bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021–10–03
28 papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. High FGFR1-4 mRNA expression levels correlate with response to selective FGFR inhibitors in breast cancer.
  2. ALDH1A1 activity in tumor-initiating cells remodels myeloid-derived suppressor cells to promote breast cancer progression.
  3. Tackling PARP inhibitor resistance.
  4. Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders.
  5. Computational modeling identifies multitargeted kinase inhibitors as effective therapies for metastatic, castration-resistant prostate cancer.
  6. INCISOR: An Algorithm to Identify Synthetic Rescue Mediators of Resistance to Targeted and Immunotherapy.
  7. Elimination of radiation-induced senescence in the brain tumor microenvironment attenuates glioblastoma recurrence.
  8. Evolution's cartographer: Mapping the fitness landscape in cancer.
  9. Regulation of a progenitor gene program by SOX4 is essential for mammary tumor proliferation.
  10. The mole rat's secret to cancer resistance.
  11. Spatial immunophenotypes predict response to anti-PD1 treatment and capture distinct paths of T cell evasion in triple negative breast cancer.
  12. p113 isoform encoded by CUX1 circular RNA drives tumor progression via facilitating ZRF1/BRD4 transactivation.
  13. Organoids derived from neoadjuvant FOLFIRINOX patients recapitulate therapy resistance in pancreatic ductal adenocarcinoma.
  14. LncRNA HIF1A-AS1 promotes gemcitabine resistance of pancreatic cancer by enhancing glycolysis through modulating the AKT/YB1/HIF-1α pathway.
  15. Epigenetic induction of lipocalin 2 expression drives acquired resistance to 5-fluorouracil in colorectal cancer through integrin β3/SRC pathway.
  16. Prostate cancer castrate resistant progression usage of non-canonical androgen receptor signaling and ketone body fuel.
  17. Chromosomal instability and aneuploidy as causes of cancer drug resistance.
  18. Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response.
  19. Matrix stiffness drives stromal autophagy and promotes formation of a protumorigenic niche.
  20. Localization of KRAS downstream target ARL4C to invasive pseudopods accelerates pancreatic cancer cell invasion.
  21. An evolving role for AXL in metastatic renal cell carcinoma.
  22. Measuring kinetics and metastatic propensity of CTCs by blood exchange between mice.
  23. IL-6 promotes drug resistance through formation of polyploid giant cancer cells and stromal fibroblast reprogramming.
  24. Desmosomal proteins of DSC2 and PKP1 promote cancer cells survival and metastasis by increasing cluster formation in circulatory system.
  25. Nuclear Envelope Disruptions Induce DNA Damage and Invasiveness.
  26. Patient derived organoids in prostate cancer: improving therapeutic efficacy in precision medicine.
  27. Micropeptide ASAP encoded by LINC00467 promotes colorectal cancer progression by directly modulating ATP synthase activity.
  28. Lineage tracing and single-cell analysis reveal proliferative Prom1+ tumour-propagating cells and their dynamic cellular transition during liver cancer progression.
  1. Clin Cancer Res. 2021 Sep 30. pii: clincanres.CCR-21-1810-A.2021. [Epub ahead of print]
    High FGFR1-4 mRNA expression levels correlate with response to selective FGFR inhibitors in breast cancer.
    Mònica Sánchez-Guixé, Cinta Hierro, José Jiménez, Cristina Viaplana, Guillermo Villacampa, Erika Monelli, Fara Brasó-Maristany, Zighereda Ogbah, Mireia Parés, Marta Guzmán, Judit Grueso, Olga Rodriguez, Mafalda Oliveira, Analía Azaro, Elena Garralda, Josep Tabernero, Oriol Casanovas, Maurizio Scaltriti, Aleix Prat, Rodrigo Dienstmann, Paolo Nuciforo, Cristina Saura, Mariona Graupera, Ana Vivancos, Jordi Rodon, Violeta Serra.
       PURPOSE: FGFR1 amplification (FGFR1amp) is recurrent in metastatic breast cancer (BC) and is associated with resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i). Multi-tyrosine kinase inhibitors (MTKI) and selective pan-FGFR inhibitors (FGFRi) are being developed for FGFR1amp BC. High-level FGFR amplification and protein expression by IHC have identified BC responders to FGFRi or MTKI, respectively.
    EXPERIMENTAL DESIGN: Here, we used preclinical models and patient samples to identify predictive biomarkers to these drugs. We evaluated the antitumor activity of an FGFRi and an MTKI in a collection of seventeen BC patient-derived xenografts (PDXs) harboring amplification in FGFR1/2/3/4 and in ten patients receiving either an FGFRi/MTKI. mRNA levels were measured on FFPE tumor samples using two commercial strategies. Proliferation and angiogenesis were evaluated by detecting Ki-67 and CD31 in viable areas by immunofluorescence.
    RESULTS: High FGFR1-4 mRNA levels but not copy number alteration (CNA) associated with FGFRi response. Treatment with MTKI showed higher response rates than with FGFRi (86% vs 53%), regardless of the FGFR1-4 mRNA levels. FGFR-addicted PDXs exhibited an antiproliferative response to either FGFRi or MTKI, and PDXs exclusively sensitive to MTKI exhibited an additional anti-angiogenic response. Consistently, clinical benefit of MTKI was not associated with high FGFR1-4 mRNA levels and it was observed in patients previously treated with anti-angiogenic drugs.
    CONCLUSION: Tailored therapy with FGFRi in molecularly-selected metastatic BC based on high FGFR1-4 mRNA levels warrants prospective validation in luminal BC CDK4/6i-resistant patients and in TNBC patients without targeted therapeutic options.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-1810
  2. Cancer Res. 2021 Sep 27. pii: canres.1337.2021. [Epub ahead of print]
    ALDH1A1 activity in tumor-initiating cells remodels myeloid-derived suppressor cells to promote breast cancer progression.
