bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021–10–31
fourteen papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. ABL allosteric inhibitors synergize with statins to enhance apoptosis of metastatic lung cancer cells.
  2. Circ0008399 interaction with WTAP promotes assembly and activity of the m6A methyltransferase complex and promotes cisplatin resistance in bladder cancer.
  3. Transcriptional reprogramming differentiates active from inactive ESR1 fusions in endocrine therapy-refractory metastatic breast cancer.
  4. Lung mesenchymal stromal cells influenced by Th2 cytokines mobilize neutrophils and facilitate metastasis by producing complement C3.
  5. Working together: Heterotypic clusters and collective cell migration in melanoma metastasis.
  6. NKX2-1 controls lung cancer progression by inducing DUSP6 to dampen ERK activity.
  7. Heterogeneity of circulating tumor cell-associated genomic gains in breast cancer and its association with the host immune response.
  8. Serial single-cell genomics reveals convergent subclonal evolution of resistance as early-stage breast cancer patients progress on endocrine plus CDK4/6 therapy.
  9. CSF2-STAT5 Signaling in TAMs Contributes to CSF1R Inhibition Resistance.
  10. Aberrant transcript usage is associated with homologous recombination deficiency and predicts therapeutic response.
  11. Metabolic memory underlying minimal residual disease in breast cancer.
  12. RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy.
  13. Novel temporal and spatial patterns of metastatic colonization from breast cancer rapid-autopsy tumor biopsies.
  14. Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse.
  1. Cell Rep. 2021 Oct 26. pii: S2211-1247(21)01350-4. [Epub ahead of print]37(4): 109880
    ABL allosteric inhibitors synergize with statins to enhance apoptosis of metastatic lung cancer cells.
    Jillian Hattaway Luttman, Jacob P Hoj, Kevin H Lin, Jiaxing Lin, Jing Jin Gu, Clay Rouse, Amanda G Nichols, Nancie J MacIver, Kris C Wood, Ann Marie Pendergast.
      Targeting mitochondrial metabolism has emerged as a treatment option for cancer patients. The ABL tyrosine kinases promote metastasis, and enhanced ABL signaling is associated with a poor prognosis in lung adenocarcinoma patients. Here we show that ABL kinase allosteric inhibitors impair mitochondrial integrity and decrease oxidative phosphorylation. To identify metabolic vulnerabilities that enhance this phenotype, we utilized a CRISPR/Cas9 loss-of-function screen and identified HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway and target of statin therapies, as a top-scoring sensitizer to ABL inhibition. Combination treatment with ABL allosteric inhibitors and statins decreases metastatic lung cancer cell survival in vitro in a synergistic manner. Notably, combination therapy in mouse models of lung cancer brain metastasis and therapy resistance impairs metastatic colonization with a concomitant increase in animal survival. Thus, metabolic combination therapy might be effective to decrease metastatic outgrowth, leading to increased survival for lung cancer patients with advanced disease.
    Keywords:  ABL kinases; HMGCR; brain metastasis; lung adenocarcinoma; statins; therapy resistance
    DOI:  https://doi.org/10.1016/j.celrep.2021.109880
  2. Cancer Res. 2021 Oct 26. pii: canres.1518.2021. [Epub ahead of print]
    Circ0008399 interaction with WTAP promotes assembly and activity of the m6A methyltransferase complex and promotes cisplatin resistance in bladder cancer.
    Wenjie Wei, Jiayin Sun, Hui Zhang, Xingyuan Xiao, Chao Huang, Liang Wang, He Zhong, Yangkai Jiang, Xiaoping Zhang, Guosong Jiang.
