bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2022–07–03
eightteen papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. Mex3a marks drug-tolerant persister colorectal cancer cells that mediate relapse after chemotherapy.
  2. Research is a process.
  3. CHD1 promotes sensitivity to Aurora kinase inhibitors by suppressing interaction of AURKA with its coactivator TPX2.
  4. Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis.
  5. Caspase-3-induced activation of SREBP2 drives drug resistance via promotion of cholesterol biosynthesis in hepatocellular carcinoma.
  6. Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence.
  7. CircEZH2/miR-133b/IGF2BP2 aggravates colorectal cancer progression via enhancing the stability of m6A-modified CREB1 mRNA.
  8. Mitochondrial RNA modifications shape metabolic plasticity in metastasis.
  9. A Phenotypic Continuum Supports Malignant Transformation in Colorectal Cancer.
  10. Combinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer.
  11. The dynamic roles of the bladder tumour microenvironment.
  12. Reduced symmetric dimethylation stabilizes vimentin and promotes metastasis in MTAP-deficient lung cancer.
  13. The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma.
  14. RNA helicase DDX24 stabilizes LAMB1 to promote hepatocellular carcinoma progression.
  15. YAP1 induces invadopodia formation by transcriptionally activating TIAM1 through enhancer in breast cancer.
  16. G6PD inhibition sensitizes ovarian cancer cells to oxidative stress in the metastatic omental microenvironment.
  17. A Targetable Myeloid Inflammatory State Governs Disease Recurrence in Clear Cell Renal Cell Carcinoma.
  18. lncRNA Linc00173 modulates glucose metabolism and multidrug chemoresistance inSCLC:Potentialmolecular panel for targeted therapy.
  1. Nat Cancer. 2022 Jun 30.
    Mex3a marks drug-tolerant persister colorectal cancer cells that mediate relapse after chemotherapy.
    Adrián Álvarez-Varela, Laura Novellasdemunt, Francisco M Barriga, Xavier Hernando-Momblona, Adrià Cañellas-Socias, Sara Cano-Crespo, Marta Sevillano, Carme Cortina, Diana Stork, Clara Morral, Gemma Turon, Felipe Slebe, Laura Jiménez-Gracia, Ginevra Caratù, Peter Jung, Giorgio Stassi, Holger Heyn, Daniele V F Tauriello, Lidia Mateo, Sabine Tejpar, Elena Sancho, Camille Stephan-Otto Attolini, Eduard Batlle.
      Colorectal cancer (CRC) patient-derived organoids predict responses to chemotherapy. Here we used them to investigate relapse after treatment. Patient-derived organoids expand from highly proliferative LGR5+ tumor cells; however, we discovered that lack of optimal growth conditions specifies a latent LGR5+ cell state. This cell population expressed the gene MEX3A, is chemoresistant and regenerated the organoid culture after treatment. In CRC mouse models, Mex3a+ cells contributed marginally to metastatic outgrowth; however, after chemotherapy, Mex3a+ cells produced large cell clones that regenerated the disease. Lineage-tracing analysis showed that persister Mex3a+ cells downregulate the WNT/stem cell gene program immediately after chemotherapy and adopt a transient state reminiscent to that of YAP+ fetal intestinal progenitors. In contrast, Mex3a-deficient cells differentiated toward a goblet cell-like phenotype and were unable to resist chemotherapy. Our findings reveal that adaptation of cancer stem cells to suboptimal niche environments protects them from chemotherapy and identify a candidate cell of origin of relapse after treatment in CRC.
    DOI:  https://doi.org/10.1038/s43018-022-00402-0
  2. Nat Cell Biol. 2022 Jun 29.
    Research is a process.
    Sarah-Maria Fendt.
      
    DOI:  https://doi.org/10.1038/s41556-022-00954-4
  3. Cancer Res. 2022 Jun 30. pii: can.22.0631. [Epub ahead of print]
    CHD1 promotes sensitivity to Aurora kinase inhibitors by suppressing interaction of AURKA with its coactivator TPX2.
