bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒10‒18
28 papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology


  1. Cancers (Basel). 2020 Oct 12. pii: E2938. [Epub ahead of print]12(10):
    Siraj S, Masoodi T, Siraj AK, Azam S, Qadri Z, Ahmed SO, AlBalawy WN, Al-Obaisi KA, Parvathareddy SK, AlManea HM, AlHussaini HF, Abduljabbar A, Alhomoud S, Al-Dayel FH, Alkuraya FS, Al-Kuraya KS.
      Colorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide, where ~50% of patients develop metastasis, despite current improved management. Genomic characterisation of metastatic CRC, and elucidating the effects of therapy on the metastatic process, are essential to help guide precision medicine. Multi-region whole-exome sequencing was performed on 191 sampled tumour regions of patient-matched therapy-naïve and treated CRC primary tumours (n = 92 tumour regions) and metastases (n = 99 tumour regions), in 30 patients. Somatic variants were analysed to define the origin, composition, and timing of seeding in the metastatic progression of therapy-naïve and treated metastatic CRC. High concordance, with few genomic differences, was observed between primary CRC and metastases. Most cases supported a late dissemination model, via either monoclonal or polyclonal seeding. Polyclonal seeding appeared more common in therapy-naïve metastases than in treated metastases. Whereby, treatment prompted for the selection of distinct resistant clones, through monoclonal seeding to distant metastatic sites. Overall, this study reinforces the importance of early clinical detection and surgical excision of the CRC tumour, whilst further highlighting the clinical challenges for metastatic CRC with increased intratumour heterogeneity (either due to early dissemination or polyclonal metastatic spread) and the underlying risk of future therapeutic resistance in treated patients.
    Keywords:  clonal evolution; clonal spread; colorectal cancer; metastasis; timing; treatment; tumour heterogeneity
    DOI:  https://doi.org/10.3390/cancers12102938
  2. Theranostics. 2020 ;10(24): 11092-11109
    Lian B, Pei YC, Jiang YZ, Xue MZ, Li DQ, Li XG, Zheng YZ, Liu XY, Qiao F, Sun WL, Ling H, He M, Yao L, Hu X, Shao ZM.
      Rationale: Paclitaxel resistance is a major concern when treating triple-negative breast cancer (TNBC) patients. We aimed to identify candidates causing paclitaxel resistance and explore their significance in TNBC therapeutics. Methods: A genome-wide CRISPR screening, integrated with transcriptome analyses, was performed to identify candidates involved in paclitaxel-resistant TNBCs. Cell proliferation, cytotoxicity, immunofluorescent staining, and xenograft assays were conducted to verify the phenotypes of paclitaxel resistance induced by candidate genes, both in vitro and in vivo. RNA sequencing, Western blotting, and chromatin immunoprecipitation assays were used to explore the underlying mechanisms. Results: MEF2-interacting transcriptional repressor (MITR), the truncated isoform of histone deacetylase 9 (HDAC9) lacking the deacetylation domain, was enriched in paclitaxel-resistant cells. Elevated MITR expression resulted in increased interleukin-11 (IL11) expression and activation of downstream JAK/STAT3 signaling. Mechanistically, MITR counteracted MEF2A-induced transcriptional suppression of IL11, ultimately causing paclitaxel resistance. By contrast, pharmacological inhibition of JAK1/2 by ruxolitinib reversed paclitaxel resistance both in vitro and in vivo. Conclusion: Our in vitro and in vivo genetic and cellular analyses elucidated the pivotal role of MITR/MEF2A/IL11 axis in paclitaxel resistance and provided a novel therapeutic strategy for TNBC patients to overcome poor chemotherapy responses.
    Keywords:  CRISPR screen; HDAC9; MITR; breast cancer; paclitaxel resistance
    DOI:  https://doi.org/10.7150/thno.44997
  3. Trends Cancer. 2020 Oct 13. pii: S2405-8033(20)30261-2. [Epub ahead of print]
    Lee LJ, Papadopoli D, Jewer M, Del Rincon S, Topisirovic I, Lawrence MG, Postovit LM.
      Tumor progression is associated with dedifferentiated histopathologies concomitant with cancer cell survival within a changing, and often hostile, tumor microenvironment. These processes are enabled by cellular plasticity, whereby intracellular cues and extracellular signals are integrated to enable rapid shifts in cancer cell phenotypes. Cancer cell plasticity, at least in part, fuels tumor heterogeneity and facilitates metastasis and drug resistance. Protein synthesis is frequently dysregulated in cancer, and emerging data suggest that translational reprograming collaborates with epigenetic and metabolic programs to effectuate phenotypic plasticity of neoplasia. Herein, we discuss the potential role of mRNA translation in cancer cell plasticity, highlight emerging histopathological correlates, and deliberate on how this is related to efforts to improve understanding of the complex tumor ecology.
    Keywords:  cancer plasticity; mRNA translation; metabolism; protein synthesis; stromal–epithelial interactions; therapy resistance; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2020.09.005
  4. Oncogene. 2020 Oct 13.
    Li Y, Li L, Qin J, Wu J, Dai X, Xu J.