    Cuicui Liu, Jiankun Qiang, Qiaodan Deng, Jie Xia, Lu Deng, Lei Zhou, Dong Wang, Xueyan He, Ying Liu, Botao Zhao, Jinhui Lv, Zuoren Yu, Qun-Ying Lei, Zhi-Ming Shao, Xiao-Yong Zhang, Lixing Zhang, Suling Liu.
      Tumor-initiating cells (TIC) are associated with tumor initiation, growth, metastasis, and recurrence. Aldehyde dehydrogenase 1A1 (ALDH1A1) is a TIC marker in many cancers, including breast cancer. However the molecular mechanisms underlying ALDH1A1 functions in solid tumors remain largely unknown. Here we demonstrate that ALDH1A1 enzymatic activity facilitates breast tumor growth. Mechanistically, ALDH1A1 decreased the intracellular pH in breast cancer cells to promote phosphorylation of TAK1, activate NFκB signaling, and increase the secretion of granulocyte macrophage colony-stimulating factor (GM-CSF), which led to myeloid-derived suppressor cell (MDSC) expansion and immunosuppression. Furthermore, the ALDH1A1 inhibitor disulfiram and chemotherapeutic agent gemcitabine cooperatively inhibited breast tumor growth and tumorigenesis by purging ALDH+ TICs and activating T cell immunity. These findings elucidate how active ALDH1A1 modulates the immune system to promote tumor development, highlghting new therapeutic strategies for malignant breast cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-1337
  3. Trends Cancer. 2021 Sep 22. pii: S2405-8033(21)00175-8. [Epub ahead of print]
    Tackling PARP inhibitor resistance.
    Kasper Fugger, Graeme Hewitt, Stephen C West, Simon J Boulton.
      Homologous recombination-deficient (HRD) tumours, including those harbouring mutations in the BRCA genes, are hypersensitive to treatment with inhibitors of poly(ADP-ribose) polymerase (PARPis). Despite high response rates, most HRD cancers ultimately develop resistance to PARPi treatment through reversion mutations or genetic/epigenetic alterations to DNA repair pathways. Counteracting these resistance pathways, thereby increasing the potency of PARPi therapy, represents a potential strategy to improve the treatment of HRD cancers. In this review, we discuss recent insights derived from genetic screens that have identified a number of novel genes that can be targeted to improve PARPi treatment of HRD cancers and may provide a means to overcome PARPi resistance.
    Keywords:  base excision repair; homologous recombination repair; nucleotide metabolism; poly(ADP-ribose) polymerase inhibitors; therapy resistance
    DOI:  https://doi.org/10.1016/j.trecan.2021.08.007
  4. Nat Cancer. 2021 Apr;2(4): 429-443
    Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders.
    Xuewei Wu, Xiaobao Yang, Yan Xiong, Ruitong Li, Takahiro Ito, Tamer A Ahmed, Zoi Karoulia, Christos Adamopoulos, Hong Wang, Li Wang, Ling Xie, Jing Liu, Beatrix Ueberheide, Stuart A Aaronson, Xian Chen, Sean G Buchanan, William R Sellers, Jian Jin, Poulikos I Poulikakos.
      CDK4/6 inhibitors (CDK4/6i) are effective in metastatic breast cancer, but they have been only modestly effective in most other tumor types. Here we show that tumors expressing low CDK6 rely on CDK4 function, and are exquisitely sensitive to CDK4/6i. In contrast, tumor cells expressing both CDK4 and CDK6 have increased reliance on CDK6 to ensure cell cycle progression. We discovered that CDK4/6i and CDK4/6 degraders potently bind and inhibit CDK6 selectively in tumors in which CDK6 is highly thermo-unstable and strongly associated with the HSP90/CDC37 complex. In contrast, CDK4/6i and CDK4/6 degraders are ineffective in antagonizing tumor cells expressing thermostable CDK6, due to their weaker binding to CDK6 in these cells. Thus, we uncover a general mechanism of intrinsic resistance to CDK4/6i and CDK4/6i-derived degraders and the need for novel inhibitors targeting the CDK4/6i-resistant, thermostable form of CDK6 for application as cancer therapeutics.
    DOI:  https://doi.org/10.1038/s43018-021-00174-z
  5. Proc Natl Acad Sci U S A. 2021 Oct 05. pii: e2103623118. [Epub ahead of print]118(40):
    Computational modeling identifies multitargeted kinase inhibitors as effective therapies for metastatic, castration-resistant prostate cancer.
    Thomas Bello, Claudia Paindelli, Luis A Diaz-Gomez, Anthony Melchiorri, Antonios G Mikos, Peter S Nelson, Eleonora Dondossola, Taranjit S Gujral.
      Castration-resistant prostate cancer (CRPC) is an advanced subtype of prostate cancer with limited therapeutic options. Here, we applied a systems-based modeling approach called kinome regularization (KiR) to identify multitargeted kinase inhibitors (KIs) that abrogate CRPC growth. Two predicted KIs, PP121 and SC-1, suppressed CRPC growth in two-dimensional in vitro experiments and in vivo subcutaneous xenografts. An ex vivo bone mimetic environment and in vivo tibia xenografts revealed resistance to these KIs in bone. Combining PP121 or SC-1 with docetaxel, standard-of-care chemotherapy for late-stage CRPC, significantly reduced tibia tumor growth in vivo, decreased growth factor signaling, and vastly extended overall survival, compared to either docetaxel monotherapy. These results highlight the utility of computational modeling in forming physiologically relevant predictions and provide evidence for the role of multitargeted KIs as chemosensitizers for late-stage, metastatic CRPC.