    Haoyan Li, Yin Wang, Kevin Lin, Varadha Balaji Venkadakrishnan, Martin Bakht, Wei Shi, Chenling Meng, Jie Zhang, Kaitlyn Tremble, Xin Liang, Jian H Song, Xu Feng, Vivien Van, Pingna Deng, Jared K Burks, Ana Aparicio, Khandan Keyomarsi, Junjie Chen, Yue Lu, Himisha Beltran, Di Zhao.
      Clinical studies have shown that subsets of cancer patients achieve a significant benefit from Aurora kinase inhibitors, suggesting an urgent need to identify biomarkers for predicting drug response. Chromodomain-helicase-DNA-binding protein 1 (CHD1) is involved in chromatin remodeling, DNA repair, and transcriptional plasticity. Prior studies have demonstrated that CHD1 has distinct expression patterns in cancers with different molecular features, but its impact on drug responsiveness remains understudied. Here, we show that CHD1 promotes the susceptibility of prostate cancer cells to inhibitors targeting Aurora kinases, while depletion of CHD1 impairs their efficacy in vitro and in vivo. Pan-cancer drug sensitivity analyses revealed that high expression of CHD1 was associated with increased sensitivity to Aurora kinase A (AURKA) inhibitors. Mechanistically, KPNA2 served as a direct target of CHD1 and suppressed the interaction of AURKA with the co-activator TPX2, thereby rendering cancer cells more vulnerable to AURKA inhibitors. Consistent with previous research reporting that loss of PTEN elevates CHD1 levels, studies in a genetically engineered mouse model, patient-derived organoids, and patient samples showed that PTEN defects are associated with a better response to AURKA inhibition in advanced prostate cancer. These observations demonstrate that CHD1 plays an important role in modulating Aurora kinases and drug sensitivities, providing new insights into biomarker-driven therapies targeting Aurora kinases for future clinical studies.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0631
  4. Mol Cell. 2022 Jun 18. pii: S1097-2765(22)00541-X. [Epub ahead of print]
    Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis.
    Dan He, Huijin Feng, Belen Sundberg, Jiaxing Yang, Justin Powers, Alec H Christian, John E Wilkinson, Cian Monnin, Daina Avizonis, Craig J Thomas, Richard A Friedman, Michael D Kluger, Michael A Hollingsworth, Paul M Grandgenett, Kelsey A Klute, F Dean Toste, Christopher J Chang, Iok In Christine Chio.
      Cancer mortality is primarily a consequence of its metastatic spread. Here, we report that methionine sulfoxide reductase A (MSRA), which can reduce oxidized methionine residues, acts as a suppressor of pancreatic ductal adenocarcinoma (PDA) metastasis. MSRA expression is decreased in the metastatic tumors of PDA patients, whereas MSRA loss in primary PDA cells promotes migration and invasion. Chemoproteomic profiling of pancreatic organoids revealed that MSRA loss results in the selective oxidation of a methionine residue (M239) in pyruvate kinase M2 (PKM2). Moreover, M239 oxidation sustains PKM2 in an active tetrameric state to promote respiration, migration, and metastasis, whereas pharmacological activation of PKM2 increases cell migration and metastasis in vivo. These results demonstrate that methionine residues can act as reversible redox switches governing distinct signaling outcomes and that the MSRA-PKM2 axis serves as a regulatory nexus between redox biology and cancer metabolism to control tumor metastasis.
    Keywords:  PKM2; cancer metabolism; glucose oxidation; metastasis; methionine oxidation; pancreatic cancer; redox signaling
    DOI:  https://doi.org/10.1016/j.molcel.2022.06.005
  5. Cancer Res. 2022 Jun 29. pii: canres.2934.2021. [Epub ahead of print]
    Caspase-3-induced activation of SREBP2 drives drug resistance via promotion of cholesterol biosynthesis in hepatocellular carcinoma.
    Etienne H Mok, Carmen Oi-Ning Leung, Lei Zhou, Martina Mang Leng Lei, Hoi Wing Leung, Man Tong, Tin Lok Wong, Eunice Y Lau, Irene Oi-Lin Ng, Jin Ding, Jing-Ping Yun, Jun Yu, Hui Lian Zhu, Chi Ho Lin, Dan Lindholm, Kit Sum Leung, Jonathan D Cybulski, David M Baker, Stephanie Ma, Terence K Lee.
