bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021–01–24
23 papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. Dll1+ quiescent tumor stem cells drive chemoresistance in breast cancer through NF-κB survival pathway.
  2. CXCL12-mediated HOXB5 overexpression facilitates Colorectal Cancer metastasis through transactivating CXCR4 and ITGB3.
  3. Translational Regulation of Cancer Metastasis.
  4. Fibroblast growth factor receptor facilitates recurrence of minimal residual disease following trastuzumab emtansine therapy.
  5. Adrenomedullin-CALCRL axis controls relapse-initiating drug tolerant acute myeloid leukemia cells.
  6. The Genetic Evolution of Treatment-Resistant Cutaneous, Acral, and Uveal Melanomas.
  7. Nicotine promotes breast cancer metastasis by stimulating N2 neutrophils and generating pre-metastatic niche in lung.
  8. The metabolism of cancer cells during metastasis.
  9. Cytoplasmic SHMT2 drives the progression and metastasis of colorectal cancer by inhibiting β-catenin degradation.
  10. Targeting the cytoskeleton against metastatic dissemination.
  11. Metastasis-associated macrophages constrain antitumor capability of natural killer cells in the metastatic site at least partially by membrane bound transforming growth factor β.
  12. Food for Growth: Distinct Nutrient Preferences between Primary Tumors and Metastases.
  13. Smoothened-activating lipids drive resistance to CDK4/6 inhibition in Hedgehog-associated medulloblastoma cells and preclinical models.
  14. Cisplatin-resistant NSCLC cells induced by hypoxia transmit resistance to sensitive cells through exosomal PKM2.
  15. Structures Identify Selpercatinib and Pralsetinib Resistance Mechanisms.
  16. Immune Reprogramming Precision Photodynamic Therapy of Peritoneal Metastasis by Scalable Stem-Cell-Derived Extracellular Vesicles.
  17. Single-cell lineages reveal the rates, routes, and drivers of metastasis in cancer xenografts.
  18. N6-methyladenosine as a biological and clinical determinant in colorectal cancer: progression and future direction.
  19. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities.
  20. Single-cell RNA sequencing reveals intratumoral heterogeneity in primary uveal melanomas and identifies HES6 as a driver of the metastatic disease.
  21. Roles and Regulations of TET Enzymes in Solid Tumors.
  22. Significance of serglycin and its binding partners in autocrine promotion of metastasis in esophageal cancer.
  23. Mapping metastasis.
  1. Nat Commun. 2021 01 18. 12(1): 432
    Dll1+ quiescent tumor stem cells drive chemoresistance in breast cancer through NF-κB survival pathway.
    Sushil Kumar, Ajeya Nandi, Snahlata Singh, Rohan Regulapati, Ning Li, John W Tobias, Christian W Siebel, Mario Andres Blanco, Andres J Klein-Szanto, Christopher Lengner, Alana L Welm, Yibin Kang, Rumela Chakrabarti.
      Development of chemoresistance in breast cancer patients greatly increases mortality. Thus, understanding mechanisms underlying breast cancer resistance to chemotherapy is of paramount importance to overcome this clinical challenge. Although activated Notch receptors have been associated with chemoresistance in cancer, the specific Notch ligands and their molecular mechanisms leading to chemoresistance in breast cancer remain elusive. Using conditional knockout and reporter mouse models, we demonstrate that tumor cells expressing the Notch ligand Dll1 is important for tumor growth and metastasis and bear similarities to tumor-initiating cancer cells (TICs) in breast cancer. RNA-seq and ATAC-seq using reporter models and patient data demonstrated that NF-κB activation is downstream of Dll1 and is associated with a chemoresistant phenotype. Finally, pharmacological blocking of Dll1 or NF-κB pathway completely sensitizes Dll1+ tumors to chemotherapy, highlighting therapeutic avenues for chemotherapy resistant breast cancer patients in the near future.
    DOI:  https://doi.org/10.1038/s41467-020-20664-5
  2. Theranostics. 2021 ;11(6): 2612-2633
    CXCL12-mediated HOXB5 overexpression facilitates Colorectal Cancer metastasis through transactivating CXCR4 and ITGB3.
    Weibo Feng, Wenjie Huang, Jie Chen, Chenyang Qiao, Danfei Liu, Xiaoyu Ji, Meng Xie, Tongyue Zhang, Yijun Wang, Mengyu Sun, Dean Tian, Daiming Fan, Yongzhan Nie, Kaichun Wu, Limin Xia.