    Keywords:  combination therapy; computational modeling; kinase; prostate cancer
    DOI:  https://doi.org/10.1073/pnas.2103623118
  6. Methods Mol Biol. 2021 ;2381 203-215
    INCISOR: An Algorithm to Identify Synthetic Rescue Mediators of Resistance to Targeted and Immunotherapy.
    Xiaoman Wang, Frederick Sagayaraj Vizeacoumar, Avinash Das Sahu.
      Despite the success of targeted therapies including immunotherapies in cancer treatments, tumor resistance to targeted therapies remains a fundamental challenge. Tumors can evolve resistance to a therapy that targets one gene by acquiring compensatory alterations in another gene, such compensatory interaction between two genes is referred to as synthetic rescue (SR) interactions. To identify SRs, here we describe an algorithm, INCISOR, that leverages tumor transcriptomics and clinical information from 10,000 patients as well as data from experimental screens. INCISOR can identify SRs that are common across several cancer-types in genome-wide fashion by sifting through half a billion possible gene-gene combinations and provide a framework to design therapies to tackle resistance.
    Keywords:  Genetic interactions; Precision oncology; Synthetic rescue; Targeted therapies; Treatment resistance
    DOI:  https://doi.org/10.1007/978-1-0716-1740-3_11
  7. Cancer Res. 2021 Sep 27. pii: canres.0752.2021. [Epub ahead of print]
    Elimination of radiation-induced senescence in the brain tumor microenvironment attenuates glioblastoma recurrence.
    Eliot Fletcher-Sananikone, Suman Kanji, Nozomi Tomimatsu, Luis Fernando Macedo Di Cristofaro, Rahul K Kollipara, Debabrata Saha, John R Floyd, Patrick Sung, Robert Hromas, Terry C Burns, Ralf Kittler, Amyn A Habib, Bipasha Mukherjee, Sandeep Burma.
      Glioblastomas (GBM) are routinely treated with ionizing radiation (IR) but inevitably recur and develop therapy resistance. During treatment, the tissue surrounding tumors is also irradiated. IR potently induces senescence, and senescent stromal cells can promote the growth of neighboring tumor cells by secreting factors that create a senescence-associated secretory phenotype (SASP). Here, we carried out transcriptomic and tumorigenicity analyses in irradiated mouse brains to elucidate how radiation-induced senescence of non-neoplastic brain cells promotes tumor growth. Following cranial irradiation, widespread senescence in the brain occurred, with the astrocytic population being particularly susceptible. Irradiated brains showed an altered transcriptomic profile characterized by upregulation of CDKN1A (p21), a key enforcer of senescence, and several SASP factors including HGF, the ligand of the receptor tyrosine kinase (RTK) Met. Pre-irradiation of mouse brains increased Met-driven growth and invasiveness of orthotopically implanted glioma cells. Importantly, irradiated p21-/- mouse brains did not exhibit senescence and consequently failed to promote tumor growth. Senescent astrocytes secreted HGF to activate Met in glioma cells and promote their migration and invasion in vitro, which could be blocked by HGF-neutralizing antibodies or the Met inhibitor crizotinib. Crizotinib also slowed the growth of glioma cells implanted in pre-irradiated brains. Treatment with the senolytic drug ABT-263 (navitoclax) selectively killed senescent astrocytes in vivo, significantly attenuating growth of glioma cells implanted in pre-irradiated brains. These results indicate that SASP factors in the irradiated tumor microenvironment drive GBM growth via RTK activation, underscoring the potential utility of adjuvant senolytic therapy for preventing GBM recurrence after radiotherapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0752
  8. Cancer Cell. 2021 Sep 14. pii: S1535-6108(21)00491-8. [Epub ahead of print]
    Evolution's cartographer: Mapping the fitness landscape in cancer.
    Calum Gabbutt, Trevor A Graham.
      Cancer treatment effectiveness could be improved if it were possible to accurately anticipate the response of the tumor to treatment. Writing in Nature, Salehi et al. combine single-cell genomics and mathematical modeling to measure cancer subclone fitness and use these measurements to accurately predict the future trajectory of cancer evolution.
    DOI:  https://doi.org/10.1016/j.ccell.2021.09.002
  9. Oncogene. 2021 Sep 28.
    Regulation of a progenitor gene program by SOX4 is essential for mammary tumor proliferation.
    M Guy Roukens, Cynthia L Frederiks, Danielle Seinstra, Luca Braccioli, Antoine A Khalil, Cornelieke Pals, Simon De Neck, Laura Bornes, Evelyne Beerling, Michal Mokry, Alain de Bruin, Bart Westendorp, Jacco van Rheenen, Paul J Coffer.
      In breast cancer the transcription factor SOX4 has been shown to be associated with poor survival, increased tumor size and metastasis formation. This has mostly been attributed to the ability of SOX4 to regulate Epithelial-to-Mesenchymal-Transition (EMT). However, SOX4 regulates target gene transcription in a context-dependent manner that is determined by the cellular and epigenetic state. In this study we have investigated the loss of SOX4 in mammary tumor development utilizing organoids derived from a PyMT genetic mouse model of breast cancer. Using CRISPR/Cas9 to abrogate SOX4 expression, we found that SOX4 is required for inhibiting differentiation by regulating a subset of genes that are highly activated in fetal mammary stem cells (fMaSC). In this way, SOX4 re-activates an oncogenic transcriptional program that is regulated in many progenitor cell-types during embryonic development. SOX4-knockout organoids are characterized by the presence of more differentiated cells that exhibit luminal or basal gene expression patterns, but lower expression of cell cycle genes. In agreement, primary tumor growth and metastatic outgrowth in the lungs are impaired in SOX4KO tumors. Finally, SOX4KO tumors show a severe loss in competitive capacity to grow out compared to SOX4-proficient cells in primary tumors. Our study identifies a novel role for SOX4 in maintaining mammary tumors in an undifferentiated and proliferative state. Therapeutic manipulation of SOX4 function could provide a novel strategy for cancer differentiation therapy, which would promote differentiation and inhibit cycling of tumor cells.