      Oxidative stress-responsive kinase 1 (OSR1) plays a critical role in multiple carcinogenic signal pathways, and its overexpression has been found in various types of cancer; however, the pathophysiological role of OSR1 in breast cancer has not been evaluated. This study aims to elaborate on the role of OSR1 in breast cancer metastasis and the specific regulatory mechanism. Our results showed that OSR1 mRNA and protein were upregulated in both human breast cancer samples and cell lines. Moreover, phosphorylated OSR1 (p-OSR1) was an independent poor prognostic indicator in patients with breast cancer. OSR1 upregulation induced epithelial-to-mesenchymal transition (EMT) in normal and malignant mammary epithelial cells with the increasing metastatic capacity. In contrast, deleting OSR1 in aggressive breast cancer cells inhibited these phenotypes. OSR1 is the critical activator for transcription factors of EMT. Mechanistically, we found that OSR1 can directly interact and phosphorylate the linker region of Smad2 at Thr220 and Smad3 at Thr179. Phosphorylated Smad2/3 translocated into the nucleus to enhance transforming growth factor-β1 (TGF-β1) autocrine signalling and increase the transcription of EMT regulators. Importantly, interruption of the OSR1-Smad2/3-TGF-β1 signalling axis elicited a robust anti-EMT and anti-metastatic effect in vitro and in vivo. Taken together, we conclude that OSR1-mediated Smad2/3-TGF-β1 signalling promotes EMT and metastasis representing a promising therapeutic target in breast cancer treatment.
    DOI:  https://doi.org/10.1038/s41388-020-01499-2
  5. Genome Biol. 2020 Oct 15. 21(1): 263
    Gu SS, Wang X, Hu X, Jiang P, Li Z, Traugh N, Bu X, Tang Q, Wang C, Zeng Z, Fu J, Meyer C, Zhang Y, Cejas P, Lim K, Wang J, Zhang W, Tokheim C, Sahu AD, Xing X, Kroger B, Ouyang Z, Long H, Freeman GJ, Brown M, Liu XS.
      BACKGROUND: Immune checkpoint blockade (ICB) therapy has improved patient survival in a variety of cancers, but only a minority of cancer patients respond. Multiple studies have sought to identify general biomarkers of ICB response, but elucidating the molecular and cellular drivers of resistance for individual tumors remains challenging. We sought to determine whether a tumor with defined genetic background exhibits a stereotypic or heterogeneous response to ICB treatment.RESULTS: We establish a unique mouse system that utilizes clonal tracing and mathematical modeling to monitor the growth of each cancer clone, as well as the bulk tumor, in response to ICB. We find that tumors derived from the same clonal populations showed heterogeneous ICB response and diverse response patterns. Primary response is associated with higher immune infiltration and leads to enrichment of pre-existing ICB-resistant cancer clones. We further identify several cancer cell-intrinsic gene expression signatures associated with ICB resistance, including increased interferon response genes and glucocorticoid response genes. These findings are supported by clinical data from ICB treatment cohorts.
    CONCLUSIONS: Our study demonstrates diverse response patterns from the same ancestor cancer cells in response to ICB. This suggests the value of monitoring clonal constitution and tumor microenvironment over time to optimize ICB response and to design new combination therapies. Furthermore, as ICB response may enrich for cancer cell-intrinsic resistance signatures, this can affect interpretations of tumor RNA-seq data for response-signature association studies.
    Keywords:  Clonal tracing; Heterogeneity; Immune checkpoint blockade; Mathematical modeling; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13059-020-02166-1
  6. Theranostics. 2020 ;10(24): 10925-10939
    Lin CC, Huang YK, Cho CF, Lin YS, Lo CC, Kuo TT, Tseng GC, Cheng WC, Chang WC, Hsiao TH, Lai LC, Shih JY, Liu YH, Chao KSC, Hsu JL, Lee PC, Sun X, Hung MC, Sher YP.
      Rationale: Brain metastasis in patients with lung cancer is life-threatening. However, the molecular mechanism for this catastrophic disease remains elusive, and few druggable targets are available. Therefore, this study aimed to identify and characterize proteins that could be used as therapeutic targets. Methods: Proteomic analyses were conducted to identify differentially expressed membrane proteins between brain metastatic lung cancer cells and primary lung cancer cells. A neuronal growth-associated protein, brain acid soluble protein 1 (BASP1), was chosen for further investigation. The clinical relevance of BASP1 in lung adenocarcinoma was first assessed. Tyrosine kinase activity assays and in vitro and in vivo functional assays were conducted to explore the oncogenic mechanisms of BASP1. Results: The protein levels of BASP1 were positively associated with tumor progression and poor prognosis in patients with lung adenocarcinoma. Membrane-bound BASP1 increased EGFR signaling and stabilized EGFR proteins by facilitating their escape from the ubiquitin-proteasome pathway. Reciprocally, activation of EGFR recruited more BASP1 to the plasma membrane, generating a positive feedback loop between BASP1 and EGFR. Moreover, the synergistic therapeutic effects of EGFR tyrosine kinase inhibitor and arsenic trioxide led to a reduction in the level of BASP1 protein observed in lung cancer cells with acquired resistance to EGFR inhibitors. Conclusions: The reciprocal interaction between BASP1 and EGFR facilitates EGFR signaling in brain metastatic lung cancer. Targeting the newly identified BASP1-EGFR interaction could open new venues for lung cancer treatment.
    Keywords:  BASP1; EGFR-TKI acquired resistance; arsenic trioxide; combination therapy; lung adenocarcinoma
    DOI:  https://doi.org/10.7150/thno.49425
  7. Theranostics. 2020 ;10(24): 11144-11158
    Yao G, Tang J, Yang X, Zhao Y, Zhou R, Meng R, Zhang S, Dong X, Zhang T, Yang K, Wu G, Xu S.