      Background: Metastasis is the major reason for the high mortality of colorectal cancer (CRC). However, the molecular mechanism underlying CRC metastasis remains unclear. Here, we report a novel role of homeobox B5 (HOXB5), a member of the HOX family, in promoting CRC metastasis. Method: The expression of HOXB5 and its target genes were examined by immunohistochemistry in human CRC. Chromatin immunoprecipitation and luciferase reporter assays were performed to measure the transcriptional regulation of target genes by HOXB5. The metastatic capacities of CRC cells were evaluated by in vivo lung and liver metastatic models. Results: The elevated expression of HOXB5 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in CRC patients. HOXB5 expression was an independent and significant risk factor for the recurrence and survival in CRC patients. Overexpression of HOXB5 promoted CRC metastasis by transactivating metastatic related genes, C-X-C motif chemokine receptor 4 (CXCR4) and integrin subunit beta 3 (ITGB3). C-X-C motif chemokine ligand 12 (CXCL12), which is the ligand of CXCR4, upregulated HOXB5 expression through the extracellular regulated protein kinase (ERK)/ETS proto-oncogene 1, transcription factor (ETS1) pathway. The knockdown of HOXB5 decreased CXCL12-enhanced CRC metastasis. Furthermore, AMD3100, a specific CXCR4 inhibitor, significantly suppressed HOXB5-mediated CRC metastasis. HOXB5 expression was positively correlated with CXCR4 and ITGB3 expression in human CRC tissues, and patients with positive co-expression of HOXB5/CXCR4, or HOXB5/ITGB3 exhibited the worst prognosis. Conclusion: Our study implicates HOXB5 as a prognostic biomarker in CRC, and defines a CXCL12-HOXB5-CXCR4 positive feedback loop that plays an important role in promoting CRC metastasis.
    Keywords:  AMD3100; C-X-C motif chemokine receptor 4; colorectal cancer; homeobox B5; metastasis
    DOI:  https://doi.org/10.7150/thno.52199
  3. Cancer Res. 2021 Jan 21.
    Translational Regulation of Cancer Metastasis.
    Douglas S Micalizzi, Richard Y Ebright, Daniel A Haber, Shyamala Maheswaran.
      Deregulation of the mRNA translational process has been observed during tumorigenesis. However, recent findings have shown that deregulation of translation also contributes specifically to cancer cell spread. During metastasis, cancer cells undergo changes in cellular state, permitting the acquisition of features necessary for cell survival, dissemination, and outgrowth. In addition, metastatic cells respond to external cues, allowing for their persistence under significant cellular and microenvironmental stresses. Recent work has revealed the importance of mRNA translation to these dynamic changes, including regulation of cell states through epithelial-to-mesenchymal transition and tumor dormancy and as a response to external stresses such as hypoxia and immune surveillance. In this review, we focus on examples of altered translation underlying these phenotypic changes and responses to external cues and explore how they contribute to metastatic progression. We also highlight the therapeutic opportunities presented by aberrant mRNA translation, suggesting novel ways to target metastatic tumor cells.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-2720
  4. NPJ Breast Cancer. 2021 Jan 21. 7(1): 5
    Fibroblast growth factor receptor facilitates recurrence of minimal residual disease following trastuzumab emtansine therapy.
    Saeed S Akhand, Hao Chen, Stephen Connor Purdy, Zian Liu, Joshua C Anderson, Christopher D Willey, Michael K Wendt.
      Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) that efficiently delivers a highly potent microtubule inhibitor to HER2 overexpressing cells. Herein, we utilize HER2 transformed human mammary epithelial cells (HME2) to demonstrate in vitro and in vivo response and recurrence upon T-DM1 treatment. Continuous in vitro dosing of HME2 cells with T-DM1 failed to produce a spontaneously resistant cell line. However, induction of epithelial-mesenchymal transition (EMT) via pretreatment with TGF-β1 was capable of promoting emergence of T-DM1-resistant (TDM1R) cells. Flow cytometric analyses indicated that induction of EMT decreased trastuzumab binding, prior to overt loss of HER2 expression in TDM1R cells. Kinome analyses of TDM1R cells indicated increased phosphorylation of ErbB1, ErbB4, and FGFR1. TDM1R cells failed to respond to the ErbB kinase inhibitors lapatinib and afatinib, but they acquired sensitivity to FIIN4, a covalent FGFR kinase inhibitor. In vivo, minimal residual disease (MRD) remained detectable via bioluminescent imaging following T-DM1-induced tumor regression. Upon cessation of the ADC, relapse occurred and secondary tumors were resistant to additional rounds of T-DM1. These recurrent tumors could be inhibited by FIIN4. Moreover, ectopic overexpression of FGFR1 was sufficient to enhance tumor growth, diminish trastuzumab binding, and promote recurrence following T-DM1-induced MRD. Finally, patient-derived xenografts from a HER2+ breast cancer patient who had progressed on trastuzumab failed to respond to T-DM1, but tumor growth was significantly inhibited by FIIN4. Overall, our studies strongly support therapeutic combination of TDM1 with FGFR-targeted agents in HER2+ breast cancer.
    DOI:  https://doi.org/10.1038/s41523-020-00213-5
  5. Nat Commun. 2021 01 18. 12(1): 422
    Adrenomedullin-CALCRL axis controls relapse-initiating drug tolerant acute myeloid leukemia cells.
    Clément Larrue, Nathan Guiraud, Pierre-Luc Mouchel, Marine Dubois, Thomas Farge, Mathilde Gotanègre, Claudie Bosc, Estelle Saland, Marie-Laure Nicolau-Travers, Marie Sabatier, Nizar Serhan, Ambrine Sahal, Emeline Boet, Sarah Mouche, Quentin Heydt, Nesrine Aroua, Lucille Stuani, Tony Kaoma, Linus Angenendt, Jan-Henrik Mikesch, Christoph Schliemann, François Vergez, Jérôme Tamburini, Christian Récher, Jean-Emmanuel Sarry.