    DOI:  https://doi.org/10.1038/s41388-021-02004-z
  10. Nat Rev Immunol. 2021 Sep 28.
    The mole rat's secret to cancer resistance.
    Lucy Bird.
      
    DOI:  https://doi.org/10.1038/s41577-021-00632-w
  11. Nat Commun. 2021 Sep 27. 12(1): 5668
    Spatial immunophenotypes predict response to anti-PD1 treatment and capture distinct paths of T cell evasion in triple negative breast cancer.
    Dora Hammerl, John W M Martens, Mieke Timmermans, Marcel Smid, Anita M Trapman-Jansen, Renée Foekens, Olga I Isaeva, Leonie Voorwerk, Hayri E Balcioglu, Rebecca Wijers, Iris Nederlof, Roberto Salgado, Hugo Horlings, Marleen Kok, Reno Debets.
      Only a subgroup of triple-negative breast cancer (TNBC) responds to immune checkpoint inhibitors (ICI). To better understand lack of response to ICI, we analyze 681 TNBCs for spatial immune cell contextures in relation to clinical outcomes and pathways of T cell evasion. Excluded, ignored and inflamed phenotypes can be captured by a gene classifier that predicts prognosis of various cancers as well as anti-PD1 response of metastatic TNBC patients in a phase II trial. The excluded phenotype, which is associated with resistance to anti-PD1, demonstrates deposits of collagen-10, enhanced glycolysis, and activation of TGFβ/VEGF pathways; the ignored phenotype, also associated with resistance to anti-PD1, shows either high density of CD163+ myeloid cells or activation of WNT/PPARγ pathways; whereas the inflamed phenotype, which is associated with response to anti-PD1, revealed necrosis, high density of CLEC9A+ dendritic cells, high TCR clonality independent of neo-antigens, and enhanced expression of T cell co-inhibitory receptors.
    DOI:  https://doi.org/10.1038/s41467-021-25962-0
  12. Mol Cancer. 2021 Sep 27. 20(1): 123
    p113 isoform encoded by CUX1 circular RNA drives tumor progression via facilitating ZRF1/BRD4 transactivation.
    Feng Yang, Anpei Hu, Yanhua Guo, Jianqun Wang, Dan Li, Xiaojing Wang, Shikai Jin, Boling Yuan, Shuang Cai, Yi Zhou, Qilan Li, Guo Chen, Haiyang Gao, Liduan Zheng, Qiangsong Tong.
       BACKGROUND: Metabolic reprogramming sustains tumorigenesis and aggressiveness of neuroblastoma (NB), the most common extracranial malignancy in childhood, while underlying mechanisms and therapeutic approaches still remain elusive.
    METHODS: Circular RNAs (circRNAs) were validated by Sanger sequencing. Co-immunoprecipitation, mass spectrometry, chromatin immunoprecipitation (ChIP) sequencing, and RNA sequencing assays were applied to explore protein interaction and target genes. Gene expression regulation was observed by ChIP, dual-luciferase reporter, real-time quantitative RT-PCR, and western blot assays. Gain- and loss-of-function studies were performed to observe the impacts of circRNA-encoded protein and its partners on the lipid metabolism, mitochondrial activity, growth, invasion, and metastasis of NB cells.
    RESULTS: A novel 113-amino acid protein (p113) of CUT-like homeobox 1 (CUX1) was identified in NB cells treated by serum deprivation. Further validating studies revealed that nuclear p113 was encoded by circRNA of CUX1, and promoted the lipid metabolic reprogramming, mitochondrial activity, proliferation, invasion, and metastasis of NB cells. Mechanistically, p113 interacted with Zuotin-related factor 1 (ZRF1) and bromodomain protein 4 (BRD4) to form a transcriptional regulatory complex, and mediated the transactivation of ZRF1/BRD4 in upregulating ALDH3A1, NDUFA1, and NDUFAF5 essential for conversion of fatty aldehydes into fatty acids, fatty acid β-oxidation, and mitochondrial complex I activity. Administration of an inhibitory peptide blocking p113-ZRF1 interaction suppressed the tumorigenesis and aggressiveness of NB cells. In clinical NB cases, high expression of p113, ZRF1, or BRD4 was associated with poor survival of patients.
    CONCLUSIONS: These results indicate that p113 isoform encoded by CUX1 circular RNA drives tumor progression via facilitating ZRF1/BRD4 transactivation.
    Keywords:  Bromodomain protein 4; Circular RNA-coding protein; Neuroblastoma progression; Zuotin-related factor 1
    DOI:  https://doi.org/10.1186/s12943-021-01421-8
  13. Clin Cancer Res. 2021 Sep 27. pii: clincanres.1681.2021. [Epub ahead of print]
    Organoids derived from neoadjuvant FOLFIRINOX patients recapitulate therapy resistance in pancreatic ductal adenocarcinoma.
    Elham Aida Farshadi, Jiang Chang, Bharath Sampadi, Michail Doukas, Freek Van 't Land, Fleur van der Sijde, Eveline E Vietsch, Joris Pothof, Bas Groot Koerkamp, Casper H J van Eijck.
       PURPOSE: We investigated whether organoids can be generated from resected tumors of patients who received eight cycles of neoadjuvant FOLFIRINOX chemotherapy before surgery, and evaluated the sensitivity/resistance of these surviving cancer cells to cancer therapy.
    EXPERIMENTAL DESIGN: We generated a library of 10 PDAC organoid lines: five each from treatment-naive and FOLFIRINOX-treated patients. We, first, assessed the histological, genetic, and transcriptional characteristics of the organoids and their matched primary PDAC tissue. Next, the organoids' response to treatment with single agents - 5-FU, irinotecan, and oxaliplatin - of the FOLFIRINOX regimen as well as combined regimen was evaluated. Finally, global mRNA-seq analyses were performed to identify FOLFIRINOX resistance pathways.