      Rationale: Radioresistance remains the major cause of local relapse and distant metastasis in lung cancer. However, the underlying molecular mechanisms remain poorly defined. This study aimed to investigate the role and regulatory mechanism of Cyclin K in lung cancer radioresistance. Methods: Expression levels of Cyclin K were measured by immunohistochemistry in human lung cancer tissues and adjacent normal lung tissues. Cell growth and proliferation, neutral comet and foci formation assays, G2/M checkpoint and a xenograft mouse model were used for functional analyses. Gene expression was examined by RNA sequencing and quantitative real-time PCR. Protein-protein interaction was assessed by immunoprecipitation and GST pull-down assays. Results: We report that Cyclin K is frequently overexpressed and correlates with poor prognosis in lung cancer patients. Functionally, we demonstrate that Cyclin K depletion results in reduced proliferation, defective G2/M checkpoint and enhanced radiosensitivity in lung cancer. Mechanistically, we reveal that Cyclin K interacts with and promotes the stabilization of β-catenin protein, thereby upregulating the expression of Cyclin D1. More importantly, we show that Cyclin D1 is the major effector that mediates the biological functions of Cyclin K in lung cancer. Conclusions: These findings suggest that Cyclin K positively modulates the β-catenin/Cyclin D1 axis to promote tumorigenesis and radioresistance in lung cancer, indicating that Cyclin K may represent a novel attractive biomarker for lung cancer radiotherapy.
    Keywords:  Cyclin D1; Cyclin K; lung cancer; radioresistance; β-catenin
    DOI:  https://doi.org/10.7150/thno.42578
  8. Nat Commun. 2020 10 12. 11(1): 5127
    Tian H, Lian R, Li Y, Liu C, Liang S, Li W, Tao T, Wu X, Ye Y, Yang X, Han J, Chen X, Li J, He Y, Li M, Wu J, Cai J.
      Despite the importance of AKT overactivation in tumor progression, results from clinical trials of various AKT inhibitors remain suboptimal, suggesting that AKT-driven tumor metastasis needs to be further understood. Herein, based on long non-coding RNA (lncRNA) profiling induced by active AKT, we identify that VAL (Vimentin associated lncRNA, LINC01546), which is directly induced by AKT/STAT3 signaling, functions as a potent pro-metastatic molecule and is essential for active AKT-induced tumor invasion, metastasis and anoikis resistance in lung adenocarcinoma (LAD). Impressively, chemosynthetic siRNAs against VAL shows great therapeutic potential in AKT overactivation-driven metastasis. Interestingly, similar to activated AKT in LAD cells, although unable to induce epithelial-mesenchymal transition (EMT), VAL exerts potent pro-invasive and pro-metastatic effects through directly binding to Vimentin and competitively abrogating Trim16-depedent Vimentin polyubiquitination and degradation. Taken together, our study provides an interesting demonstration of a lncRNA-mediated mechanism for active AKT-driven EMT-independent LAD metastasis and indicates the great potential of targeting VAL or Vimentin stability as a therapeutic approach.
    DOI:  https://doi.org/10.1038/s41467-020-18929-0
  9. Cancer Cell. 2020 Oct 12. pii: S1535-6108(20)30485-2. [Epub ahead of print]38(4): 441-443
    Hillis AL, Toker A.
      Predictive biomarkers can facilitate optimal patient selection for targeted cancer therapies. In this issue of Cancer Cell, Ros et al. show the utility of noninvasive metabolic imaging of labeled carbon transfer from pyruvate to lactate to detect early response and FOXM1-mediated resistance to PI3K inhibition in estrogen-receptor-positive breast cancer.
    DOI:  https://doi.org/10.1016/j.ccell.2020.09.011
  10. Cancer Cell. 2020 Oct 12. pii: S1535-6108(20)30484-0. [Epub ahead of print]38(4): 443-445
    Kugel S, Hingorani SR.
      Cellular plasticity contributes to intratumoral heterogeneity, metastatic spread, and treatment resistance of cancers. In this issue of Cancer Cell, Gabitova-Cornell et al. identify the potential to inadvertently develop an undifferentiated and more aggressive pancreas cancer with agents commonly prescribed to manage heart disease risk.
    DOI:  https://doi.org/10.1016/j.ccell.2020.09.010
  11. Oncogene. 2020 Oct 12.
    Tiede S, Kalathur RKR, Lüönd F, von Allmen L, Szczerba BM, Hess M, Vlajnic T, Müller B, Canales Murillo J, Aceto N, Christofori G.
      Despite major progress in breast cancer research, the functional contribution of distinct cancer cell clones to malignant tumor progression and metastasis remains largely elusive. We have assessed clonal heterogeneity within individual primary tumors and metastases and also during the distinct stages of malignant tumor progression using clonal tracking of cancer cells in the MMTV-PyMT mouse model of metastatic breast cancer. Comparative gene expression analysis of clonal subpopulations reveals a substantial level of heterogeneity across and also within the various stages of breast carcinogenesis. The intra-stage heterogeneity is primarily manifested by differences in cell proliferation, also found within invasive carcinomas of luminal A-, luminal B-, and HER2-enriched human breast cancer. Surprisingly, in the mouse model of clonal tracing of cancer cells, chemotherapy mainly targets the slow-proliferative clonal populations and fails to efficiently repress the fast-proliferative populations. These insights may have considerable impact on therapy selection and response in breast cancer patients.