      Cisplatin (CDDP)-based chemotherapy is the first-line treatment for muscle-invasive and metastatic bladder cancer (BC), yet most patients rapidly develop resistance. N6-methyladenosine (m6A) methylation is a pervasive RNA modification, and its specific role and potential mechanism in the regulation of CDDP chemosensitivity in BC remain unclear. Furthermore, studies have not yet fully elucidated whether circRNA can directly regulate m6A modification of mRNA. Here we report upregulation of a novel circRNA, hsa_circ_0008399 (circ0008399), by eukaryotic translation initiation factor 4A3 (EIF4A3) in BC tissues and cell lines. Functionally, circ0008399 inhibited apoptosis of BC cells. Mechanistically, circ0008399 bound Wilms' tumor 1-associating protein (WTAP) to promote formation of the WTAP/METTL3/METTL14 m6A methyltransferase complex. Circ0008399 increased expression of TNF alpha-induced protein 3 (TNFAIP3) by increasing its mRNA stability in an m6A-dependent manner. In BC patients, high expression of circ0008399 and WTAP was associated with poor outcomes. Importantly, activation of the circ0008399/WTAP/TNFAIP3 pathway decreased BC chemosensitivity to CDDP, and targeting the circ0008399/WTAP/TNFAIP3 axis enhanced the CDDP efficacy. Collectively, these findings give novel insights into circRNA-mediated regulation of m6A modifications and provide potential therapeutic targets for BC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-1518
  3. Cancer Res. 2021 Oct 28. pii: canres.CAN-21-1256-E.2021. [Epub ahead of print]
    Transcriptional reprogramming differentiates active from inactive ESR1 fusions in endocrine therapy-refractory metastatic breast cancer.
    Xuxu Gou, Meenakshi Anurag, Jonathan T Lei, Beom-Jun Kim, Purba Singh, Sinem Seker, Diana Fandino, Airi Han, Saif Rehman, Jianhong Hu, Viktoriya Korchina, Harshavardhan Doddapaneni, Lacey E Dobrolecki, Nicholas Mitsiades, Michael T Lewis, Alana L Welm, Shunqiang Li, Adrian V Lee, Dan R Robinson, Charles E Foulds, Matthew J Ellis.
      Genomic analysis has recently identified multiple ESR1 gene translocations in estrogen receptor-alpha positive (ERα+) metastatic breast cancer (MBC) that encode chimeric proteins whereby the ESR1 ligand binding domain (LBD) is replaced by C-terminal sequences from many different gene partners. Here we functionally screened 15 ESR1 fusions and identified 10 that promoted estradiol-independent cell growth, motility, invasion, EMT and resistance to fulvestrant. RNA sequencing identified a gene expression pattern specific to functionally active ESR1 gene fusions that was subsequently reduced to a diagnostic 24-gene signature. This signature was further examined in 20 ERα+ patient-derived xenografts (PDXs) and in 55 ERα+ MBC samples. The 24-gene signature successfully identified cases harboring ESR1 gene fusions and also accurately diagnosed the presence of activating ESR1 LBD point mutations. Therefore, the 24-gene signature represents an efficient approach to screening samples for the presence of diverse somatic ESR1 mutations and translocations that drive endocrine treatment failure in MBC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-1256
  4. Nat Commun. 2021 Oct 27. 12(1): 6202
    Lung mesenchymal stromal cells influenced by Th2 cytokines mobilize neutrophils and facilitate metastasis by producing complement C3.
    Zhiyuan Zheng, Ya-Nan Li, Shanfen Jia, Mengting Zhu, Lijuan Cao, Min Tao, Jingting Jiang, Shenghua Zhan, Yongjing Chen, Ping-Jin Gao, Weiguo Hu, Ying Wang, Changshun Shao, Yufang Shi.