      Drug tolerant/resistant leukemic stem cell (LSC) subpopulations may explain frequent relapses in acute myeloid leukemia (AML), suggesting that these relapse-initiating cells (RICs) persistent after chemotherapy represent bona fide targets to prevent drug resistance and relapse. We uncover that calcitonin receptor-like receptor (CALCRL) is expressed in RICs, and that the overexpression of CALCRL and/or of its ligand adrenomedullin (ADM), and not CGRP, correlates to adverse outcome in AML. CALCRL knockdown impairs leukemic growth, decreases LSC frequency, and sensitizes to cytarabine in patient-derived xenograft models. Mechanistically, the ADM-CALCRL axis drives cell cycle, DNA repair, and mitochondrial OxPHOS function of AML blasts dependent on E2F1 and BCL2. Finally, CALCRL depletion reduces LSC frequency of RICs post-chemotherapy in vivo. In summary, our data highlight a critical role of ADM-CALCRL in post-chemotherapy persistence of these cells, and disclose a promising therapeutic target to prevent relapse in AML.
    DOI:  https://doi.org/10.1038/s41467-020-20717-9
  6. Clin Cancer Res. 2020 Dec 15.
    The Genetic Evolution of Treatment-Resistant Cutaneous, Acral, and Uveal Melanomas.
    Alvin P Makohon-Moore, Evan J Lipson, Jody E Hooper, Amanda Zucker, Jungeui Hong, Craig M Bielski, Akimasa Hayashi, Collin Tokheim, Priscilla Baez, Rajya Kappagantula, Zachary Kohutek, Vladimir Makarov, Nadeem Riaz, Michael A Postow, Paul B Chapman, Rachel Karchin, Nicholas D Socci, David B Solit, Timothy A Chan, Barry S Taylor, Suzanne L Topalian, Christine A Iacobuzio-Donahue.
       PURPOSE: Melanoma is a biologically heterogeneous disease composed of distinct clinicopathologic subtypes that frequently resist treatment. To explore the evolution of treatment resistance and metastasis, we used a combination of temporal and multilesional tumor sampling in conjunction with whole-exome sequencing of 110 tumors collected from 7 patients with cutaneous (n = 3), uveal (n = 2), and acral (n = 2) melanoma subtypes.
    EXPERIMENTAL DESIGN: Primary tumors, metastases collected longitudinally, and autopsy tissues were interrogated. All but 1 patient died because of melanoma progression.
    RESULTS: For each patient, we generated phylogenies and quantified the extent of genetic diversity among tumors, specifically among putative somatic alterations affecting therapeutic resistance.
    CONCLUSIONS: In 4 patients who received immunotherapy, we found 1-3 putative acquired and intrinsic resistance mechanisms coexisting in the same patient, including mechanisms that were shared by all tumors within each patient, suggesting that future therapies directed at overcoming intrinsic resistance mechanisms may be broadly effective.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-2984
  7. Nat Commun. 2021 01 20. 12(1): 474
    Nicotine promotes breast cancer metastasis by stimulating N2 neutrophils and generating pre-metastatic niche in lung.
    Abhishek Tyagi, Sambad Sharma, Kerui Wu, Shih-Ying Wu, Fei Xing, Yin Liu, Dan Zhao, Ravindra Pramod Deshpande, Ralph B D'Agostino, Kounosuke Watabe.
      Smoking has a profound impact on tumor immunity, and nicotine, which is the major addictive component of smoke, is known to promote tumor progression despite being a non-carcinogen. In this study, we demonstrate that chronic exposure of nicotine plays a critical role in the formation of pre-metastatic niche within the lungs by recruiting pro-tumor N2-neutrophils. This pre-metastatic niche promotes the release of STAT3-activated lipocalin 2 (LCN2), a secretory glycoprotein from the N2-neutrophils, and induces mesenchymal-epithelial transition of tumor cells thereby facilitating colonization and metastatic outgrowth. Elevated levels of serum and urine LCN2 is elevated in early-stage breast cancer patients and cancer-free females with smoking history, suggesting that LCN2 serve as a promising prognostic biomarker for predicting increased risk of metastatic disease in female smoker(s). Moreover, natural compound, salidroside effectively abrogates nicotine-induced neutrophil polarization and consequently reduced lung metastasis of hormone receptor-negative breast cancer cells. Our findings suggest a pro-metastatic role of nicotine-induced N2-neutrophils for cancer cell colonization in the lungs and illuminate the therapeutic use of salidroside to enhance the anti-tumor activity of neutrophils in breast cancer patients.
    DOI:  https://doi.org/10.1038/s41467-020-20733-9
  8. Nat Rev Cancer. 2021 Jan 18.
    The metabolism of cancer cells during metastasis.
    Gabriele Bergers, Sarah-Maria Fendt.
      Metastasis formation is the major cause of death in most patients with cancer. Despite extensive research, targeting metastatic seeding and colonization is still an unresolved challenge. Only recently, attention has been drawn to the fact that metastasizing cancer cells selectively and dynamically adapt their metabolism at every step during the metastatic cascade. Moreover, many metastases display different metabolic traits compared with the tumours from which they originate, enabling survival and growth in the new environment. Consequently, the stage-dependent metabolic traits may provide therapeutic windows for preventing or reducing metastasis, and targeting the new metabolic traits arising in established metastases may allow their eradication.