    DOI:  https://doi.org/10.1038/s41388-020-01508-4
  12. Nat Commun. 2020 Oct 16. 11(1): 5265
    Valle S, Alcalá S, Martin-Hijano L, Cabezas-Sáinz P, Navarro D, Muñoz ER, Yuste L, Tiwary K, Walter K, Ruiz-Cañas L, Alonso-Nocelo M, Rubiolo JA, González-Arnay E, Heeschen C, Garcia-Bermejo L, Hermann PC, Sánchez L, Sancho P, Fernández-Moreno MÁ, Sainz B.
      Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer death, has a 5-year survival rate of approximately 7-9%. The ineffectiveness of anti-PDAC therapies is believed to be due to the existence of a subpopulation of tumor cells known as cancer stem cells (CSCs), which are functionally plastic, and have exclusive tumorigenic, chemoresistant and metastatic capacities. Herein, we describe a 2D in vitro system for long-term enrichment of pancreatic CSCs that is amenable to biological and CSC-specific studies. By changing the carbon source from glucose to galactose in vitro, we force PDAC cells to utilize OXPHOS, resulting in enrichment of CSCs defined by increased CSC biomarker and pluripotency gene expression, greater tumorigenic potential, induced but reversible quiescence, increased OXPHOS activity, enhanced invasiveness, and upregulated immune evasion properties. This CSC enrichment method can facilitate the discovery of new CSC-specific hallmarks for future development into targets for PDAC-based therapies.
    DOI:  https://doi.org/10.1038/s41467-020-18954-z
  13. Theranostics. 2020 ;10(24): 10940-10956
    Liu XY, Jiang W, Ma D, Ge LP, Yang YS, Gou ZC, Xu XE, Shao ZM, Jiang YZ.
      Background: Taxanes are frontline chemotherapeutic drugs for patients with triple-negative breast cancer (TNBC); however, chemoresistance reduces their effectiveness. We hypothesized that the molecular profiling of tumor samples before and after neoadjuvant chemotherapy (NAC) would help identify genes associated with drug resistance. Methods: We sequenced 10 samples by RNA-seq from 8 NAC patients with TNBC: 3 patients with a pathologic complete response (pCR) and the other 5 with non-pCR. Differentially expressed genes that predicted chemotherapy response were selected for in vitro functional screening via a small-scale siRNAs pool. The clinical and functional significance of the gene of interest in TNBC was further investigated in vitro and in vivo, and biochemical assays and imaging analysis were applied to study the mechanisms. Results: Synaptotagmin-like 4 (SYTL4), a Rab effector in vesicle transport, was identified as a leading functional candidate. High SYTL4 expression indicated a poor prognosis in multiple TNBC cohorts, specifically in taxane-treated TNBCs. SYTL4 was identified as a novel chemoresistant gene as validated in TNBC cells, a mouse model and patient-derived organoids. Mechanistically, downregulating SYTL4 stabilized the microtubule network and slowed down microtubule growth rate. Furthermore, SYTL4 colocalized with microtubules and interacted with microtubules through its middle region containing the linker and C2A domain. Finally, we found that SYTL4 was able to bind microtubules and inhibit the in vitro microtubule polymerization. Conclusion: SYTL4 is a novel chemoresistant gene in TNBC and its upregulation indicates poor prognosis in taxane-treated TNBC. Further, SYTL4 directly binds microtubules and decreases microtubule stability.
    Keywords:  SYTL4; Triple-negative breast cancer; microtubule polymerization; paclitaxel resistance
    DOI:  https://doi.org/10.7150/thno.45207
  14. Oncogene. 2020 Oct 15.
    Xu L, Huan L, Guo T, Wu Y, Liu Y, Wang Q, Huang S, Xu Y, Liang L, He X.
      Epigenetic alteration is one of the hallmarks of colorectal cancer (CRC). Many driver genes are regulated by DNA methylation in CRC. However, the role of DNA methylation regulating lncRNAs remain elusive. Here, we identify that SNHG11 (small nucleolar RNA host gene 11) is upregulated by promotor hypomethylation in CRC and is associated with poor prognosis in CRC patients. SNHG11 can promote CRC cell migration and metastasis under hypoxia. Interestingly, the DNA-binding motif of SNHG11 is similar to that of HIF-1α. In addition, SNHG11-associated genes are enriched with members of the HIF-1 signaling pathway in CRC. Mechanistically, SNHG11 binds to the pVHLrecognition sites on HIF-1α, thus blocking the interaction of pVHL with HIF-1α and preventing its ubiquitination and degradation. Moreover, SNHG11 upregulates the expression of HIF-1α target genes, i.e., AK4, ENO1, HK2, and Twist1. Notably, SNHG11 can bind to the HRE sites in the promoter of these genes and increase their transcription. In summary, these results identify a SNHG11/ HIF-1α axis that plays a pivotal role in tumor invasion and metastasis.
    DOI:  https://doi.org/10.1038/s41388-020-01512-8
  15. Cancer Res. 2020 Oct 16. pii: canres.0957.2020. [Epub ahead of print]
    Yu J, Mohamed Yuso PAB, Woutersen DTJ, Goh P, Harmston N, Smits R, Epstein D, Virshup DM, Madan B.