      Accumulating evidence has demonstrated that drug resistance can be acquired in cancer through the repopulation of tumors by cancer stem cell (CSC) expansion. Here, we investigated mechanisms driving resistance and CSC repopulation in hepatocellular carcinoma (HCC) as a cancer model using two drug-resistant, patient-derived tumor xenografts that mimicked the development of acquired resistance to sorafenib or lenvatinib treatment observed in HCC patients. RNA sequencing analysis revealed that cholesterol biosynthesis was most commonly enriched in the drug-resistant xenografts. Comparison of the genetic profiles of CD133+ stem cells and CD133- bulk cells from liver regeneration and HCC mouse models showed that the cholesterol pathway was preferentially upregulated in liver CSCs compared to normal liver stem cells. Consistently, SREBP2-mediated cholesterol biosynthesis was crucial for the augmentation of liver CSCs, and loss of SREBP2 conferred sensitivity to tyrosine kinase inhibitors, suggesting a role in regulation of acquired drug resistance in HCC. Similarly, exogenous cholesterol-treated HCC cells showed enhanced cancer stemness abilities and drug resistance. Mechanistically, caspase-3 (CASP3)-mediated cleavage of SREBP2 from the endoplasmic reticulum to promote cholesterol biosynthesis, which consequently caused resistance to sorafenib/lenvatinib treatment by driving activation of the sonic hedgehog signaling pathway. Simvastatin, an FDA-approved cholesterol-lowering drug, not only suppressed HCC tumor growth but also sensitized HCC cells to sorafenib. These findings demonstrate that CSC populations in HCC expand via CASP3-dependent, SREBP2-mediated cholesterol biosynthesis in response to tyrosine kinase inhibitor therapy and that targeting cholesterol biosynthesis can overcome acquired drug resistance.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-2934
  6. Cancer Discov. 2022 Jun 27. pii: candisc.0576.2021-5-3 12:14:47.513. [Epub ahead of print]
    Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence.
    Simon Linder, Marlous Hoogstraat, Suzan Stelloo, Nils Eickhoff, Karianne Schuurman, Hilda de Barros, Maartje Alkemade, Elise M Bekers, Tesa M Severson, Joyce Sanders, Chia-Chi Flora Huang, Tunc Morova, Umut Berkay Altintas, Liesbeth Hoekman, Yongsoo Kim, Sylvan C Baca, Martin Sjostrom, Anniek Zaalberg, Dorine C Hintzen, Jeroen de Jong, Roelof J C Kluin, Iris de Rink, Claudia Giambartolomei, Ji-Heui Seo, Bogdan Pasaniuc, Maarten Altelaar, Rene H Medema, Felix Y Feng, Amina Zoubeidi, Matthew L Freedman, Lodewyk F A Wessels, Lisa M Butler, Nathan A Lack, Henk van der Poel, Andries M Bergman, Wilbert Zwart.
      In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multi-omics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from high-risk prostate cancer patients enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors towards a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 - from inactive chromatin sites towards active cis-regulatory elements that dictate pro-survival signals. Notably, treatment-induced FOXA1 sites were enriched for circadian clock component ARNTL. Post-treatment ARNTL levels associated with poor outcome, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy, and revealed an acquired dependency on circadian regulator ARNTL, a novel candidate therapeutic target.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0576
  7. Mol Cancer. 2022 Jun 30. 21(1): 140
    CircEZH2/miR-133b/IGF2BP2 aggravates colorectal cancer progression via enhancing the stability of m6A-modified CREB1 mRNA.
    Bing Yao, Qinglin Zhang, Zhou Yang, Fangmei An, He Nie, Hui Wang, Cheng Yang, Jing Sun, Ke Chen, Jingwan Zhou, Bing Bai, Shouyong Gu, Wei Zhao, Qiang Zhan.
       BACKGROUND: Aberrant expression of circular RNAs (circRNAs) contributes to the initiation and progression of human malignancies, but the underlying mechanisms remain largely elusive.