    RESULTS: All 10 patient-derived PDAC organoids recapitulate histological, genetic, and transcriptional characteristics of their primary tumor tissue. Neoadjuvant FOLFIRINOXtreated organoids display resistance to FOLFIRINOX (5/5), irinotecan (5/5) and oxaliplatin (4/5) when compared to treatment-naive organoids (FOLFIRINOX: 1/5, irinotecan: 2/5, oxaliplatin: 0/5). 5-FU treatment responses between naive and treated organoids were similar. Comparative global transcriptome analysis of treatment-naive and FOLFIRINOX samples - in both organoids and corresponding matched tumor tissues - uncovered modulated pathways mainly involved in genomic instability, energy metabolism, and innate immune system.
    CONCLUSION: Resistance development in neoadjuvant FOLFIRINOX organoids, recapitulating their primary tumor resistance, suggests continuation of FOLFIRINOX therapy as an adjuvant treatment may not be advantageous for these patients. Gene expression profiles of PDAC organoids identify targetable pathways involved in chemoresistance development upon neoadjuvant FOLFIRINOX treatment, thus opening up combination therapy possibilities.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-1681
  14. Cancer Res. 2021 Sep 30. pii: canres.0281.2021. [Epub ahead of print]
    LncRNA HIF1A-AS1 promotes gemcitabine resistance of pancreatic cancer by enhancing glycolysis through modulating the AKT/YB1/HIF-1α pathway.
    Fengyu Xu, Mengqi Huang, Qingyong Chen, Yi Niu, Yuhang Hu, Ping Hu, Ding Chen, Chi He, Kang Huang, Zhu Zeng, Jiang Tang, Fan Wang, Yong Zhao, Chunyou Wang, Gang Zhao.
      Gemcitabine (GEM) resistance is a major challenge for chemotherapy of pancreatic cancer (PC). Previous studies have reported on the role of lncRNA in tumorigenesis of PC, however, the involvement of lncRNA in the development of GEM resistance of PC remains unclear. In the present study, we demonstrated that the antisense RNA1 of HIF-1α (HIF1A-AS1) was significantly elevated in the GEM-resistant PC cells. Gain- and lost-of-function experiments validated that HIF1A-AS1 promoted GEM resistance of PC cells both in vitro and vivo. We further revealed that HIF1A-AS1 upregulated HIF-1α expression and thus promoted glycolysis to enhance GEM resistance of PC cells. Mechanistically, HIF1A-AS1 facilitated the interaction between serine/threonine kinase AKT and Y-box binding protein 1 (YB1), which promoted phosphorylation of YB1 (pYB1). Meanwhile, HIF1A-AS1 recruited pYB1 to HIF-1α mRNA which consequently promoted translation of HIF-1α. Furthermore, HIF-1α promoted HIF1A-AS1 transcription by directly binding to the HIF-1α response element in the promoter area of HIF1A-AS1 to form a positive feedback. Consistently, both HIF1A-AS1 and HIF-1α were upregulated in PC tissues and associated with poor overall survival. Together, our results underline a reciprocal loop of HIF1A-AS1 and HIF-1α which contributes to GEM resistance of PC and indicate that HIF1A-AS1 might serve as a novel therapeutic target for GEM resistance of PC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0281
  15. Oncogene. 2021 Sep 29.
    Epigenetic induction of lipocalin 2 expression drives acquired resistance to 5-fluorouracil in colorectal cancer through integrin β3/SRC pathway.
    Wenyi Zhang, Rulu Pan, Mei Lu, Qian Zhang, Ziqi Lin, Yuan Qin, Zhanyu Wang, Siqing Gong, Huan Lin, Shuyi Chong, Liting Lu, Wanqin Liao, Xincheng Lu.
      The therapeutic efficacy of 5-fluorouracil (5-FU) is often reduced by the development of drug resistance. We observed significant upregulation of lipocalin 2 (LCN2) expression in a newly established 5-FU-resistant colorectal cancer (CRC) cell line. In this study, we demonstrated that 5-FU-treated CRC cells developed resistance through LCN2 upregulation caused by LCN2 promoter demethylation and that feedback between LCN2 and NF-κB further amplified LCN2 expression. High LCN2 expression was associated with poor prognosis in CRC patients. LCN2 attenuated the cytotoxicity of 5-FU by activating the SRC/AKT/ERK-mediated antiapoptotic program. Mechanistically, the LCN2-integrin β3 interaction enhanced integrin β3 stability, thus recruiting SRC to the cytomembrane for autoactivation, leading to downstream AKT/ERK cascade activation. Targeting LCN2 or SRC compromised the growth of CRC cells with LCN2-induced 5-FU resistance. Our findings demonstrate a novel mechanism of acquired resistance to 5-FU, suggesting that LCN2 can be used as a biomarker and/or therapeutic target for advanced CRC.
    DOI:  https://doi.org/10.1038/s41388-021-02029-4
  16. Oncogene. 2021 Sep 28.
    Prostate cancer castrate resistant progression usage of non-canonical androgen receptor signaling and ketone body fuel.
    Estefania Labanca, Juan Bizzotto, Pablo Sanchis, Nicolas Anselmino, Jun Yang, Peter D A Shepherd, Alejandra Paez, Valeria Antico-Arciuch, Sofia Lage-Vickers, Anh G Hoang, Ximing Tang, Maria Gabriela Raso, Mark Titus, Eleni Efstathiou, Javier Cotignola, John Araujo, Christopher Logothetis, Elba Vazquez, Nora Navone, Geraldine Gueron.