    DOI:  https://doi.org/10.1038/s41568-020-00320-2
  9. Theranostics. 2021 ;11(6): 2966-2986
    Cytoplasmic SHMT2 drives the progression and metastasis of colorectal cancer by inhibiting β-catenin degradation.
    Chunqi Liu, Liang Wang, Xiaocong Liu, Yuping Tan, Lei Tao, Yuzhou Xiao, Pengchi Deng, Huijuan Wang, Qianyi Deng, Yiyun Lin, Hui Jie, Huaqin Zhang, Jing Zhang, Yong Peng, Hu Zhang, Zongguang Zhou, Qingxiang Sun, Xiaobo Cen, Yinglan Zhao.
      Introduction: Serine hydroxymethyltransferase 2 (SHMT2) plays a critical role in serine-glycine metabolism to drive cancer cell proliferation. However, the nonmetabolic function of SHMT2 in tumorigenesis, especially in human colorectal cancer (CRC) progression, remains largely unclear. Methods: SHMT2 expression in human CRC cells was identified by western blot and immunofluorescence assay. The CRC cell proliferation, migration, and invasion after SHMT2 knockdown or overexpression were explored through in vitro and in vivo assays. Immunofluorescence, mRNA-seq, co-immunoprecipitation, chromatin immunoprecipitation-qPCR and immunohistochemistry assays were used to investigate the underlying mechanisms behind the SHMT2 nonmetabolic function. Results: We demonstrated that SHMT2 was distributed in the cytoplasm and nucleus of human CRC cells. SHMT2 knockdown resulted in the significant inhibition of CRC cell proliferation, which was not restored by serine, glycine, or formate supplementation. The invasion and migration of CRC cells were suppressed after SHMT2 knockdown. Mechanistically, SHMT2 interacted with β-catenin in the cytoplasm. This interaction inhibited the ubiquitylation-mediated degradation of β-catenin and subsequently modulated the expression of its target genes, leading to the promotion of CRC cell proliferation and metastasis. Notably, the lysine 64 residue on SHMT2 (SHMT2K64) mediated its interaction with β-catenin. Moreover, transcription factor TCF4 interacted with β-catenin, which in turn increased SHMT2 expression, forming an SHMT2/β-catenin positive feedback loop. In vivo xenograft experiments confirmed that SHMT2 promoted the growth and metastasis of CRC cells. Finally, the level of SHMT2 was found to be significantly increased in human CRC tissues. The SHMT2 level was correlated with an increased level of β-catenin, associated with CRC progression and predicted poor patient survival. Conclusion: Taken together, our findings reveal a novel nonmetabolic function of SHMT2 in which it stabilizes β-catenin to prevent its ubiquitylation-mediated degradation and provide a potential therapeutic strategy for CRC therapy.
    Keywords:  colorectal cancer; cytoplasmic SHMT2; nonmetabolic function; ubiquitylation-mediated degradation; β-catenin
    DOI:  https://doi.org/10.7150/thno.48699
  10. Cancer Metastasis Rev. 2021 Jan 20.
    Targeting the cytoskeleton against metastatic dissemination.
    Carmen Ruggiero, Enzo Lalli.
      Cancer is a pathology characterized by a loss or a perturbation of a number of typical features of normal cell behaviour. Indeed, the acquisition of an inappropriate migratory and invasive phenotype has been reported to be one of the hallmarks of cancer. The cytoskeleton is a complex dynamic network of highly ordered interlinking filaments playing a key role in the control of fundamental cellular processes, like cell shape maintenance, motility, division and intracellular transport. Moreover, deregulation of this complex machinery contributes to cancer progression and malignancy, enabling cells to acquire an invasive and metastatic phenotype. Metastasis accounts for 90% of death from patients affected by solid tumours, while an efficient prevention and suppression of metastatic disease still remains elusive. This results in the lack of effective therapeutic options currently available for patients with advanced disease. In this context, the cytoskeleton with its regulatory and structural proteins emerges as a novel and highly effective target to be exploited for a substantial therapeutic effort toward the development of specific anti-metastatic drugs. Here we provide an overview of the role of cytoskeleton components and interacting proteins in cancer metastasis with a special focus on small molecule compounds interfering with the actin cytoskeleton organization and function. The emerging involvement of microtubules and intermediate filaments in cancer metastasis is also reviewed.
    Keywords:  Anti-metastatic drugs; Cancer metastasis; Cytoskeleton; Invasion; Migration; Small molecule compounds
    DOI:  https://doi.org/10.1007/s10555-020-09936-0
  11. J Immunother Cancer. 2021 Jan;pii: e001740. [Epub ahead of print]9(1):
    Metastasis-associated macrophages constrain antitumor capability of natural killer cells in the metastatic site at least partially by membrane bound transforming growth factor β.
    Demi Brownlie, Dahlia Doughty-Shenton, Daniel Yh Soong, Colin Nixon, Neil O Carragher, Leo M Carlin, Takanori Kitamura.