      Pre-metastatic niche formation is critical for the colonization of disseminated cancer cells in distant organs. Here we find that lung mesenchymal stromal cells (LMSCs) at pre-metastatic stage possess potent metastasis-promoting activity. RNA-seq reveals an upregulation of complement 3 (C3) in those LMSCs. C3 is found to promote neutrophil recruitment and the formation of neutrophil extracellular traps (NETs), which facilitate cancer cell metastasis to the lungs. C3 expression in LMSCs is induced and sustained by Th2 cytokines in a STAT6-dependent manner. LMSCs-driven lung metastasis is abolished in Th1-skewing Stat6-deficient mice. Blockade of IL-4 by antibody also attenuates LMSCs-driven cancer metastasis to the lungs. Consistently, metastasis is greatly enhanced in Th2-skewing T-bet-deficient mice or in nude mice adoptively transferred with T-bet-deficient T cells. Increased C3 levels are also detected in breast cancer patients. Our results suggest that targeting the Th2-STAT6-C3-NETs cascade may reduce breast cancer metastasis to the lungs.
    DOI:  https://doi.org/10.1038/s41467-021-26460-z
  5. Dev Cell. 2021 Oct 25. pii: S1534-5807(21)00804-2. [Epub ahead of print]56(20): 2783-2784
    Working together: Heterotypic clusters and collective cell migration in melanoma metastasis.
    William T Frantz, Craig J Ceol.
      In this issue of Developmental Cell, Campbell et al. (2021) show that melanoma cells with distinct invasive or proliferative gene signatures can form heterotypic clusters that extravasate collectively and readily seed the growth of metastatic lesions. These findings highlight interactions between heterogenous tumor cells as being critical for metastasis.
    DOI:  https://doi.org/10.1016/j.devcel.2021.10.003
  6. Oncogene. 2021 Oct 23.
    NKX2-1 controls lung cancer progression by inducing DUSP6 to dampen ERK activity.
    Kelley Ingram, Shiela C Samson, Rediet Zewdu, Rebecca G Zitnay, Eric L Snyder, Michelle C Mendoza.
      The RAS→RAF→MEK→ERK pathway is hyperactivated in the majority of human lung adenocarcinoma (LUAD). However, the initial activating mutations induce homeostatic feedback mechanisms that limit ERK activity. How ERK activation reaches the tumor-promoting levels that overcome the feedback and drive malignant progression is unclear. We show here that the lung lineage transcription factor NKX2-1 suppresses ERK activity. In human tissue samples and cell lines, xenografts, and genetic mouse models, NKX2-1 induces the ERK phosphatase DUSP6, which inactivates ERK. In tumor cells from late-stage LUAD with silenced NKX2-1, re-introduction of NKX2-1 induces DUSP6 and inhibits tumor growth and metastasis. We show that DUSP6 is necessary for NKX2-1-mediated inhibition of tumor progression in vivo and that DUSP6 expression is sufficient to inhibit RAS-driven LUAD. Our results indicate that NKX2-1 silencing, and thereby DUSP6 downregulation, is a mechanism by which early LUAD can unleash ERK hyperactivation for tumor progression.
    DOI:  https://doi.org/10.1038/s41388-021-02076-x
  7. Cancer Res. 2021 Oct 28. pii: canres.CAN-21-1079-A.2021. [Epub ahead of print]
    Heterogeneity of circulating tumor cell-associated genomic gains in breast cancer and its association with the host immune response.
    Susan J Done, Nisha Kanwar, Zaldy Balde, Ranju Nair, Melanie Dawe, Shiyi Chen, Manjula Maganti, Eshetu G Atenafu, Sabrina Manolescu, Carrie X Wei, Amanda Mao, Fred Fu, Dan Wang, Alison Cheung, Yulia Yerofeyeva, Rachel Peters, Kela Liu, Christine Desmedt, Christos Sotiriou, Borbala Szekely, Janina Kulka, Trevor D McKee, Naoto Hirano, John M S Bartlett, Martin J Yaffe, Philippe L Bedard, David McCready.