      Prostate cancer (PCa) that progresses after androgen deprivation therapy (ADT) remains incurable. The underlying mechanisms that account for the ultimate emergence of resistance to ADT, progressing to castrate-resistant prostate cancer (CRPC), include those that reactivate androgen receptor (AR), or those that are entirely independent or cooperate with androgen signaling to underlie PCa progression. The intricacy of metabolic pathways associated with PCa progression spurred us to develop a metabolism-centric analysis to assess the metabolic shift occurring in PCa that progresses with low AR expression. We used PCa patient-derived xenografts (PDXs) to assess the metabolic changes after castration of tumor-bearing mice and subsequently confirmed main findings in human donor tumor that progressed after ADT. We found that relapsed tumors had a significant increase in fatty acids and ketone body (KB) content compared with baseline. We confirmed that critical ketolytic enzymes (ACAT1, OXCT1, BDH1) were dysregulated after castrate-resistant progression. Further, these enzymes are increased in the human donor tissue after progressing to ADT. In an in silico approach, increased ACAT1, OXCT1, BDH1 expression was also observed for a subset of PCa patients that relapsed with low AR and ERG (ETS-related gene) expression. Further, expression of these factors was also associated with decreased time to biochemical relapse and decreased progression-free survival. Our studies reveal the key metabolites fueling castration resistant progression in the context of a partial or complete loss of AR dependence.
    DOI:  https://doi.org/10.1038/s41388-021-02008-9
  17. Trends Cancer. 2021 Sep 28. pii: S2405-8033(21)00190-4. [Epub ahead of print]
    Chromosomal instability and aneuploidy as causes of cancer drug resistance.
    Devon A Lukow, Jason M Sheltzer.
      High levels of aneuploidy and chromosomal instability (CIN) are correlated with poor patient outcomes, though the mechanism(s) underlying this relationship have not been established. Recent evidence has demonstrated that chromosome copy number changes can function as point mutation-independent sources of drug resistance in cancer, which may partially explain this clinical association. CIN generates intratumoral heterogeneity in the form of gene dosage alterations, upon which the selective pressures induced by drug treatments can act. Thus, although CIN and aneuploidy impair cell fitness under most conditions, CIN can augment cellular adaptability, establishing CIN as a bet-hedging mechanism in tumor evolution. CIN may also endow cancers with unique vulnerabilities, which could be exploited therapeutically to achieve better patient outcomes.
    Keywords:  aneuploidy; chromosomal instability; drug resistance; tumor evolution
    DOI:  https://doi.org/10.1016/j.trecan.2021.09.002
  18. Nat Genet. 2021 Sep 30.
    Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response.
    Kevin C Johnson, Kevin J Anderson, Elise T Courtois, Amit D Gujar, Floris P Barthel, Frederick S Varn, Diane Luo, Martine Seignon, Eunhee Yi, Hoon Kim, Marcos R H Estecio, Dacheng Zhao, Ming Tang, Nicholas E Navin, Rahul Maurya, Chew Yee Ngan, Niels Verburg, Philip C de Witt Hamer, Ketan Bulsara, Michael L Samuels, Sunit Das, Paul Robson, Roel G W Verhaak.
      Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to therapeutic resistance. We integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes and bulk multi-omic profiles across 11 adult IDH mutant or IDH wild-type gliomas to delineate sources of intratumoral heterogeneity. We showed that local DNA methylation disorder is associated with cell-cell DNA methylation differences, is elevated in more aggressive tumors, links with transcriptional disruption and is altered during the environmental stress response. Glioma cells under in vitro hypoxic and irradiation stress increased local DNA methylation disorder and shifted cell states. We identified a positive association between genetic and epigenetic instability that was supported in bulk longitudinally collected DNA methylation data. Increased DNA methylation disorder associated with accelerated disease progression and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work identified an epigenetically facilitated adaptive stress response process and highlights the importance of epigenetic heterogeneity in shaping therapeutic outcomes.
    DOI:  https://doi.org/10.1038/s41588-021-00926-8
  19. Proc Natl Acad Sci U S A. 2021 Oct 05. pii: e2105367118. [Epub ahead of print]118(40):
    Matrix stiffness drives stromal autophagy and promotes formation of a protumorigenic niche.
    Anna Hupfer, Anna Brichkina, Anke Koeniger, Corinna Keber, Carsten Denkert, Petra Pfefferle, Frederik Helmprobst, Axel Pagenstecher, Alexander Visekruna, Matthias Lauth.
      Increased stiffness of solid tissues has long been recognized as a diagnostic feature of several pathologies, most notably malignant diseases. In fact, it is now well established that elevated tissue rigidity enhances disease progression and aggressiveness and is associated with a poor prognosis in patients as documented, for instance, for lung fibrosis or the highly desmoplastic cancer of the pancreas. The underlying mechanisms of the interplay between physical properties and cellular behavior are, however, not very well understood. Here, we have found that switching culture conditions from soft to stiff substrates is sufficient to evoke (macro) autophagy in various fibroblast types. Mechanistically, this is brought about by stiffness-sensing through an Integrin αV-focal adhesion kinase module resulting in sequestration and posttranslational stabilization of the metabolic master regulator AMPKα at focal adhesions, leading to the subsequent induction of autophagy. Importantly, stiffness-induced autophagy in stromal cells such as fibroblasts and stellate cells critically supports growth of adjacent cancer cells in vitro and in vivo. This process is Integrin αV dependent, opening possibilities for targeting tumor-stroma crosstalk. Our data thus reveal that the mere change in mechanical tissue properties is sufficient to metabolically reprogram stromal cell populations, generating a tumor-supportive metabolic niche.
    Keywords:  AMPK; ITGAV; autophagy; pancreatic stellate cells; tumor stroma
    DOI:  https://doi.org/10.1073/pnas.2105367118
  20. Elife. 2021 Sep 30. pii: e66721. [Epub ahead of print]10
    Localization of KRAS downstream target ARL4C to invasive pseudopods accelerates pancreatic cancer cell invasion.