       BACKGROUND: Metastatic breast cancer is a leading cause of cancer-related death in women worldwide. Infusion of natural killer (NK) cells is an emerging immunotherapy for such malignant tumors, although elimination of the immunosuppressive tumor environment is required to improve its efficacy. The effects of this "metastatic" tumor environment on NK cells, however, remain largely unknown. Previous studies, including our own, have demonstrated that metastasis-associated macrophages (MAMs) are one of the most abundant immune cell types in the metastatic tumor niche in mouse models of metastatic breast cancer. We thus investigated the effects of MAMs on antitumor functions of NK cells in the metastatic tumor microenvironment.
    METHODS: MAMs were isolated from the tumor-bearing lung of C57BL/6 mice intravenously injected with E0771-LG mouse mammary tumor cells. The effects of MAMs on NK cell cytotoxicity towards E0771-LG cells were evaluated in vitro by real-time fluorescence microscopy. The effects of MAM depletion on NK cell activation, maturation, and accumulation in the metastatic lung were evaluated by flow cytometry (CD69, CD11b, CD27) and in situ hybridization (Ncr1) using colony-stimulating factor 1 (CSF-1) receptor conditional knockout (Csf1r-cKO) mice. Finally, metastatic tumor loads in the chest region of mice were determined by bioluminescence imaging in order to evaluate the effect of MAM depletion on therapeutic efficacy of endogenous and adoptively transferred NK cells in suppressing metastatic tumor growth.
    RESULTS: MAMs isolated from the metastatic lung suppressed NK cell-induced tumor cell apoptosis in vitro via membrane-bound transforming growth factor β (TGF-β) dependent mechanisms. In the tumor-challenged mice, depletion of MAMs increased the percentage of activated (CD69+) and mature (CD11b+CD27-) NK cells and the number of Ncr1 + NK cells as well as NK cell-mediated tumor rejection in the metastatic site. Moreover, MAM depletion or TGF-β receptor antagonist treatment significantly enhanced the therapeutic efficacy of NK cell infusion in suppressing early metastatic tumor outgrowth.
    CONCLUSION: This study demonstrates that MAMs are a main negative regulator of NK cell function within the metastatic tumor niche, and MAM targeting is an attractive strategy to improve NK cell-based immunotherapy for metastatic breast cancer.
    Keywords:  breast neoplasms; immunotherapy; killer cells; macrophages; natural; tumor microenvironment
    DOI:  https://doi.org/10.1136/jitc-2020-001740
  12. Mol Cell. 2021 Jan 21. pii: S1097-2765(20)30965-5. [Epub ahead of print]81(2): 220-222
    Food for Growth: Distinct Nutrient Preferences between Primary Tumors and Metastases.
    Yannick Audet-Delage, Julie St-Pierre.
      In this issue of Molecular Cell, Rinaldi et al. (2021) reveal how nutrient availability in the metastatic niche of breast cancer cells shapes their growth signaling, highlighting potential avenues for therapeutic interventions.
    DOI:  https://doi.org/10.1016/j.molcel.2020.12.044
  13. J Clin Invest. 2021 Jan 21. pii: 141171. [Epub ahead of print]
    Smoothened-activating lipids drive resistance to CDK4/6 inhibition in Hedgehog-associated medulloblastoma cells and preclinical models.
    Vikas Daggubati, Jordan Hochstetler, Anirudh Bommireddy, Abrar Choudhury, Alexis Leigh Krup, Pervinder K Choksi, Pakteema Tong, Amy Li, Libin Xu, Jeremy F Reiter, David R Raleigh.
      Medulloblastoma is an aggressive pediatric brain tumor that can be driven by misactivation of the Hedgehog (HH) pathway. CDK6 is a critical effector of oncogenic Hedgehog signaling, but attempts to target the Hedgehog pathway in medulloblastoma have been encumbered by resistance to single-agent molecular therapy. We identified resistance mechanisms to CDK6 inhibition in HH-associated medulloblastoma by performing orthogonal CRISPR and CRISPR interference screens in medulloblastoma cells treated with a CDK4/6 inhibitor, and RNA-sequencing of a mouse model of HH-associated medulloblastoma with genetic deletion of Cdk6. Our concordant in vitro and in vivo data revealed decreased ribosomal protein expression underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, leading to endoplasmic reticular (ER) stress and activation of the unfolded protein response (UPR). These pathways increased the activity of enzymes producing Smoothened-activating sterol lipids that sustained oncogenic HH signaling in medulloblastoma despite cell cycle attenuation. Consistently, we demonstrated concurrent genetic deletion or pharmacological inhibition of CDK6 and HSD11ß2, an enzyme producing Smoothened-activating lipids, additively blocked cancer growth in multiple mouse genetic models of HH-associated medulloblastoma. Our data reveal a resistance pathway to CDK4/6 inhibition and a combination therapy to treat the most common malignant brain tumor in children that we believe are novel.
    Keywords:  Cancer; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/JCI141171
  14. Theranostics. 2021 ;11(6): 2860-2875
    Cisplatin-resistant NSCLC cells induced by hypoxia transmit resistance to sensitive cells through exosomal PKM2.