      Tumor cells that preferentially enter circulation include the precursors of metastatic cancer. Previously, we characterized circulating tumor cells (CTC) from patients with breast cancer and identified a signature of genomic regions with recurrent copy number gains. Through fluorescence in situ hybridization, we now show that these CTC-associated regions are detected within the matched untreated primary tumors of these patients (21-69%, median 55.5%, n=19). Furthermore, they are more prevalent in the metastases of patients who died from breast cancer after multiple rounds of treatment (70-100%, median 93%, n=41). Diversity indices revealed that higher spatial heterogeneity for these regions within primary tumors is associated with increased dissemination and metastasis. An identified subclone with multiple regions gained (MRG clone) was enriched in a post-treatment primary breast carcinoma as well as multiple metastatic tumors and local breast recurrences obtained at autopsy, indicative of a distinct early subclone with the capability to resist multiple lines of treatment and eventually cause death. Additionally, multiplex immunofluorescence revealed that tumor heterogeneity is significantly associated with the degree of infiltration of B lymphocytes in triple-negative breast cancer, a subtype with a large immune component. Collectively, these data reveal the functional potential of genetic subclones that comprise heterogeneous primary breast carcinomas and are selected for in CTCs and post-treatment breast cancer metastases. In addition, they uncover a relationship between tumor heterogeneity and host immune response in the tumor microenvironment.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-1079
  8. Nat Cancer. 2021 Jun;2(6): 658-671
    Serial single-cell genomics reveals convergent subclonal evolution of resistance as early-stage breast cancer patients progress on endocrine plus CDK4/6 therapy.
    Jason I Griffiths, Jinfeng Chen, Patrick A Cosgrove, Anne O'Dea, Priyanka Sharma, Cynthia Ma, Meghna Trivedi, Kevin Kalinsky, Kari B Wisinski, Ruth O'Regan, Issam Makhoul, Laura M Spring, Aditya Bardia, Frederick R Adler, Adam L Cohen, Jeffrey T Chang, Qamar J Khan, Andrea H Bild.
      Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for metastatic estrogen receptor positive (ER+) breast cancer patients but its value in earlier stage patients is unclear. We examined evolutionary trajectories of early-stage breast cancer tumors, using single cell RNA sequencing (scRNAseq) of serial biopsies from the FELINE clinical trial (#NCT02712723) of endocrine therapy (letrozole) alone or combined with the CDK inhibitor ribociclib. Despite differences in subclonal diversity evolution across patients and treatments, common resistance phenotypes emerged. Resistant tumors treated with combination therapy showed accelerated loss of estrogen signaling with convergent up-regulation of JNK signaling through growth factor receptors. In contrast, cancer cells maintaining estrogen signaling during mono- or combination therapy showed potentiation of CDK4/6 activation and ERK upregulation through ERBB4 signaling. These results indicate that combination therapy in early-stage ER+ breast cancer leads to emergence of resistance through a shift from estrogen to alternative growth signal-mediated proliferation.
    DOI:  https://doi.org/10.1038/s43018-021-00215-7
  9. Cancer Discov. 2021 Oct 29.
    CSF2-STAT5 Signaling in TAMs Contributes to CSF1R Inhibition Resistance.
      CSF1R inhibition combined with STAT5 blockade normalized TAM phenotype and sustained tumor control.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2021-155
  10. Cancer Res. 2021 Oct 28. pii: canres.2023.2021. [Epub ahead of print]
    Aberrant transcript usage is associated with homologous recombination deficiency and predicts therapeutic response.
    Hyeon Gu Kang, Haeun Hwangbo, Myung Ji Kim, Sinae Kim, Eun Ji Lee, Min Ji Park, Jae-Weon Kim, Byoung-Gie Kim, Eun-Hae Cho, Suhwan Chang, Jung-Yun Lee, Jung Kyoon Choi.