    METHODS: High-throughput sequencing was performed to screen aberrantly expressed circRNAs or miRNAs in colorectal cancer (CRC) and adjacent normal tissues. A series of gain- and loss-of-function studies were conducted to evaluate the biological behaviors of CRC cells. RNA pulldown, mass spectrometry, RIP, qRT-PCR, Western blot, luciferase reporter assays and MeRIP-seq analysis were further applied to dissect the detailed mechanisms.
    RESULTS: Here, a novel circRNA named circEZH2 (hsa_circ_0006357) was screened out by RNA-seq in CRC tissues, whose expression is closely related to the clinicpathological characteristics and prognosis of CRC patients. Biologically, circEZH2 facilitates the proliferation and migration of CRC cells in vitro and in vivo. Mechanistically, circEZH2 interacts with m6A reader IGF2BP2 and blocks its ubiquitination-dependent degradation. Meanwhile, circEZH2 could serve as a sponge of miR-133b, resulting in the upregulation of IGF2BP2. Particularly, circEZH2/IGF2BP2 enhances the stability of CREB1 mRNA, thus aggravating CRC progression.
    CONCLUSIONS: Our findings not only reveal the pivotal roles of circEZH2 in modulating CRC progression, but also advocate for attenuating circEZH2/miR-133b/IGF2BP2/ CREB1 regulatory axis to combat CRC.
    Keywords:  CREB1; CircEZH2; Colorectal cancer; IGF2BP2; miR-133b
    DOI:  https://doi.org/10.1186/s12943-022-01608-7
  8. Nature. 2022 Jun 29.
    Mitochondrial RNA modifications shape metabolic plasticity in metastasis.
    Sylvain Delaunay, Gloria Pascual, Bohai Feng, Kevin Klann, Mikaela Behm, Agnes Hotz-Wagenblatt, Karsten Richter, Karim Zaoui, Esther Herpel, Christian Münch, Sabine Dietmann, Jochen Hess, Salvador Aznar Benitah, Michaela Frye.
      Aggressive and metastatic cancers show enhanced metabolic plasticity1, but the precise underlying mechanisms of this remain unclear. Here we show how two NOP2/Sun RNA methyltransferase 3 (NSUN3)-dependent RNA modifications-5-methylcytosine (m5C) and its derivative 5-formylcytosine (f5C) (refs.2-4)-drive the translation of mitochondrial mRNA to power metastasis. Translation of mitochondrially encoded subunits of the oxidative phosphorylation complex depends on the formation of m5C at position 34 in mitochondrial tRNAMet. m5C-deficient human oral cancer cells exhibit increased levels of glycolysis and changes in their mitochondrial function that do not affect cell viability or primary tumour growth in vivo; however, metabolic plasticity is severely impaired as mitochondrial m5C-deficient tumours do not metastasize efficiently. We discovered that CD36-dependent non-dividing, metastasis-initiating tumour cells require mitochondrial m5C to activate invasion and dissemination. Moreover, a mitochondria-driven gene signature in patients with head and neck cancer is predictive for metastasis and disease progression. Finally, we confirm that this metabolic switch that allows the metastasis of tumour cells can be pharmacologically targeted through the inhibition of mitochondrial mRNA translation in vivo. Together, our results reveal that site-specific mitochondrial RNA modifications could be therapeutic targets to combat metastasis.
    DOI:  https://doi.org/10.1038/s41586-022-04898-5
  9. Cancer Discov. 2022 Jul 01. OF1
    A Phenotypic Continuum Supports Malignant Transformation in Colorectal Cancer.
      Epigenetic and transcriptional changes support chromatin accessibility alterations and promote a malignant state.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-120
  10. Nat Commun. 2022 Jun 27. 13(1): 3671
    Combinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer.
    Joyce V Lee, Filomena Housley, Christina Yau, Rachel Nakagawa, Juliane Winkler, Johanna M Anttila, Pauliina M Munne, Mariel Savelius, Kathleen E Houlahan, Daniel Van de Mark, Golzar Hemmati, Grace A Hernandez, Yibing Zhang, Susan Samson, Carole Baas, Laura J Esserman, Laura J van 't Veer, Hope S Rugo, Christina Curtis, Juha Klefström, Mehrdad Matloubian, Andrei Goga.