    Dongliang Wang, Chaoshuai Zhao, Fei Xu, Aimi Zhang, Mingming Jin, Kunchi Zhang, Liu Liu, Qian Hua, Jian Zhao, Jianjun Liu, Hao Yang, Gang Huang.
      Hypoxia is commonly observed in solid tumors and contributes to the resistance of DNA damage drugs. However, the mechanisms behind this resistance are still unclear. In this study, we aimed to explore the effects of hypoxia-induced exosomes on non-small cell lung cancer (NSCLC). Methods: NSCLC cells were subjected to either normoxic or hypoxic conditions to assess cell survival and changes in the expression levels of key proteins. Comparative proteomics were performed to identify exosomal PKM2 in normoxic or hypoxic cisplatin-resistant NSCLC cells-derived exosomes. Functions of hypoxia induced-exosomal PKM2 in promoting cisplatin resistance to NSCLC cells were evaluated both in vitro and in vivo experiments and the molecular mechanisms of hypoxia induced-exosomal PKM2 were demonstrated using flow cytometry, immunoblotting, oxidative stress detection and histological examination. A series of in vitro experiments were performed to evaluate the function of hypoxia-induced exosomes on cancer-associated fibroblasts (CAFs). Results: Hypoxia exacerbated the cisplatin resistance in lung cancer cells due to the increased expression of PKM2 that was observed in the exosomes secreted by hypoxic cisplatin-resistance cells. We identified that hypoxia-induced exosomal PKM2 transmitted cisplatin-resistance to sensitive NSCLC cells in vitro and in vivo. Mechanistically, hypoxia-induced exosomal PKM2 promoted glycolysis in NSCLC cells to produce reductive metabolites, which may neutralize reactive oxygen species (ROS) induced by cisplatin. Additionally, hypoxia-induced exosomal PKM2 inhibited apoptosis in a PKM2-BCL2-dependent manner. Moreover, hypoxia-induced exosomal PKM2 reprogrammed CAFs to create an acidic microenvironment promoting NSCLC cells proliferation and cisplatin resistance. Conclusions: Our findings revealed that hypoxia-induced exosomes transmit cisplatin resistance to sensitive NSCLC cells by delivering PKM2. Exosomal PKM2 may serve as a promising biomarker and therapeutic target for cisplatin resistance in NSCLC.
    Keywords:  CAFs; Drug-resistance; Exosomes; NSCLC; PKM2
    DOI:  https://doi.org/10.7150/thno.51797
  15. Cancer Discov. 2021 Jan 22.
    Structures Identify Selpercatinib and Pralsetinib Resistance Mechanisms.
      The crystal structures of these RET-bound TKIs showed that these drugs uniquely wrap around RET.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2021-009
  16. ACS Nano. 2021 Jan 22.
    Immune Reprogramming Precision Photodynamic Therapy of Peritoneal Metastasis by Scalable Stem-Cell-Derived Extracellular Vesicles.
    Amandine Pinto, Iris Marangon, Julie Méreaux, Alba Nicolás-Boluda, Grégory Lavieu, Claire Wilhelm, Laure Sarda-Mantel, Amanda K A Silva, Marc Pocard, Florence Gazeau.
      The dissemination of tumor metastasis in the peritoneal cavity, also called peritoneal metastasis (PM) or carcinomatosis, represents a late stage of gastrointestinal and gynecological cancer with very poor prognosis, even when cytoreductive surgery is effective, due to residual microscopic disease. Photodynamic therapy (PDT) in the management of peritoneal metastasis has been clinically limited by the low tumor selectivity of photosensitizers (PS) and important adverse effects. Here, we propose extracellular nanovesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) as the fourth generation of immune active PS vectors that are able to target peritoneal metastasis with superior selectivity, potentiate PDT cytotoxicity at the tumor site without affecting healthy tissues, modulate the tumor microenvironment of immunocompetent colorectal and ovarian carcinomatosis models, and promote an antitumor immune response. A pioneering strategy was developed for high yield, large-scale production of MSC-EVs encapsulating the drug meta(tetrahydroxyphenyl)chlorin (mTHPC) (EVs-mTHPC) that is compatible with requirements of clinical translation and also preserves the topology and integrity of naturally produced EVs. Intraperitoneal injection of EVs-mTHPC showed an impressive enhancement of tumoral selectivity in comparison to the free drug and to the liposomal formulation Foslip (mean ratio of PS in tumors/organs of 40 for EVs-mTHPC versus 1.5 for the free PS and 5.5 for Foslip). PDT mediated by EVs-mTHPC permitted an important tumoral necrosis (55% of necrotic tumoral nodules versus 18% for Foslip (p < 0.0001)) and promoted antitumor immune cell infiltration, mainly proinflammatory M1-like CD80+ and CD8+ T cell effector. Intratumor proliferation was significantly decreased after PDT with EVs-mTHPC. Overall EVs vectorization of mTHPC afforded important tumoral selectivity while overcoming the PDT toxicity of the free drug and prolonged mice survival in the colorectal carcinomatosis model. MSC-EVs produced by our scalable manufacturing method appears like the clinically relevant fourth-generation PDT vehicle to overcome current limitations of PDT in the treatment of peritoneal metastasis and promote a hot tumor immune environment in PM.