      BRCA1/2 mutations account for only a small fraction of homologous recombination (HR) deficiency (HRD) cases. Recently developed genomic HRD (gHRD) tests suffer confounding factors that cause low precision in predicting samples that will respond to PARP inhibitors and DNA damaging agents. Here we present molecular and clinical evidence of transcriptional HRD (tHRD) that is based on aberrant transcript usage (TU) of minor isoforms. Specifically, increased TU of non-functional isoforms of DNA repair genes was prevalent in breast and ovarian cancer with gHRD. Functional assays validated the association of aberrant TU with impaired HR activity. Machine learning-based tHRD detection by the TU pattern of key genes was superior to directly screening for gHRD or BRCA1/2 mutations in accurately predicting responses of cell lines and cancer patients to PARP inhibitors and genotoxic drugs. This approach demonstrated the capability of tHRD status to reflect functional HR status, including in a cohort of olaparib treated ovarian cancer with acquired platinum resistance. Diagnostic tests based on tHRD are expected to broaden the clinical utility of PARP inhibitors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-2023
  11. Mol Syst Biol. 2021 Oct;17(10): e10141
    Metabolic memory underlying minimal residual disease in breast cancer.
    Ksenija Radic Shechter, Eleni Kafkia, Katharina Zirngibl, Sylwia Gawrzak, Ashna Alladin, Daniel Machado, Christian Lüchtenborg, Daniel C Sévin, Britta Brügger, Kiran R Patil, Martin Jechlinger.
      Tumor relapse from treatment-resistant cells (minimal residual disease, MRD) underlies most breast cancer-related deaths. Yet, the molecular characteristics defining their malignancy have largely remained elusive. Here, we integrated multi-omics data from a tractable organoid system with a metabolic modeling approach to uncover the metabolic and regulatory idiosyncrasies of the MRD. We find that the resistant cells, despite their non-proliferative phenotype and the absence of oncogenic signaling, feature increased glycolysis and activity of certain urea cycle enzyme reminiscent of the tumor. This metabolic distinctiveness was also evident in a mouse model and in transcriptomic data from patients following neo-adjuvant therapy. We further identified a marked similarity in DNA methylation profiles between tumor and residual cells. Taken together, our data reveal a metabolic and epigenetic memory of the treatment-resistant cells. We further demonstrate that the memorized elevated glycolysis in MRD is crucial for their survival and can be targeted using a small-molecule inhibitor without impacting normal cells. The metabolic aberrances of MRD thus offer new therapeutic opportunities for post-treatment care to prevent breast tumor recurrence.
    Keywords:  glycolysis; metabolic modeling; multi-omics integration; oncogenic memory; organoids
    DOI:  https://doi.org/10.15252/msb.202010141
  12. Elife. 2021 Oct 27. pii: e65759. [Epub ahead of print]10
    RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy.
    Tomasz Radaszkiewicz, Michaela Nosková, Kristína Gömöryová, Olga Vondálová Blanářová, Katarzyna Anna Radaszkiewicz, Markéta Picková, Ráchel Víchová, Tomáš Gybeľ, Karol Kaiser, Lucia Demková, Lucia Kučerová, Tomáš Bárta, David Potěšil, Zbyněk Zdráhal, Karel Souček, Vítězslav Bryja.
      RNF43 is an E3 ubiquitin ligase and known negative regulator of WNT/β-catenin signaling. We demonstrate that RNF43 is also a regulator of noncanonical WNT5A-induced signaling in human cells. Analysis of the RNF43 interactome using BioID and immunoprecipitation showed that RNF43 can interact with the core receptor complex components dedicated to the noncanonical Wnt pathway such as ROR1, ROR2, VANGL1, and VANGL2. RNF43 triggers VANGL2 ubiquitination and proteasomal degradation and clathrin-dependent internalization of ROR1 receptor and inhibits ROR2 activation. These activities of RNF43 are physiologically relevant and block pro-metastatic WNT5A signaling in melanoma. RNF43 inhibits responses to WNT5A, which results in the suppression of invasive properties of melanoma cells. Furthermore, RNF43 prevented WNT5A-assisted development of resistance to BRAF V600E and MEK inhibitors. Next, RNF43 acted as melanoma suppressor and improved response to targeted therapies in vivo. In line with these findings, RNF43 expression decreases during melanoma progression and RNF43-low patients have a worse prognosis. We conclude that RNF43 is a newly discovered negative regulator of WNT5A-mediated biological responses that desensitizes cells to WNT5A.
