high sensitivity to BMP4. Activation of ribosomal translation (RPL27A, RPS27) was upregulated within one day in cultures that were very sensitive to BMP4.
    CONCLUSION: The changes in composition of patient-derived GBM cultures obtained after treatment with BMP4 correlate with treatment efficacy. OLIG1/2 expression can predict this efficacy, and upregulation of RPL27A and RPS27 are useful early-response markers.
    Keywords:  BMP; drug therapy; glioblastoma; single-cell RNA-sequencing; tumor heterogeneity
    DOI:  https://doi.org/10.1093/neuonc/noac143
  16. Clin Cancer Res. 2022 Jun 02. pii: clincanres.3189.2021-9-2 12:04:46.737. [Epub ahead of print]
    Integrated DNA and RNA Sequencing Reveals Drivers of Endocrine Resistance in Estrogen Receptor-Positive Breast Cancer.
    Youli Xia, Xiaping He, Lorna Renshaw, Carlos Martinez-Perez, Charlene Kay, Mark Gray, James Meehan, Joel S Parker, Charles M Perou, Lisa A Carey, J Michael Dixon, Arran Turnbull.
      PURPOSE: Endocrine therapy resistance (ETR) remains the greatest challenge in treating patients with hormone receptor-positive breast cancer. We set out to identify molecular mechanisms underlying ETR through in-depth genomic analysis of breast tumors.EXPERIMENTAL DESIGN: We collected pre-treatment and sequential on-treatment tumor samples from 35 patients with estrogen receptor-positive breast cancer treated with neoadjuvant then adjuvant ET; 3 had intrinsic resistance, 19 acquired resistance, and 13 remained sensitive. Response was determined by changes in tumor volume neoadjuvantly and by monitoring for adjuvant recurrence. Twelve patients received 2 or more lines of ET, with subsequent treatment lines being initiated at the time of development of resistance to the previous ET. DNA whole-exome sequencing and RNA-sequencing were performed on all samples, totalling 169 unique specimens. DNA mutations, copy number alterations and gene expression data were analyzed through unsupervised and supervised analyses to identify molecular features related to ETR.
    RESULTS: Mutations enriched in ETR included ESR1 and GATA3. The known ESR1 D538G variant conferring ETR was identified, as was a rarer E380Q variant that confers endocrine hypersensitivity. Resistant tumors which acquired resistance had distinct gene expression profiles compared to paired sensitive tumors, showing elevated pathways including ER, HER2, GATA3, AKT, RAS and p63 signaling. Integrated analysis in individual patients highlighted the diversity of ETR mechanisms.
    CONCLUSIONS: The mechanisms underlying ETR are multiple and characterized by diverse changes in both somatic genetic and transcriptomic profiles; to overcome resistance will require an individualized approach utilizing genomic and genetic biomarkers and drugs tailored to each patient.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-3189
  17. Cancer Discov. 2022 Jun 02. OF1
    Precancer Atlases Could Help Intercept Malignancies.
      This spatial and temporal map of tumor microenvironments in premalignant lesions could hold answers to detecting oncogenic cells before they become invasive cancer. Two research groups have piloted precancer atlases to study the immune microenvironment of squamous lung cancer and melanoma.
    DOI:  https://doi.org/10.1158/2159-8290.CD-NB2022-0041
  18. Cancer Res. 2022 Jun 03. pii: canres.3217.2021-9-22 14:53:05.437. [Epub ahead of print]
    A Genome-wide screen identifies PDPK1 as a target to enhance the efficacy of MEK1/2 inhibitors in NRAS mutant melanoma.
    Weijia Cai, Mai Q Nguyen, Nicole A Wilski, Timothy J Purwin, Megane Vernon, Manoela Tiago, Andrew E Aplin.
      Melanomas frequently harbor activating NRAS mutations. However, limited advance has been made in developing targeted therapy options for NRAS mutant melanoma patients. MEK inhibitors (MEKi) show modest efficacy in the clinic and their actions need to be optimized. In this study, we performed a genome-wide CRISPR-Cas9-based screen and demonstrated that loss of Phosphoinositide-dependent kinase-1 (PDPK1) enhances the efficacy of MEKi. The synergistic effects of PDPK1 loss and MEKi was validated in NRAS mutant melanoma cell lines using pharmacological and molecular approaches. Combined PDPK1 inhibitors (PDPK1i) with MEKi suppressed NRAS mutant xenograft growth and induced gasdermin E-associated pyroptosis. In an immune-competent allograft model, PDPK1i+MEKi increased the ratio of intratumoral CD8+ T cells, delayed tumor growth and prolonged survival; the combination treatment was less effective against tumors in immune-deficient mice. These data suggest PDPK1i+MEKi as an efficient immunostimulatory strategy against NRAS mutant melanoma.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3217
  19. J Clin Invest. 2022 Jun 01. pii: e159839. [Epub ahead of print]132(11):
    Hypoxia-inducible factors: cancer progression and clinical translation.
    Elizabeth E Wicks, Gregg L Semenza.
      Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis that match O2 supply and demand for each of the 50 trillion cells in the adult human body. Cancer cells co-opt this homeostatic system to drive cancer progression. HIFs activate the transcription of thousands of genes that mediate angiogenesis, cancer stem cell specification, cell motility, epithelial-mesenchymal transition, extracellular matrix remodeling, glucose and lipid metabolism, immune evasion, invasion, and metastasis. In this Review, the mechanisms and consequences of HIF activation in cancer cells are presented. The current status and future prospects of small-molecule HIF inhibitors for use as cancer therapeutics are discussed.