      A subset of Wnt-addicted cancers are sensitive to targeted therapies that block Wnt secretion or receptor engagement. RNF43 loss-of-function mutations that increase cell surface Wnt receptor abundance cause sensitivity to Wnt inhibitors. However, it is not clear which of the clinically identified RNF43 mutations affect its function in vivo. Here we assayed 119 missense and 45 truncating RNF43 mutations found in human cancers using a combination of cell-based reporter assays, genome editing, flow cytometry, and immunofluorescence microscopy. Five common germline variants of RNF43 exhibited wild-type activity. Cancer-associated missense mutations in the RING ubiquitin ligase domain and a subset of mutations in the extracellular domain hyperactivated Wnt/β-catenin signaling through formation of inactive dimers with endogenous RNF43 or ZNRF3. RNF43 C-terminal truncation mutants including the common G659fs mutant were loss-of-function specifically when endogenous mutations were examined, unlike their behavior in transient transfection assays. PDX and cell lines with C-terminal truncations showed increased cell surface FZD and Wnt/β-catenin signaling and were responsive to PORCN inhibition in vivo, providing clear evidence of RNF43 impairment. Our study provides potential guidelines for patient assignment, as virtually all RNF43 nonsense and frameshift mutations including those in the C-terminal domain and a large number of patient-associated missense mutations in the RING domain and N-terminal region compromise its activity and therefore predict response to upstream Wnt inhibitors in cancers without microsatellite instability. This study expands the landscape of actionable RNF43 mutations, extending the benefit of these therapies to additional patients.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-0957
  16. Cancers (Basel). 2020 Oct 09. pii: E2896. [Epub ahead of print]12(10):
    Mukaida N, Zhang D, Sasaki SI.
      Bone metastasis is frequently complicated in patients with advanced solid cancers such as breast, prostate and lung cancers, and impairs patients' quality of life and prognosis. At the first step of bone metastasis, cancer cells adhere to the endothelium in bone marrow and survive in a dormant state by utilizing hematopoietic niches present therein. Once a dormant stage is disturbed, cancer cells grow through the interaction with various bone marrow resident cells, particularly osteoclasts and osteoblasts. Consequently, osteoclast activation is a hallmark of bone metastasis. As a consequence, the drugs targeting osteoclast activation are frequently used to treat bone metastasis but are not effective to inhibit cancer cell growth in bone marrow. Thus, additional types of resident cells are presumed to contribute to cancer cell growth in bone metastasis sites. Cancer-associated fibroblasts (CAFs) are fibroblasts that accumulate in cancer tissues and can have diverse roles in cancer progression and metastasis. Given the presence of CAFs in bone metastasis sites, CAFs are emerging as an important cellular player in bone metastasis. Hence, in this review, we will discuss the potential roles of CAFs in tumor progression, particularly bone metastasis.
    Keywords:  bone metastasis; cancer-associated fibroblast; fibroblast; mesenchymal stem cell; myofibroblast
    DOI:  https://doi.org/10.3390/cancers12102896
  17. Cancer Res. 2020 Oct 16. pii: canres.1871.2020. [Epub ahead of print]
    Kolapalli SP, Sahu R, Chauhan NR, Jena KK, Mehto S, Das SK, Jain A, Rout M, Dash R, Swain RK, Lee DY, Rusten TE, Chauhan S, Chauhan S.
      DZIP3/hRUL138 is a poorly characterized RNA binding RING E3-ubiquitin ligase with functions in embryonic development. Here we demonstrate that DZIP3 is a crucial driver of cancer cell growth, migration, and invasion. In mice and zebrafish cancer models, DZIP3 promoted tumor growth and metastasis. In line with these results, DZIP3 was frequently overexpressed in several cancer types. Depletion of DZIP3 from cells resulted in reduced expression of Cyclin D1 and a subsequent G1 arrest and defect in cell growth. Mechanistically, DZIP3 utilized its two different domains to interact and stabilize Cyclin D1 both at mRNA and protein levels. Using an RNA-binding lysine-rich region, DZIP3 interacted with the AU-rich region in 3'UTR of Cyclin D1 mRNA and stabilized it. Using a RING E3-ligase domain, DZIP3 interacted and increased K63-linked ubiquitination of Cyclin D1 protein to stabilize it. Remarkably, DZIP3 interacted with, ubiquitinated, and stabilized Cyclin D1 predominantly in the G1 phase of the cell cycle where it is needed for cell cycle progression. In agreement with this, a strong positive correlation of mRNA expression between DZIP3 and Cyclin D1 in different cancer types was observed. Additionally, DZIP3 regulated several cell cycle proteins by modulating the Cyclin D1-E2F axes. Taken together, this study demonstrates for the first time that DZIP3 employs a unique two-pronged mechanism in its stabilization of Cyclin D1 to drive cell cycle and cancer progression.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1871
  18. Clin Cancer Res. 2020 Oct 14. pii: clincanres.2701.2020. [Epub ahead of print]
    Shah M, Wedam S, Cheng J, Fiero MH, Xia H, Li F, Fan J, Zhang X, Yu J, Song P, Chen W, Ricks TK, Chen XH, Goldberg KB, Gong Y, Pierce WF, Tang S, Theoret MR, Pazdur R, Amiri-Kordestani L, Beaver JA.