    Keywords:  BRAF V600E; RNF43; ROR1; VANGL1; WNT5A; cancer biology; cell biology; human; melanoma; mouse
    DOI:  https://doi.org/10.7554/eLife.65759
  13. Genome Med. 2021 Oct 28. 13(1): 170
    Novel temporal and spatial patterns of metastatic colonization from breast cancer rapid-autopsy tumor biopsies.
    Xiaomeng Huang, Yi Qiao, Samuel W Brady, Rachel E Factor, Erinn Downs-Kelly, Andrew Farrell, Jasmine A McQuerry, Gajendra Shrestha, David Jenkins, W Evan Johnson, Adam L Cohen, Andrea H Bild, Gabor T Marth.
       BACKGROUND: Metastatic breast cancer is a deadly disease with a low 5-year survival rate. Tracking metastatic spread in living patients is difficult and thus poorly understood.
    METHODS: Via rapid autopsy, we have collected 30 tumor samples over 3 timepoints and across 8 organs from a triple-negative metastatic breast cancer patient. The large number of sites sampled, together with deep whole-genome sequencing and advanced computational analysis, allowed us to comprehensively reconstruct the tumor's evolution at subclonal resolution.
    RESULTS: The most unique, previously unreported aspect of the tumor's evolution that we observed in this patient was the presence of "subclone incubators," defined as metastatic sites where substantial tumor evolution occurs before colonization of additional sites and organs by subclones that initially evolved at the incubator site. Overall, we identified four discrete waves of metastatic expansions, each of which resulted in a number of new, genetically similar metastasis sites that also enriched for particular organs (e.g., abdominal vs bone and brain). The lung played a critical role in facilitating metastatic spread in this patient: the lung was the first site of metastatic escape from the primary breast lesion, subclones at this site were likely the source of all four subsequent metastatic waves, and multiple sites in the lung acted as subclone incubators. Finally, functional annotation revealed that many known drivers or metastasis-promoting tumor mutations in this patient were shared by some, but not all metastatic sites, highlighting the need for more comprehensive surveys of a patient's metastases for effective clinical intervention.
    CONCLUSIONS: Our analysis revealed the presence of substantial tumor evolution at metastatic incubator sites in a patient, with potentially important clinical implications. Our study demonstrated that sampling of a large number of metastatic sites affords unprecedented detail for studying metastatic evolution.
    Keywords:  Metastatic breast cancer; Subclone; Tumor evolution
    DOI:  https://doi.org/10.1186/s13073-021-00989-6
  14. Nat Commun. 2021 Oct 29. 12(1): 6248
    Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse.
    Michael Fraser, Julie Livingstone, Jeffrey L Wrana, Antonio Finelli, Housheng Hansen He, Theodorus van der Kwast, Alexandre R Zlotta, Robert G Bristow, Paul C Boutros.
      Driver gene mutations that are more prevalent in metastatic, castration-resistant prostate cancer (mCRPC) than localized disease represent candidate prognostic biomarkers. We analyze 1,844 localized (1,289) or mCRPC (555) tumors and quantify the prevalence of 113 somatic driver single nucleotide variants (SNVs), copy number aberrations (CNAs), and structural variants (SVs) in each state. One-third are significantly more prevalent in mCRPC than expected while a quarter are less prevalent. Mutations in AR and its enhancer are more prevalent in mCRPC, as are those in TP53, MYC, ZNRF3 and PRKDC. ZNRF3 loss is associated with decreased ZNRF3 mRNA abundance, WNT, cell cycle & PRC1/2 activity, and genomic instability. ZNRF3 loss, RNA downregulation and hypermethylation are prognostic of metastasis and overall survival, independent of clinical and pathologic indices. These data demonstrate a strategy for identifying biomarkers of localized cancer aggression, with ZNRF3 loss as a predictor of metastasis in prostate cancer.
    DOI:  https://doi.org/10.1038/s41467-021-26489-0
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