bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2022–09–04
24 papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. ZFP281 drives a mesenchymal-like dormancy program in early disseminated breast cancer cells that prevents metastatic outgrowth in the lung.
  2. ABL kinases regulate translation in HER2+ cells through Y-box-binding protein 1 to facilitate colonization of the brain.
  3. Simultaneous JAK/FGFR Inhibition Restores Anti-AR Sensitivity in CRPC.
  4. Sublethal cytochrome c release generates drug-tolerant persister cells.
  5. Human WDR5 promotes breast cancer growth and metastasis via KMT2-independent translation regulation.
  6. S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c-Myc pathway in patients with estrogen receptor-positive breast cancer.
  7. RARγ: The Bone of Contention for Endothelial Cells in Prostate Cancer Metastasis.
  8. An alternatively spliced p62 isoform confers resistance to chemotherapy in breast cancer.
  9. Pumping Iron: Ferritinophagy Promotes Survival and Therapy Resistance in Pancreatic Cancer.
  10. Targeting acetylcholine signaling modulates persistent drug tolerance in EGFR-mutant lung cancer and impedes tumor relapse.
  11. Reciprocal interactions between the gut microbiome and mammary tissue mast cells promote metastatic dissemination of HR+ breast tumors.
  12. CircSMARCC1 facilitates tumor progression by disrupting the crosstalk between prostate cancer cells and tumor-associated macrophages via miR-1322/CCL20/CCR6 signaling.
  13. Coupling live-cell imaging and in situ isolation of the same single cell to profile the transient states of predicted drug-tolerant cells.
  14. Gain of Chromosome 1q Perturbs a Competitive Endogenous RNA Network to Promote Melanoma Metastasis.
  15. Genome-wide in vivo screen of circulating tumor cells identifies SLIT2 as a regulator of metastasis.
  16. High-dimensional and spatial analysis reveals immune landscape dependent progression in cutaneous squamous cell carcinoma.
  17. Tumor-infiltrated activated B cells suppress liver metastasis of colorectal cancers.
  18. The m6A demethylase ALKBH5-mediated upregulation of DDIT4-AS1 maintains pancreatic cancer stemness and suppresses chemosensitivity by activating the mTOR pathway.
  19. Transcriptomic Profiling Highlights Rectal Tumors with Improved Prognosis.
  20. Mutational signature 3 detected from clinical panel sequencing is associated with responses to olaparib in breast and ovarian cancers.
  21. Genome-Scale CRISPR Screen Identifies LAPTM5 driving lenvatinib resistance in hepatocellular carcinoma.
  22. Extracellular vesicles and particles impact the systemic landscape of cancer.
  23. Suppression of Ca2+ signaling enhances melanoma progression.
  24. Cellular hierarchies predict drug response in acute myeloid leukemia.
  1. Nat Cancer. 2022 Sep 01.
    ZFP281 drives a mesenchymal-like dormancy program in early disseminated breast cancer cells that prevents metastatic outgrowth in the lung.
    Ana Rita Nobre, Erica Dalla, Jihong Yang, Xin Huang, Lena Wullkopf, Emma Risson, Pedram Razghandi, Melisa Lopez Anton, Wei Zheng, Jose A Seoane, Christina Curtis, Ephraim Kenigsberg, Jianlong Wang, Julio A Aguirre-Ghiso.
      Increasing evidence shows that cancer cells can disseminate from early evolved primary lesions much earlier than the classical metastasis models predicted. Here, we reveal at a single-cell resolution that mesenchymal-like (M-like) and pluripotency-like programs coordinate dissemination and a long-lived dormancy program of early disseminated cancer cells (DCCs). The transcription factor ZFP281 induces a permissive state for heterogeneous M-like transcriptional programs, which associate with a dormancy signature and phenotype in vivo. Downregulation of ZFP281 leads to a loss of an invasive, M-like dormancy phenotype and a switch to lung metastatic outgrowth. We also show that FGF2 and TWIST1 induce ZFP281 expression to induce the M-like state, which is linked to CDH1 downregulation and upregulation of CDH11. We found that ZFP281 not only controls the early dissemination of cancer cells but also locks early DCCs in a dormant state by preventing the acquisition of an epithelial-like proliferative program and consequent metastases outgrowth.
    DOI:  https://doi.org/10.1038/s43018-022-00424-8
  2. Cell Rep. 2022 Aug 30. pii: S2211-1247(22)01086-5. [Epub ahead of print]40(9): 111268
    ABL kinases regulate translation in HER2+ cells through Y-box-binding protein 1 to facilitate colonization of the brain.
    Courtney M McKernan, Aaditya Khatri, Molly Hannigan, Jessica Child, Qiang Chen, Benjamin Mayro, David Snyder, Christopher V Nicchitta, Ann Marie Pendergast.