      Few patients with triple negative breast cancer (TNBC) benefit from immune checkpoint inhibitors with complete and durable remissions being quite rare. Oncogenes can regulate tumor immune infiltration, however whether oncogenes dictate diminished response to immunotherapy and whether these effects are reversible remains poorly understood. Here, we report that TNBCs with elevated MYC expression are resistant to immune checkpoint inhibitor therapy. Using mouse models and patient data, we show that MYC signaling is associated with low tumor cell PD-L1, low overall immune cell infiltration, and low tumor cell MHC-I expression. Restoring interferon signaling in the tumor increases MHC-I expression. By combining a TLR9 agonist and an agonistic antibody against OX40 with anti-PD-L1, mice experience tumor regression and are protected from new TNBC tumor outgrowth. Our findings demonstrate that MYC-dependent immune evasion is reversible and druggable, and when strategically targeted, may improve outcomes for patients treated with immune checkpoint inhibitors.
    DOI:  https://doi.org/10.1038/s41467-022-31238-y
  11. Nat Rev Urol. 2022 Jun 28.
    The dynamic roles of the bladder tumour microenvironment.
    Yu-Cheng Lee, Hung-Ming Lam, Charles Rosser, Dan Theodorescu, William C Parks, Keith Syson Chan.
      Bladder cancer is a prevalent but currently understudied cancer type and patient outcomes are poor when it progresses to the muscle-invasive stage. Current research in bladder cancer focuses on the genetic and epigenetic alterations occurring within the urothelial cell compartment; however, the stromal compartment receives less attention. Dynamic changes and intercellular communications occur in the tumour microenvironment (TME) of the bladder - a new concept and niche that we designate as the bladder TME (bTME) - during tumour evolution, metastatic progression and in the context of therapeutic response. Collagens and their cognate receptors, the discoidin domain receptors, have a role in various steps of the metastatic cascade and in immune checkpoint resistance. Furthermore, the presence of another TME niche, the metastatic TME (met-TME), is a novel concept that could support divergent progression of metastatic colonization in different organs, resulting in distant metastases with distinct characteristics and genetics from the primary tumour. The stroma has divergent roles in mediating therapeutic response to BCG immunotherapy and immune checkpoint inhibitors, as well as conventional chemotherapy or trimodality therapy (that is, maximal transurethral resection of bladder tumour, chemotherapy and radiotherapy). The local bTME and distant met-TME are currently conceptually and therapeutically unexploited niches that should be actively investigated. New biological insights from these TMEs will enable rational design of strategies that co-target the tumour and stroma, which are expected to improve the outcomes of patients with advanced bladder cancer.
    DOI:  https://doi.org/10.1038/s41585-022-00608-y
  12. EMBO Rep. 2022 Jun 29. e54265
    Reduced symmetric dimethylation stabilizes vimentin and promotes metastasis in MTAP-deficient lung cancer.
    Wen-Hsin Chang, Yi-Ju Chen, Yi-Jing Hsiao, Ching-Cheng Chiang, Chia-Yu Wang, Ya-Ling Chang, Qi-Sheng Hong, Chien-Yu Lin, Shr-Uen Lin, Gee-Chen Chang, Hsuan-Yu Chen, Yu-Ju Chen, Ching-Hsien Chen, Pan-Chyr Yang, Sung-Liang Yu.
      The aggressive nature and poor prognosis of lung cancer led us to explore the mechanisms driving disease progression. Utilizing our invasive cell-based model, we identified methylthioadenosine phosphorylase (MTAP) and confirmed its suppressive effects on tumorigenesis and metastasis. Patients with low MTAP expression display worse overall and progression-free survival. Mechanistically, accumulation of methylthioadenosine substrate in MTAP-deficient cells reduce the level of protein arginine methyltransferase 5 (PRMT5)-mediated symmetric dimethylarginine (sDMA) modification on proteins. We identify vimentin as a dimethyl-protein whose dimethylation levels drop in response to MTAP deficiency. The sDMA modification on vimentin reduces its protein abundance but trivially affects its filamentous structure. In MTAP-deficient cells, lower sDMA modification prevents ubiquitination-mediated vimentin degradation, thereby stabilizing vimentin and contributing to cell invasion. MTAP and PRMT5 negatively correlate with vimentin in lung cancer samples. Taken together, we propose a mechanism for metastasis involving vimentin post-translational regulation.