    Keywords:  antitumor immune response; carcinomatosis; extracellular vesicles; liposome; metastasis; photodynamic therapy; vectorization
    DOI:  https://doi.org/10.1021/acsnano.0c09938
  17. Science. 2021 Jan 21. pii: eabc1944. [Epub ahead of print]
    Single-cell lineages reveal the rates, routes, and drivers of metastasis in cancer xenografts.
    Jeffrey J Quinn, Matthew G Jones, Ross A Okimoto, Shigeki Nanjo, Michelle M Chan, Nir Yosef, Trever G Bivona, Jonathan S Weissman.
      Detailed phylogenies of tumor populations can recount the history and chronology of critical events during cancer progression, such as metastatic dissemination. We applied a Cas9-based, single-cell lineage tracer to study the rates, routes, and drivers of metastasis in a lung cancer xenograft mouse model. We report deeply resolved phylogenies for tens of thousands of cancer cells traced over months of growth and dissemination. This revealed stark heterogeneity in metastatic capacity, arising from pre-existing and heritable differences in gene expression. We demonstrate that these identified genes can drive invasiveness, and uncovered an unanticipated suppressive role for KRT17 We also show that metastases disseminated via multidirectional tissue routes and complex seeding topologies. Overall, we demonstrate the power of tracing cancer progression at subclonal resolution and vast scale.
    DOI:  https://doi.org/10.1126/science.abc1944
  18. Theranostics. 2021 ;11(6): 2581-2593
    N6-methyladenosine as a biological and clinical determinant in colorectal cancer: progression and future direction.
    Jinming Li, Lei Liang, Yongzhi Yang, Xinxiang Li, Yanlei Ma.
      Colorectal cancer (CRC) is one of the most prevalent cancers and one of the leading causes of cancer death. Recent studies have provided evidence that N6-methyladenosine (m6A), the most abundant RNA modifications in eukaryote, performs many functions in RNA metabolism including translation, splicing, storage, trafficking and degradation. Aberrant regulation of m6A modification in mRNAs and noncoding RNAs found in CRC tissues is crucial for cancer formation, progression, invasion and metastasis. Further, m6A regulators and m6A-related RNAs may become promising biomarkers, prognosis predictors as well as therapeutic targets. Here, we review the biological and clinical roles of m6A modification in CRC, and discuss the potential of m6A in clinical translation.
    Keywords:  RNA modification; cancer progression; cancer treatment; colorectal cancer; m6A
    DOI:  https://doi.org/10.7150/thno.52366
  19. Cancer Cell. 2021 Jan 05. pii: S1535-6108(20)30662-0. [Epub ahead of print]
    Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities.
    Carl M Gay, C Allison Stewart, Elizabeth M Park, Lixia Diao, Sarah M Groves, Simon Heeke, Barzin Y Nabet, Junya Fujimoto, Luisa M Solis, Wei Lu, Yuanxin Xi, Robert J Cardnell, Qi Wang, Giulia Fabbri, Kasey R Cargill, Natalie I Vokes, Kavya Ramkumar, Bingnan Zhang, Carminia M Della Corte, Paul Robson, Stephen G Swisher, Jack A Roth, Bonnie S Glisson, David S Shames, Ignacio I Wistuba, Jing Wang, Vito Quaranta, John Minna, John V Heymach, Lauren Averett Byers.
      Despite molecular and clinical heterogeneity, small cell lung cancer (SCLC) is treated as a single entity with predictably poor results. Using tumor expression data and non-negative matrix factorization, we identify four SCLC subtypes defined largely by differential expression of transcription factors ASCL1, NEUROD1, and POU2F3 or low expression of all three transcription factor signatures accompanied by an Inflamed gene signature (SCLC-A, N, P, and I, respectively). SCLC-I experiences the greatest benefit from the addition of immunotherapy to chemotherapy, while the other subtypes each have distinct vulnerabilities, including to inhibitors of PARP, Aurora kinases, or BCL-2. Cisplatin treatment of SCLC-A patient-derived xenografts induces intratumoral shifts toward SCLC-I, supporting subtype switching as a mechanism of acquired platinum resistance. We propose that matching baseline tumor subtype to therapy, as well as manipulating subtype switching on therapy, may enhance depth and duration of response for SCLC patients.
    Keywords:  ASCL1; EMT; NEUROD1; POU2F3; SCLC; intratumoral heterogeneity; neuroendocrine
    DOI:  https://doi.org/10.1016/j.ccell.2020.12.014
  20. Cell Death Differ. 2021 Jan 18.
    Single-cell RNA sequencing reveals intratumoral heterogeneity in primary uveal melanomas and identifies HES6 as a driver of the metastatic disease.
    Charlotte Pandiani, Thomas Strub, Nicolas Nottet, Yann Cheli, Giovanni Gambi, Karine Bille, Chrystel Husser, Mélanie Dalmasso, Guillaume Béranger, Sandra Lassalle, Virginie Magnone, Florence Pédeutour, Marie Irondelle, Célia Maschi, Sacha Nahon-Estève, Arnaud Martel, Jean-Pierre Caujolle, Paul Hofman, Kévin LeBrigand, Irwin Davidson, Stéphanie Baillif, Pascal Barbry, Robert Ballotti, Corine Bertolotto.