      Patients with human epidermal growth factor receptor 2-positive (HER2+/ERBB2) breast cancer often present with brain metastasis. HER2-targeted therapies have not been successful to treat brain metastases in part due to poor blood-brain barrier (BBB) penetrance and emergence of resistance. Here, we report that Abelson (ABL) kinase allosteric inhibitors improve overall survival and impair HER2+ brain metastatic outgrowth in vivo. Mechanistically, ABL kinases phosphorylate the RNA-binding protein Y-box-binding protein 1 (YB-1). ABL kinase inhibition disrupts binding of YB-1 to the ERBB2 mRNA and impairs translation, leading to a profound decrease in HER2 protein levels. ABL-dependent tyrosine phosphorylation of YB-1 promotes HER2 translation. Notably, loss of YB-1 inhibits brain metastatic outgrowth and impairs expression of a subset of ABL-dependent brain metastatic targets. These data support a role for ABL kinases in the translational regulation of brain metastatic targets through YB-1 and offer a therapeutic target for HER2+ brain metastasis patients.
    Keywords:  ABL kinase; CP: Cancer; CP: Molecular biology; HER2; RNA-binding protein; Y-box-binding protein 1; brain metastasis; breast cancer; mRNA translation
    DOI:  https://doi.org/10.1016/j.celrep.2022.111268
  3. Cancer Discov. 2022 Sep 02. OF1
    Simultaneous JAK/FGFR Inhibition Restores Anti-AR Sensitivity in CRPC.
      Elevated JAK/FGFR activity supports lineage plasticity and antiandrogen resistance in prostate cancer.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-159
  4. Cell. 2022 Sep 01. pii: S0092-8674(22)00978-3. [Epub ahead of print]185(18): 3356-3374.e22
    Sublethal cytochrome c release generates drug-tolerant persister cells.
    Halime Kalkavan, Mark J Chen, Jeremy C Crawford, Giovanni Quarato, Patrick Fitzgerald, Stephen W G Tait, Colin R Goding, Douglas R Green.
      Drug-tolerant persister cells (persisters) evade apoptosis upon targeted and conventional cancer therapies and represent a major non-genetic barrier to effective cancer treatment. Here, we show that cells that survive treatment with pro-apoptotic BH3 mimetics display a persister phenotype that includes colonization and metastasis in vivo and increased sensitivity toward ferroptosis by GPX4 inhibition. We found that sublethal mitochondrial outer membrane permeabilization (MOMP) and holocytochrome c release are key requirements for the generation of the persister phenotype. The generation of persisters is independent of apoptosome formation and caspase activation, but instead, cytosolic cytochrome c induces the activation of heme-regulated inhibitor (HRI) kinase and engagement of the integrated stress response (ISR) with the consequent synthesis of ATF4, all of which are required for the persister phenotype. Our results reveal that sublethal cytochrome c release couples sublethal MOMP to caspase-independent initiation of an ATF4-dependent, drug-tolerant persister phenotype.
    Keywords:  ATF4; Bcl-2 family; GPX4; HRI; ferroptosis; persister integrated stress response
    DOI:  https://doi.org/10.1016/j.cell.2022.07.025
  5. Elife. 2022 Aug 31. pii: e78163. [Epub ahead of print]11
    Human WDR5 promotes breast cancer growth and metastasis via KMT2-independent translation regulation.
    Wesley L Cai, Jocelyn Fang-Yi Chen, Huacui Chen, Emily Wingrove, Sarah J Kurley, Lok Hei Chan, Meiling Zhang, Anna Arnal-Estape, Minghui Zhao, Amer Balabaki, Wenxue Li, Xufen Yu, Ethan D Krop, Yali Dou, Yansheng Liu, Jian Jin, Thomas F Westbrook, Don X Nguyen, Qin Yan.
      Metastatic breast cancer remains a major cause of cancer related deaths in women and there are few effective therapies against this advanced disease. Emerging evidence suggests that key steps of tumor progression and metastasis are controlled by reversible epigenetic mechanisms. Using an in vivo genetic screen, we identified WDR5 as an actionable epigenetic regulator that is required for metastatic progression in models of triple-negative breast cancer. We found that knockdown of WDR5 in breast cancer cells independently impaired their tumorigenic as well as metastatic capabilities. Mechanistically, WDR5 promotes cell growth by increasing ribosomal gene expression and translation efficiency in a KMT2-independent manner. Consistently, pharmacological inhibition or degradation of WDR5 impedes cellular translation rate and the clonogenic ability of breast cancer cells. Furthermore, combination of WDR5-targeting with mTOR inhibitors leads to potent suppression of translation and proliferation of breast cancer cells. These results reveal novel therapeutic strategies to treat metastatic breast cancer.