    Akikazu Harada, Shinji Matsumoto, Yoshiaki Yasumizu, Toshiyuki Akama, Hidetoshi Eguchi, Akira Kikuchi.
      Pancreatic cancer has a high mortality rate due to metastasis. Whereas KRAS is mutated in most pancreatic cancer patients, controlling KRAS or its downstream effectors has not been succeeded clinically. ARL4C is a small G protein whose expression is induced by the Wnt and EGF-RAS pathways. In the present study, we found that ARL4C is frequently overexpressed in pancreatic cancer patients and showed that its localization to invasive pseudopods is required for cancer cell invasion. IQGAP1 was identified as a novel interacting protein for ARL4C. ARL4C recruited IQGAP1 and its downstream effector, MMP14, to invasive pseudopods. Specific localization of ARL4C, IQGAP1, and MMP14 was the active site of invasion, which induced degradation of the extracellular matrix. Moreover, subcutaneously injected antisense oligonucleotide against ARL4C into tumor-bearing mice suppressed metastasis of pancreatic cancer. These results suggest that ARL4C-IQGAP1-MMP14 signaling is activated at invasive pseudopods of pancreatic cancer cells.
    Keywords:  cancer biology; cell biology; human
    DOI:  https://doi.org/10.7554/eLife.66721
  21. Clin Cancer Res. 2021 Oct 01. pii: clincanres.3029.2021. [Epub ahead of print]
    An evolving role for AXL in metastatic renal cell carcinoma.
    Andrew W Hahn, Daniel J George, Neeraj Agarwal.
      High tumoral expression of AXL was associated with inferior response to anti-PD-1 therapy and increased tumoral PD-L1 expression in patients with metastatic renal cell carcinoma, with particularly poor outcomes in those with high AXL and PD-L1. AXL expression has potential as a biomarker and therapeutic target.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-3029
  22. Nat Commun. 2021 Sep 28. 12(1): 5680
    Measuring kinetics and metastatic propensity of CTCs by blood exchange between mice.
    Bashar Hamza, Alex B Miller, Lara Meier, Max Stockslager, Sheng Rong Ng, Emily M King, Lin Lin, Kelsey L DeGouveia, Nolawit Mulugeta, Nicholas L Calistri, Haley Strouf, Christina Bray, Felicia Rodriguez, William A Freed-Pastor, Christopher R Chin, Grissel C Jaramillo, Megan L Burger, Robert A Weinberg, Alex K Shalek, Tyler Jacks, Scott R Manalis.
      Existing preclinical methods for acquiring dissemination kinetics of rare circulating tumor cells (CTCs) en route to forming metastases have not been capable of providing a direct measure of CTC intravasation rate and subsequent half-life in the circulation. Here, we demonstrate an approach for measuring endogenous CTC kinetics by continuously exchanging CTC-containing blood over several hours between un-anesthetized, tumor-bearing mice and healthy, tumor-free counterparts. By tracking CTC transfer rates, we extrapolated half-life times in the circulation of between 40 and 260 s and intravasation rates between 60 and 107,000 CTCs/hour in mouse models of small-cell lung cancer (SCLC), pancreatic ductal adenocarcinoma (PDAC), and non-small cell lung cancer (NSCLC). Additionally, direct transfer of only 1-2% of daily-shed CTCs using our blood-exchange technique from late-stage, SCLC-bearing mice generated macrometastases in healthy recipient mice. We envision that our technique will help further elucidate the role of CTCs and the rate-limiting steps in metastasis.
    DOI:  https://doi.org/10.1038/s41467-021-25917-5
  23. Oncogenesis. 2021 Sep 29. 10(9): 65
    IL-6 promotes drug resistance through formation of polyploid giant cancer cells and stromal fibroblast reprogramming.
    Na Niu, Jun Yao, Robert C Bast, Anil K Sood, Jinsong Liu.
      To understand the role of polyploid giant cancer cells (PGCCs) in drug resistance and disease relapse, we examined the mRNA expression profile of PGCCs following treatment with paclitaxel in ovarian cancer cells. An acute activation of IL-6 dominated senescence-associated secretory phenotype lasted 2-3 weeks and declined during the termination phase of polyploidy. IL-6 activates embryonic stemness during the initiation of PGCCs and can reprogram normal fibroblasts into cancer-associated fibroblasts (CAFs) via increased collagen synthesis, activation of VEGF expression, and enrichment of CAFs and the GPR77 + /CD10 + fibroblast subpopulation. Blocking the IL-6 feedback loop with tocilizumab or apigenin prevented PGCC formation, attenuated embryonic stemness and the CAF phenotype, and inhibited tumor growth in a patient-derived xenograft high-grade serous ovarian carcinoma model. Thus, IL-6 derived by PGCCs is capable of reprogramming both cancer and stromal cells and contributes to the evolution and remodeling of cancer. Targeting IL-6 in PGCCs may represent a novel approach to combating drug resistance.
    DOI:  https://doi.org/10.1038/s41389-021-00349-4
  24. Sci Adv. 2021 Oct;7(40): eabg7265
    Desmosomal proteins of DSC2 and PKP1 promote cancer cells survival and metastasis by increasing cluster formation in circulatory system.
    Koukou Li, Renfei Wu, Muya Zhou, Haibo Tong, Kathy Q Luo.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/sciadv.abg7265
  25. Cancer Discov. 2021 Oct 01.
    Nuclear Envelope Disruptions Induce DNA Damage and Invasiveness.
      Nuclear envelope (NE) disruptions induce DNA damage which increases tumor cell invasion.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2021-138
  26. Mol Cancer. 2021 Sep 29. 20(1): 125
    Patient derived organoids in prostate cancer: improving therapeutic efficacy in precision medicine.