    Keywords:  Methylproteome; Methylthioadenosine (MTA); Post-translational modification (PTM); Protein arginine methyltransferase 5 (PRMT5); Symmetric dimethylarginine (sDMA)
    DOI:  https://doi.org/10.15252/embr.202154265
  13. Nat Commun. 2022 Jun 29. 13(1): 3750
    The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma.
    Multiple Myeloma Research Consortium
      Multiple myeloma is the second most common hematological malignancy. Despite significant advances in treatment, relapse is common and carries a poor prognosis. Thus, it is critical to elucidate the genetic factors contributing to disease progression and drug resistance. Here, we carry out integrative clinical sequencing of 511 relapsed, refractory multiple myeloma (RRMM) patients to define the disease's molecular alterations landscape. The NF-κB and RAS/MAPK pathways are more commonly altered than previously reported, with a prevalence of 45-65% each. In the RAS/MAPK pathway, there is a long tail of variants associated with the RASopathies. By comparing our RRMM cases with untreated patients, we identify a diverse set of alterations conferring resistance to three main classes of targeted therapy in 22% of our cohort. Activating mutations in IL6ST are also enriched in RRMM. Taken together, our study serves as a resource for future investigations of RRMM biology and potentially informs clinical management.
    DOI:  https://doi.org/10.1038/s41467-022-31430-0
  14. Cancer Res. 2022 Jun 28. pii: canres.3748.2021. [Epub ahead of print]
    RNA helicase DDX24 stabilizes LAMB1 to promote hepatocellular carcinoma progression.
    Hong Shan, Tianze Liu, Hairun Gan, Simeng He, Jia Deng, Xinyan Hu, Luting Li, Li Cai, JianZhong He, Haoyu Long, Jianxun Cai, Hanjie Li, Qianqian Zhang, Lijie Wang, Fangbin Chen, Yuming Chen, Haopei Zhang, Jian Li, Lukun Yang, Ye Liu, Jianhua Yang, Dong-Ming Kuang, Pengfei Pang, Huanhuan He.
      Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies. Elucidating the underlying mechanisms of this disease could provide new therapeutic strategies for treating HCC. Here, we identified a novel role of DEAD-box helicase 24 (DDX24), a member of the DEAD-box protein family, in promoting HCC progression. DDX24 levels were significantly elevated in HCC tissues and were associated with poor prognosis of HCC. Overexpression of DDX24 promoted HCC migration and proliferation in vitro and in vivo, whereas suppression of DDX24 inhibited both functions. Mechanistically, DDX24 bound the mRNA618-624nt of laminin subunit beta 1 (LAMB1) and increased its stability in a manner dependent upon the interaction between nucleolin (NCL) and the C-terminal region of DDX24. Moreover, RFX8 was identified as a DDX24 promoter-binding protein that transcriptionally upregulated DDX24 expression. Collectively, these findings demonstrate that the RFX8/DDX24/LAMB1 axis promotes HCC progression, providing potential therapeutic targets for HCC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3748
  15. Oncogene. 2022 Jun 30.
    YAP1 induces invadopodia formation by transcriptionally activating TIAM1 through enhancer in breast cancer.
    Jie Shen, Qingwen Huang, Weiyi Jia, Shengjie Feng, Liang Liu, Xiaolan Li, Deding Tao, Daxing Xie.
      Yes-associated protein 1 (YAP1), a central component of the Hippo pathway, plays an important role in tumor metastasis; however, the underlying mechanism remains to be elucidated. Invadopodia are actin-rich protrusions containing multiple proteases and have been widely reported to promote cell invasiveness by degrading the extracellular matrix. In the present study, we report that YAP1 induces invadopodia formation and promotes tumor metastasis in breast cancer cells. We also identify TIAM1, a guanine nucleotide exchange factor, as a target of the YAP1-TEAD4 complex. Our results demonstrate that YAP1 could promote TEAD4 binding to the enhancer region of TIAM1, which activates TIAM1 expression, subsequently increasing RAC1 activity and inducing invadopodia formation. These findings reveal the functional role of Hippo signaling in the regulation of invadopodia and provide potential molecular targets for preventing tumor metastasis in breast cancer.