      On April 17, 2020, the FDA approved tucatinib in combination with trastuzumab and capecitabine for the treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. This was the first new molecular entity evaluated under Project Orbis, an FDA Oncology Center of Excellence initiative which supports concurrent review of oncology drugs by multiple global health authorities. Approval was based on the HER2CLIMB trial, which randomized patients to receive tucatinib or placebo with trastuzumab and capecitabine. Tucatinib demonstrated efficacy compared to placebo in progression-free survival (PFS) (HR: 0.54, 95% CI: 0.42-0.71, p<0.00001) and overall survival (OS) (HR: 0.66, 95% CI: 0.50-0.87, p=0.00480). Patients with either treated and stable or active brain metastases made up 48% of the study population. PFS in patients with brain metastases confirmed benefit (HR: 0.48, 95% CI: 0.34-0.69, p<0.00001). The benefit in patients with brain metastases allowed for inclusion of this specific population in the indication. Important safety signals included diarrhea and hepatotoxicity which are listed under Warnings and Precautions. This article summarizes the FDA thought process and data supporting the favorable benefit-risk profile and approval of tucatinib.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-2701
  19. Theranostics. 2020 ;10(24): 11063-11079
    Chen L, Long X, Duan S, Liu X, Chen J, Lan J, Liu X, Huang W, Geng J, Zhou J.
      Metastasis is a major cause of death in patients with colorectal cancer (CRC). Cysteine-rich protein 2 (CSRP2) has been recently implicated in the progression and metastasis of a variety of cancers. However, the biological functions and underlying mechanisms of CSRP2 in the regulation of CRC progression are largely unknown. Methods: Immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR) and Western blotting (WB) were used to detect the expression of CSRP2 in CRC tissues and paracancerous tissues. CSRP2 function in CRC was determined by a series of functional tests in vivo and in vitro. WB and immunofluorescence were used to determine the relation between CSRP2 and epithelial-mesenchymal transition (EMT). Co-immunoprecipitation and scanning electron microscopy were used to study the molecular mechanism of CSRP2 in CRC. Results: The CSRP2 expression level in CRC tissues was lower than in adjacent normal tissues and indicated poor prognosis in CRC patients. Functionally, CSRP2 could suppress the proliferation, migration, and invasion of CRC cells in vitro and inhibit CRC tumorigenesis and metastasis in vivo. Mechanistic investigations revealed a physical interaction between CSRP2 and p130Cas. CSRP2 could inhibit the activation of Rac1 by preventing the phosphorylation of p130Cas, thus activating the Hippo signaling pathway, and simultaneously inhibiting the ERK and PAK/LIMK/cortactin signaling pathways, thereby inhibiting the EMT and metastasis of CRC. Rescue experiments showed that blocking the p130Cas and Rac1 activation could inhibit EMT induced by CSRP2 silencing. Conclusion: Our results suggest that the CSRP2/p130Cas/Rac1 axis can inhibit CRC aggressiveness and metastasis through the Hippo, ERK, and PAK signaling pathways. Therefore, CSRP2 may be a potential therapeutic target for CRC.
    Keywords:  CSRP2; Colorectal cancer; ERK; Hippo; PAK
    DOI:  https://doi.org/10.7150/thno.45674
  20. Cancer Res. 2020 Oct 13. pii: canres.1590.2020. [Epub ahead of print]
    Li Y, Bai L, Yu H, Cai D, Wang X, Huang B, Peng S, Huang M, Cao G, Kaz AM, Grady WM, Wang J, Luo Y.
      DNA methylation contributes to malignant transformation, but little is known about how the methylation drives colorectal cancer evolution at the early stages. Here we identify aberrant INA (α-internexin) gene methylation in colon adenoma and adenocarcinoma by filtering data obtained from a genome-wide screen of methylated genes. The gene encoding INA, a type IV intermediate filament, was frequently hypermethylated in CpG islands located in the promoter region. This hypermethylation preferentially occurred in large tumors and was a prognostic marker for poor overall survival in colorectal cancer patients. This type of epigenetic alteration silenced INA expression in both adenoma and adenocarcinoma tissues. Gene silencing of INA in colorectal cancer cells increased cell proliferation, migration, and invasion. Restored INA expression blocked migration and invasion in vitro and reduced lung metastasis in vivo. Mechanistically, INA directly inhibited microtubule polymerization in vitro and decreased intracellular microtubule plus-end assembly rates. A peptide array screen surveying the tubulin-binding sites in INA identified a tubulin-binding motif located in the N-terminal head domain that plays a tumor-suppressive role by binding to unpolymerized tubulins and impeding microtubule polymerization. Thus, epigenetic inactivation of INA is an intermediate filament reorganization event that is essential to accelerate microtubule polymerization in the early stages of colorectal cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1590
  21. Theranostics. 2020 ;10(24): 11127-11143
    Vaidya A, Ayat N, Buford M, Wang H, Shankardass A, Zhao Y, Gilmore H, Wang Z, Lu ZR.