    Sahithi Pamarthy, Hatem E Sabaawy.
      With advances in the discovery of the clinical and molecular landscapes of prostate cancer (PCa), implementation of precision medicine-guided therapeutic testing in the clinic has become a priority. Patient derived organoids (PDOs) are three-dimensional (3D) tissue cultures that promise to enable the validation of preclinical drug testing in precision medicine and coclinical trials by modeling PCa for predicting therapeutic responses with a reliable efficacy. We evaluate the advances in 3D culture and PDO use to model clonal heterogeneity and screen for effective targeted therapies, with a focus on the technological advances in generating PDOs. Recent innovations include the utilization of PDOs both in original research and/or correlative studies in clinical trials to examine drug effects within the PCa tumor microenvironment (TME). There has also been a significant improvement with the utilization of various extracellular matrices and single cell assays for the generation and long-term propagation of PDOs. Single cell derived PDOs could faithfully recapitulate the original tumor and reflect the heterogeneity features. While most PDO use for precision medicine understandably involved tissues derived from metastatic patients, we envision that the generation of PDOs from localized PCa along with the incorporation of cells of the TME in tissue models would fulfill the great potential of PDOs in predicting drug clinical benefits. We conclude that single cell derived PDOs reiterate the molecular features of the original tumor and represent a reliable pre-clinical PCa model to understand individual tumors and design tailored targeted therapies.
    Keywords:  Patient derived organoids; Precision medicine; Prostate cancer; Targeted therapy
    DOI:  https://doi.org/10.1186/s12943-021-01426-3
  27. J Clin Invest. 2021 Sep 30. pii: e152911. [Epub ahead of print]
    Micropeptide ASAP encoded by LINC00467 promotes colorectal cancer progression by directly modulating ATP synthase activity.
    Qiwei Ge, Dingjiacheng Jia, Dong Cen, Yadong Qi, Chengyu Shi, Junhong Li, Lingjie Sang, Luo-Jia Yang, Jiamin He, Aifu Lin, Shujie Chen, Liangjing Wang.
      Emerging evidence has shown that open reading frames inside lncRNA could encode micropeptides. However, their roles in cellular energy metabolism and tumor progression remain largely unknown. Here, we identified a 94-amino acid-length micropeptide encoded by lncRNA LINC00467 in colorectal cancer. We also characterized its conservation across higher mammals, localization to mitochondria, and the concerted local functions. This peptide enhanced the ATP synthase construction by interacting with the subunit α and γ (ATP5A and ATP5C), increased ATP synthase activity and mitochondrial oxygen consumption rate, and thereby promoted colorectal cancer cell proliferation. Hence, this micropeptide was termed as "ATP synthase associated peptide" (ASAP). Furthermore, loss of ASAP suppressed patient-derived xenograft growth with attenuated ATP synthase activity and mitochondrial ATP production. Clinically, high expression of ASAP and LINC00467 predicted poor prognosis of colorectal cancer patients. Taken together, our findings revealed a colorectal cancer-associated micropeptide as a vital player in mitochondrial metabolism and provided a therapeutic target for colorectal cancer.
    Keywords:  Colorectal cancer; Gastroenterology; Noncoding RNAs; Oncology
    DOI:  https://doi.org/10.1172/JCI152911
  28. Gut. 2021 Sep 29. pii: gutjnl-2021-324321. [Epub ahead of print]
    Lineage tracing and single-cell analysis reveal proliferative Prom1+ tumour-propagating cells and their dynamic cellular transition during liver cancer progression.
    Lei Zhou, Ken Ho Yu, Tin Lok Wong, Zhao Zhang, Chun Ho Chan, Jane Hc Loong, Noelia Che, Hua Jian Yu, Kel Vin Tan, Man Tong, Elly S Ngan, Joshua Wk Ho, Stephanie Ma.
       OBJECTIVE: Hepatocellular carcinoma (HCC) has high intratumoral heterogeneity, which contributes to therapeutic resistance and tumour recurrence. We previously identified Prominin-1 (PROM1)/CD133 as an important liver cancer stem cell (CSC) marker in human HCC. The aim of this study was to investigate the heterogeneity and properties of Prom1+ cells in HCC in intact mouse models.
    DESIGN: We established two mouse models representing chronic fibrotic HCC and rapid steatosis-related HCC. We performed lineage tracing post-HCC induction using Prom1C-L/+; Rosa26tdTomato/+ mice, and targeted depletion using Prom1C-L/+; Rosa26DTA/+ mice. Single-cell RNA sequencing (scRNA-seq) was carried out to analyse the transcriptomic profile of traced Prom1+ cells.
    RESULTS: Prom1 in HCC tumours marks proliferative tumour-propagating cells with CSC-like properties. Lineage tracing demonstrated that these cells display clonal expansion in situ in primary tumours. Labelled Prom1+ cells exhibit increasing tumourigenicity in 3D culture and allotransplantation, as well as potential to form cancers of differential lineages on transplantation. Depletion of Prom1+ cells impedes tumour growth and reduces malignant cancer hallmarks in both HCC models. scRNA-seq analysis highlighted the heterogeneity of Prom1+ HCC cells, which follow a trajectory to the dedifferentiated status with high proliferation and stem cells traits. Conserved gene signature of Prom1 linage predicts poor prognosis in human HCC. The activated oxidant detoxification underlies the protective mechanism of dedifferentiated transition and lineage propagation.
    CONCLUSION: Our study combines in vivo lineage tracing and scRNA-seq to reveal the heterogeneity and dynamics of Prom1+ HCC cells, providing insights into the mechanistic role of malignant CSC-like cells in HCC progression.
    Keywords:  hepatocellular carcinoma; stem cells
    DOI:  https://doi.org/10.1136/gutjnl-2021-324321
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