    DOI:  https://doi.org/10.1172/JCI159839
  20. STAR Protoc. 2022 Jun 17. 3(2): 101413
    In vivo gain-of-function cDNA library screening for colonization genes in a mouse model of pulmonary metastasis.
    Zhenbo Tu, Antoine E Karnoub.
      We provide a protocol for gain-of-function (GOF) cDNA screen of genes that foster cancer cell colonization of secondary tissues, the last and most lethal step of the metastasis cascade. We present techniques for cDNA viral library preparation and delivery leading up to the recovery of colonization-promoting sequences in a proof-of-concept DU145-based mouse model of pulmonary metastasis. Adapted to other cDNA libraries and cancer models, this approach would prove widely useful in enumerating intrinsic genetic determinants underlying metastatic colonization. For complete details on the use and execution of this protocol, please refer to Tu et al. (2021).
    Keywords:  Cancer; Cell Biology; Gene Expression; Metabolism; Microscopy; Model Organisms; Molecular Biology; Molecular/Chemical Probes
    DOI:  https://doi.org/10.1016/j.xpro.2022.101413
  21. Cancer Discov. 2022 Jun 03. OF1
    ZBP1-Driven Necroptosis Potentiates Immunotherapy and Is Blocked by ADAR1.
      ADAR1 binds endogenous Z-RNA and masks the immunotherapeutic potential of ZBP1-induced necroptosis.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-101
  22. J Clin Oncol. 2022 Jun 01. JCO2102745
    Integration of Genomic Biology Into Therapeutic Strategies of Gastric Cancer Peritoneal Metastasis.
    Yong Xiang Gwee, Daryl Kai Ann Chia, Jimmy So, Wim Ceelen, Wei Peng Yong, Patrick Tan, Chin-Ann Johnny Ong, Raghav Sundar.
      The peritoneum is a common site of metastasis in advanced gastric cancer (GC). Diagnostic laparoscopy is now routinely performed as part of disease staging, leading to an earlier diagnosis of synchronous peritoneal metastasis (PM). The biology of GCPM is unique and aggressive, leading to a dismal prognosis. These tumors tend to be resistant to traditional systemic therapy, and yet, this remains the current standard-of-care recommended by most international clinical guidelines. As this is an area of unmet clinical need, several translational studies and clinical trials have focused on addressing this specific disease state. Advances in genomic sequencing and molecular profiling have revealed several promising therapeutic targets and elucidated novel biology, particularly on the role of the surrounding tumor microenvironment in GCPM. Peritoneal-specific clinical trials are being designed with a combination of locoregional therapeutic strategies with systemic therapy. In this review, we summarize the new knowledge of cancer biology, advances in surgical techniques, and emergence of novel therapies as an integrated strategy emerges to address GCPM as a distinct clinical entity.
    DOI:  https://doi.org/10.1200/JCO.21.02745
  23. Nat Commun. 2022 Jun 01. 13(1): 3055
    Persister state-directed transitioning and vulnerability in melanoma.
    Heike Chauvistré, Batool Shannan, Sheena M Daignault-Mill, Robert J Ju, Daniel Picard, Stefanie Egetemaier, Renáta Váraljai, Christine S Gibhardt, Antonio Sechi, Farnusch Kaschani, Oliver Keminer, Samantha J Stehbens, Qin Liu, Xiangfan Yin, Kirujan Jeyakumar, Felix C E Vogel, Clemens Krepler, Vito W Rebecca, Linda Kubat, Smiths S Lueong, Jan Forster, Susanne Horn, Marc Remke, Michael Ehrmann, Annette Paschen, Jürgen C Becker, Iris Helfrich, Daniel Rauh, Markus Kaiser, Sheraz Gul, Meenhard Herlyn, Ivan Bogeski, José Neptuno Rodríguez-López, Nikolas K Haass, Dirk Schadendorf, Alexander Roesch.
      Melanoma is a highly plastic tumor characterized by dynamic interconversion of different cell identities depending on the biological context. Melanoma cells with high expression of the H3K4 demethylase KDM5B (JARID1B) rest in a slow-cycling, yet reversible persister state. Over time, KDM5Bhigh cells can promote rapid tumor repopulation with equilibrated KDM5B expression heterogeneity. The cellular identity of KDM5Bhigh persister cells has not been studied so far, missing an important cell state-directed treatment opportunity in melanoma. Here, we have established a doxycycline-titratable system for genetic induction of permanent intratumor expression of KDM5B and screened for chemical agents that phenocopy this effect. Transcriptional profiling and cell functional assays confirmed that the dihydropyridine 2-phenoxyethyl 4-(2-fluorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxylate (termed Cpd1) supports high KDM5B expression and directs melanoma cells towards differentiation along the melanocytic lineage and to cell cycle-arrest. The high KDM5B state additionally prevents cell proliferation through negative regulation of cytokinetic abscission. Moreover, treatment with Cpd1 promoted the expression of the melanocyte-specific tyrosinase gene specifically sensitizing melanoma cells for the tyrosinase-processed antifolate prodrug 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG). In summary, our study provides proof-of-concept for a dual hit strategy in melanoma, in which persister state-directed transitioning limits tumor plasticity and primes melanoma cells towards lineage-specific elimination.
    DOI:  https://doi.org/10.1038/s41467-022-30641-9
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