      Antineoplastic resistance represents a multifaceted challenge for cancer therapy and diagnostics. Extensive molecular heterogeneity, even within neoplasms of the same type, can elicit distinct outcomes of administering therapeutic pressures, frequently leading to the development of drug-resistant populations. Improved success of oncotherapies merits the exploration of precise molecular imaging technologies that can detect not only anatomical but also molecular changes in tumors and their microenvironment, early on in the treatment regimen. To this end, we developed magnetic resonance molecular imaging (MRMI) strategies to target the extracellular matrix oncoprotein, extradomain-B fibronectin (EDB-FN), for non-invasive assessment and therapeutic monitoring of drug-resistant colorectal cancer (CRC). Methods: Two drug-resistant CRC lines generated from parent DLD-1 and RKO cells by long-term treatment with 5'-FU and 5'-FU plus CB-839 respectively, were characterized for functional and gene expression changes using 3D culture, transwell invasion, qRT-PCR, and western blot assays. Contrast-enhanced MRMI of EDB-FN was performed in athymic nu/nu mice bearing subcutaneous tumor xenografts with 40 µmol/kg dose of macrocyclic ZD2-targeted contrast agent MT218 [ZD2-N3-Gd (HP-DO3A)] on a 3T MRS 3000 scanner. Immunohistochemistry was conducted on patient specimens and xenografts using anti-EDB-FN antibody G4. Results: Analyses of TCGA and GTEx databases revealed poor prognosis of colon cancer patients with higher levels of EDB-FN. Similarly, immunohistochemical staining of patient specimens showed increased EDB-FN expression in primary colon adenocarcinoma and hepatic metastases, but none in normal adjacent tissues. Drug-resistant DLD1-DR and RKO-DR cells were also found to demonstrate enhanced invasive potential and significantly elevated EDB-FN expression over their parent counterparts. MRMI of EDB-FN with 40 µmol/kg dose of MT218 (60% lower than the clinical dose) resulted in robust signal enhancement in the drug-resistant CRC xenografts with 84-120% increase in their contrast-to-noise ratios (CNRs) over the non-resistant counterparts. The feasibility of non-invasive therapeutic monitoring using MRMI of EDB-FN was also evaluated in drug-resistant DLD1-DR tumors treated with a pan-AKT inhibitor MK2206-HCl. The treated drug-resistant tumors failed to respond to therapy, which was accurately detected by MRMI with MT218, demonstrating higher signal enhancement and increased CNRs in the 4-week follow-up scans over the pre-treatment scans. Conclusions: EDB-FN is a promising molecular marker for assessing drug resistance. MRMI of EDB-FN with MT218 at a significantly reduced dose can facilitate effective non-invasive assessment and treatment response monitoring of drug-resistant CRC, highlighting its translational potential for active surveillance and management of CRC and other malignancies.
    Keywords:  EDB-FN.; MRMI; colorectal cancer; drug resistance; therapeutic monitoring
    DOI:  https://doi.org/10.7150/thno.47448
  22. Nat Rev Dis Primers. 2020 Oct 15. 6(1): 83
    Coleman RE, Croucher PI, Padhani AR, Clézardin P, Chow E, Fallon M, Guise T, Colangeli S, Capanna R, Costa L.
      Bone is the most frequent site for metastasis for many cancers, notably for tumours originating in the breast and the prostate. Tumour cells can escape from the primary tumour site and colonize the bone microenvironment. Within the bone, these disseminated tumour cells, as well as those arising in the context of multiple myeloma, may assume a state of dormancy, remaining quiescent for years before resuming proliferation and causing overt metastasis, which causes bone destruction via activation of osteoclast-mediated osteolysis. This structural damage can lead to considerable morbidity, including pain, fractures and impaired quality of life. Although treatment of bone metastases and myeloma bone disease is rarely curative, disease control is often possible for many years through the use of systemic anticancer treatments on a background of multidisciplinary supportive care. This care should include bone-targeted agents to inhibit tumour-associated osteolysis and prevent skeletal morbidity as well as use of appropriate local treatments such as radiation therapy, orthopaedic surgery and specialist palliative care to minimize the impact of metastatic bone disease on physical functioning. In this Primer, we provide an overview of the clinical features, the pathophysiology and the specific treatment approaches to prevent and treat bone metastases from solid tumours as well as myeloma bone disease.
    DOI:  https://doi.org/10.1038/s41572-020-00216-3
  23. Proc Natl Acad Sci U S A. 2020 Oct 12. pii: 202011912. [Epub ahead of print]
    Xuan B, Ghosh D, Jiang J, Shao R, Dawson MR.
      Polyploidal giant cancer cells (PGCCs) are multinucleated chemoresistant cancer cells found in heterogeneous solid tumors. Due in part to their apparent dormancy, the effect of PGCCs on cancer progression has remained largely unstudied. Recent studies have highlighted the critical role of PGCCs as aggressive and chemoresistant cancer cells, as well as their ability to undergo amitotic budding to escape dormancy. Our recent study demonstrated the unique biophysical properties of PGCCs, as well as their unusual migratory persistence. Here we unveil the critical function of vimentin intermediate filaments (VIFs) in maintaining the structural integrity of PGCCs and enhancing their migratory persistence. We performed in-depth single-cell analysis to examine the distribution of VIFs and their role in migratory persistence. We found that PGCCs rely heavily on their uniquely distributed and polarized VIF network to enhance their transition from a jammed to an unjammed state to allow for directional migration. Both the inhibition of VIFs with acrylamide and small interfering RNA knockdown of vimentin significantly decreased PGCC migration and resulted in a loss of PGCC volume. Because PGCCs rely on their VIF network to direct migration and to maintain their enlarged morphology, targeting vimentin or vimentin cross-linking proteins could provide a therapeutic approach to mitigate the impact of these chemoresistant cells in cancer progression and to improve patient outcomes with chemotherapy.
    Keywords:  PGCC; breast cancer; chemoresistance; polyploidy; vimentin
    DOI:  https://doi.org/10.1073/pnas.2011912117
  24. Oncogene. 2020 Oct 12.
    He Q, Lin Z, Wang Z, Huang W, Tian D, Liu M, Xia L.