      Intratumor heterogeneity has been recognized in numerous cancers as a major source of metastatic dissemination. In uveal melanomas, the existence and identity of specific subpopulations, their biological function and their contribution to metastasis remain unknown. Here, in multiscale analyses using single-cell RNA sequencing of six different primary uveal melanomas, we uncover an intratumoral heterogeneity at the genomic and transcriptomic level. We identify distinct transcriptional cell states and diverse tumor-associated populations in a subset of the samples. We also decipher a gene regulatory network underlying an invasive and poor prognosis state driven in part by the transcription factor HES6. HES6 heterogenous expression has been validated by RNAscope assays within primary human uveal melanomas, which further unveils the existence of these cells conveying a dismal prognosis in tumors diagnosed with a favorable outcome using bulk analyses. Depletion of HES6 impairs proliferation, migration and metastatic dissemination in vitro and in vivo using the chick chorioallantoic membrane assay, demonstrating the essential role of HES6 in uveal melanomas. Thus, single-cell analysis offers an unprecedented view of primary uveal melanoma heterogeneity, identifies bona fide biomarkers for metastatic cells in the primary tumor, and reveals targetable modules driving growth and metastasis formation. Significantly, our findings demonstrate that HES6 is a valid target to stop uveal melanoma progression.
    DOI:  https://doi.org/10.1038/s41418-020-00730-7
  21. Trends Cancer. 2021 Jan 16. pii: S2405-8033(20)30338-1. [Epub ahead of print]
    Roles and Regulations of TET Enzymes in Solid Tumors.
    Julie K Bray, Meelad M Dawlaty, Amit Verma, Anirban Maitra.
      The mechanisms governing the methylome profile of tumor suppressors and oncogenes have expanded with the discovery of oxidized states of 5-methylcytosine (5mC). Ten-eleven translocation (TET) enzymes are a family of dioxygenases that iteratively catalyze 5mC oxidation and promote cytosine demethylation, thereby creating a dynamic global and local methylation landscape. While the catalytic function of TET enzymes during stem cell differentiation and development have been well studied, less is known about the multifaceted roles of TET enzymes during carcinogenesis. This review outlines several tiers of TET regulation and overviews how TET deregulation promotes a cancer phenotype. Defining the tissue-specific and context-dependent roles of TET enzymes will deepen our understanding of the epigenetic perturbations that promote or inhibit carcinogenesis.
    Keywords:  5-hydroxymethylcytosine; carcinogenesis; epigenetics; ten-eleven translocation
    DOI:  https://doi.org/10.1016/j.trecan.2020.12.011
  22. Theranostics. 2021 ;11(6): 2722-2741
    Significance of serglycin and its binding partners in autocrine promotion of metastasis in esophageal cancer.
    Yun Zhu, Alfred K Y Lam, Daisy K Y Shum, Di Cui, Jun Zhang, Dong Dong Yan, Bin Li, Wen Wen Xu, Nikki P Y Lee, Kin Tak Chan, Simon Law, Sai Wah Tsao, Annie L M Cheung.
      Rationale: Little is known about the roles of proteoglycans in esophageal cancer. This study aims to investigate the roles and mechanisms of serglycin (SRGN) proteoglycan in promoting metastasis of esophageal squamous cell carcinoma (ESCC). Methods: Reverse phase protein array analysis was used to identify activated signaling pathways in SRGN-overexpressing cells. Chemokine array was used to identify differentially secreted factors from SRGN-overexpressing cells. Binding between SRGN and potential interacting partners was evaluated using proximity ligation assay and co-immunoprecipitation. The glycosaminoglycan (GAG) chains of SRGN were characterized using fluorophore-assisted carbohydrate electrophoresis. Tissue microarray and serum samples were used to determine the correlation of SRGN expression with clinicopathological parameters and patient survival. Results: In vitro and in vivo experiments showed that SRGN promoted invasion and metastasis in ESCC via activating ERK pathway, stabilizing c-Myc and upregulating the secretion of matrix metalloproteinases. SRGN-knockdown suppressed tumorigenic hallmarks. These SRGN-elicited functions were carried out in an autocrine manner by inducing the secretion of midkine (MDK), which was further identified as a novel binding partner of SRGN for the formation of a SRGN/MDK/CD44 complex. In addition, SRGN interacted with MDK and matrix metalloproteinase 2 in ESCC via its GAG chains, which were mainly decorated with chondroitin sulfate comprising of ∆di-4S and ∆di-6S CS. Clinically, high expression of serum SRGN in serum of patients with ESCC was an independent prognostic marker for poor survival. Conclusions: This study provides the first evidence that elevated serum SRGN has prognostic significance in patients with ESCC, and sheds light on the molecular mechanism by which elevated circulating SRGN in cancer patients might promote cancer progression.
    Keywords:  Serglycin; biomarker; esophageal squamous cell carcinoma; metastasis; midkine
    DOI:  https://doi.org/10.7150/thno.49547
  23. Nat Rev Genet. 2021 Feb;22(2): 69
    Mapping metastasis.
    Dorothy Clyde.
      
    DOI:  https://doi.org/10.1038/s41576-020-00319-3
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