    DOI:  https://doi.org/10.1038/s41388-022-02344-4
  16. Cell Rep. 2022 Jun 28. pii: S2211-1247(22)00801-4. [Epub ahead of print]39(13): 111012
    G6PD inhibition sensitizes ovarian cancer cells to oxidative stress in the metastatic omental microenvironment.
    Shree Bose, Qiang Huang, Yunhan Ma, Lihua Wang, Grecia O Rivera, Yunxin Ouyang, Regina Whitaker, Rebecca A Gibson, Christopher D Kontos, Andrew Berchuck, Rebecca A Previs, Xiling Shen.
      Ovarian cancer (OC) is the most lethal gynecological malignancy, with aggressive metastatic disease responsible for the majority of OC-related deaths. In particular, OC tumors preferentially metastasize to and proliferate rapidly in the omentum. Here, we show that metastatic OC cells experience increased oxidative stress in the omental microenvironment. Metabolic reprogramming, including upregulation of the pentose phosphate pathway (PPP), a key cellular redox homeostasis mechanism, allows OC cells to compensate for this challenge. Inhibition of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, reduces tumor burden in pre-clinical models of OC, suggesting that this adaptive metabolic dependency is important for OC omental metastasis.
    Keywords:  CP: Cancer; CP: Metabolism; metabolism; metastasis; ovarian cancer
    DOI:  https://doi.org/10.1016/j.celrep.2022.111012
  17. Cancer Discov. 2022 Jun 27. pii: candisc.0925.2021. [Epub ahead of print]
    A Targetable Myeloid Inflammatory State Governs Disease Recurrence in Clear Cell Renal Cell Carcinoma.
    Phillip M Rappold, Lynda Vuong, Josef Leibold, Nicholas H Chakiryan, Michael Curry, Fengshen Kuo, Erich Sabio, Hui Jiang, Briana G Nixon, Ming Liu, Anders E Berglund, Andrew W Silagy, Ankur Mascareno, Mahdi Golkaram, Mahtab Marker, Albert Reising, Alexander Savchenko, John M Millholland, Ying-Bei Chen, Paul Russo, Jonathan Coleman, Ed Reznik, Brandon J Manley, Irina Ostrovnaya, Vladimir Makarov, Renzo G DiNatale, Kyle A Blum, Xiaoxiao Ma, Diego Chowell, Ming O Li, David B Solit, Scott W Lowe, Timothy A Chan, Robert J Motzer, Martin H Voss, A Ari Hakimi.
      It is poorly understood how the tumor immune microenvironment influences disease recurrence in localized clear cell renal cell carcinoma (ccRCC). Here we perform whole-transcriptomic profiling of 236 tumors from patients assigned to the placebo-only arm of a randomized, adjuvant clinical trial for high-risk localized ccRCC. Unbiased pathway analysis identifies myeloid-derived interleukin-6 (IL-6) as a key mediator. Furthermore, a novel myeloid gene signature strongly correlates with disease recurrence and overall survival on uni- and multivariate analysis and is linked to TP53 inactivation across multiple datasets. Strikingly, effector T cell gene signatures, infiltration patterns, and exhaustion markers were not associated with disease recurrence. Targeting immunosuppressive myeloid inflammation with an adenosine A2A receptor antagonist in a novel, immunocompetent, Tp53-inactivated mouse model significantly reduces metastatic development. Our findings suggest myeloid inflammation promotes disease recurrence in ccRCC, is targetable, and provide a potential biomarker-based framework for the design of future immuno-oncology trials in ccRCC.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0925
  18. Mol Ther. 2022 Jun 27. pii: S1525-0016(22)00374-4. [Epub ahead of print]
    lncRNA Linc00173 modulates glucose metabolism and multidrug chemoresistance inSCLC:Potentialmolecular panel for targeted therapy.
      
    DOI:  https://doi.org/10.1016/j.ymthe.2022.06.014
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