      Metastasis is the main reason for high mortality in hepatocellular carcinoma (HCC) patients and the molecular mechanism remains unclear. Therefore, it is important to elucidate the mechanism underlying HCC metastasis. Here, we report a novel role of SIX homeobox 4 (SIX4), one of the SIX gene family, in promoting HCC metastasis. The elevated expression of SIX4 was positively correlated with loss of tumor encapsulation, microvascular invasion, higher TNM stage, and poor prognosis in human HCC. SIX4 expression was an independent and significant risk factor for the recurrence and survival in HCC patients. Upregulation of SIX4 promoted HCC invasion and metastasis, whereas downregulation of SIX4 decreased HCC invasion and metastasis. SIX4 transactivated Yes1 associated transcriptional regulator (YAP1) and MET proto-oncogene, receptor tyrosine kinase (MET) expression through directly binding to their promoters. Knockdown of YAP1 and c-MET inhibited SIX4-medicated HCC metastasis, while the stable overexpression of YAP1 and c-MET reversed the decreased metastasis induced by SIX4 knockdown. Hepatocyte growth factor (HGF), the specific ligand of c-MET, upregulated SIX4 expression through ERK/NF-κB pathway. Knockdown of SIX4 significantly decreased HGF-enhanced HCC metastasis. In human HCC tissues, SIX4 expression was positively correlated with nuclear YAP1, c-MET and HGF expression. Patients with positive coexpression of SIX4/ nuclear YAP1, SIX4/c-MET or HGF/SIX4 had the poorest prognosis. Moreover, the combination treatment of YAP1 inhibitor Verteporfin and c-MET inhibitor Capmatinib significantly suppressed SIX4-mediated HCC metastasis. In conclusion, SIX4 is a prognostic biomarker in HCC patients and targeting the HGF-SIX4-c-MET positive feedback loop may provide a promising strategy for the treatment of SIX4-driven HCC metastasis.
    DOI:  https://doi.org/10.1038/s41388-020-01500-y
  25. Cancer Res. 2020 Oct 16. pii: canres.3626.2019. [Epub ahead of print]
    Zheng ZQ, Li ZX, Guan JL, Liu X, Li JY, Chen Y, Lin L, Kou J, Lv JW, Zhang LL, Zhou GQ, Liu RQ, Chen F, He XJ, Li YQ, Li F, Xu SS, Ma J, Liu N, Sun Y.
      Frontier evidence suggests that dysregulation of long non-coding RNAs (lncRNAs) is ubiquitous in all human tumors, indicating that lncRNAs might have essential roles in tumorigenesis. Therefore, an in-depth study of the roles of lncRNA in nasopharyngeal carcinoma (NPC) carcinogenesis might be helpful to provide novel therapeutic targets. Here we report that lncRNA TINCR was significantly upregulated in NPC and was associated positively with poor survival. Silencing TINCR inhibited NPC progression and cisplatin resistance. Mechanistically, TINCR bound ACLY and protected it from ubiquitin degradation to maintain total cellular acetyl-CoA levels. Accumulation of cellular acetyl-CoA promoted de novo lipid biosynthesis and histone H3K27 acetylation, which ultimately regulated the peptidyl arginine deiminase 1 (PADI1)-MAPK-MMP-2/9 pathway. In addition, IGF2BP3 interacted with TINCR and slowed its decay, which partially accounted for TINCR upregulation in NPC. These findings demonstrate that TINCR acts as a crucial driver of NPC progression and chemoresistance and highlights the newly identified TINCR-ACLY-PADI1-MAPK-MMP2/9 axis as a potential therapeutic target in NPC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-3626
  26. Cancer Res. 2020 Oct 16. pii: canres.1145.2020. [Epub ahead of print]
    Saint Fleur-Lominy S, Evensen NA, Bhatla T, Sethia G, Narang S, Choi JH, Ma X, Yang JJ, Kelly S, Raetz E, Harvey RC, Willman C, Loh ML, Hunger SP, Brown PA, Getz KM, Meydan C, Mason CE, Tsirigos A, Carroll WL.
      Although B cell acute lymphoblastic leukemia (ALL) is the most common malignancy in children and while highly curable, it remains a leading cause of cancer-related mortality. The outgrowth of tumor subclones carrying mutations in genes responsible for resistance to therapy has led to a Darwinian model of clonal selection. Previous work has indicated that alterations in the epigenome might contribute to clonal selection yet the extent to which the chromatin state is altered under the selective pressures of therapy is unknown. To address this, we performed chromatin immunoprecipitation, gene expression analysis, and enhanced reduced representation bisulfite sequencing on a cohort of paired diagnosis and relapse samples from individual patients who all but one relapsed within 36 months of initial diagnosis. The chromatin state at diagnosis varied widely among patients: while the majority of peaks remained stable between diagnosis and relapse, yet a significant fraction were either lost or newly gained with some patients showing few differences and others showing massive changes of the epigenetic state. Evolution of the epigenome was associated with pathways previously linked to therapy resistance as well as novel candidate pathways through alterations in pyrimidine biosynthesis and downregulation of polycomb repressive complex 2 targets. Three novel, relapse-specific super-enhancers were shared by a majority of patients including one associated with S100A8, the top upregulated gene seen at relapse in childhood B-ALL. Overall, our results support a role of the epigenome in clonal evolution and uncover new candidate pathways associated with relapse.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1145
  27. Cancers (Basel). 2020 Oct 12. pii: E2929. [Epub ahead of print]12(10):
    Wang Z.
      
    DOI:  https://doi.org/10.3390/cancers12102929