    Keywords:  cancer biology; chromosomes; gene expression; mouse
    DOI:  https://doi.org/10.7554/eLife.78163
  6. Mol Cancer. 2022 Aug 30. 21(1): 171
    S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c-Myc pathway in patients with estrogen receptor-positive breast cancer.
    Hongnan Mo, Xuefeng Liu, Yu Xue, Hongyan Chen, Shichao Guo, Zhangfu Li, Shuang Wang, Caiming Li, Jiashu Han, Ming Fu, Yongmei Song, Dan Li, Fei Ma.
       BACKGROUND: CDK4/6 inhibitors combined with endocrine therapy has become the preferred treatment approach for patients with estrogen receptor-positive metastatic breast cancer. However, the predictive biomarkers and mechanisms of innate resistance to CDK4/6 inhibitors remain largely unknown. We sought to elucidate the molecular hallmarks and therapeutically actionable features of patients with resistance to CDK4/6 inhibitors.
    METHODS: A total of 36 patients received palbociclib and endocrine therapy were included in this study as the discovery cohort. Next-generation sequencing of circulating tumour DNA in these patients was performed to evaluate somatic alterations associated with innate resistance to palbociclib. Then the candidate biomarker was validated in another independent cohort of 104 patients and publicly available datasets. The resistance was verified in parental MCF-7 and T47D cells, as well as their derivatives with small interfering RNA transfection and lentivirus infection. The relevant mechanism was examined by RNA sequencing, chromatin immunoprecipitation and luciferase assay. Patient-derived organoid and patient-derived xenografts studies were utilized to evaluated the antitumor activity of rational combinations.
    RESULTS: In the discovery cohort, S6K1 amplification (3/35, 9%) was identified as an important reason for innate resistance to CDK4/6 inhibitors. In the independent cohort, S6K1 was overexpressed in 15/104 (14%) patients. In those who had received palbociclib treatment, patients with high-expressed S6K1 had significantly worse progression free survival than those with low S6K1 expression (hazard ratio = 3.0, P = 0.0072). Meta-analysis of public data revealed that patients with S6K1 amplification accounted for 12% of breast cancers. Breast cancer patients with high S6K1 expression had significantly worse relapse-free survival (hazard ratio = 1.31, P < 0.0001). In breast cancer cells, S6K1 overexpression, caused by gene amplification, was sufficient to promote resistance to palbociclib. Mechanistically, S6K1 overexpression increased the expression levels of G1/S transition-related proteins and the phosphorylation of Rb, mainly through the activation of c-Myc pathway. Notably, this resistance could be abrogated by the addition of mTOR inhibitor, which blocked the upstream of S6K1, in vitro and in vivo.
    CONCLUSIONS: S6K1 amplification is an important mechanism of innate resistance to palbociclib in breast cancers. Breast cancers with S6K1 amplification could be considered for combinations of CDK4/6 and S6K1 antagonists.
    Keywords:  Breast cancer; CDK4/6 inhibitors; Circulating tumour DNA; Drug resistance; S6K1
    DOI:  https://doi.org/10.1186/s12943-022-01642-5
  7. Cancer Res. 2022 Sep 02. 82(17): 2975-2976
    RARγ: The Bone of Contention for Endothelial Cells in Prostate Cancer Metastasis.
    Snigdha Bhowmick, Neil A Bhowmick.
      Excessive bone deposition associated with prostate cancer bone metastases is believed to aid in metastatic progression. One mechanism of osteoblast expansion is the transdifferentiation of bone marrow endothelial cells. Prostate cancer cells contribute several secreted factors, including bone morphogenetic protein 4 (BMP4), to the microenvironment that support osteoblastic transdifferentiation. In this issue of Cancer Research, Yu and colleagues share their findings of how BMP-mediated endothelial conversion can be inhibited by treatment with retinoic acid receptor (RAR) agonists. Using agonists like the all-trans retinoic acid or palovarotene, the authors demonstrated the role of the interaction of BMP-activated SMAD1 with RARγ for osteoblastic differentiation. RARγ agonists potentiated the proteasomal degradation of the Smad1-RARγ complex, blocking BMP signaling. Because palovarotene is clinically effective in the treatment of aberrant bone formation found in fibrodysplasia ossificans progressiva, its repurposing for the treatment of osteoblastic cancer metastasis is promising. However, patient selection and dose-finding studies will be critical for the translation of these findings to complement standard of care for patients with bone metastatic prostate cancer. See related article by Yu et al., p. 3158.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2251
  8. Cancer Res. 2022 Aug 29. pii: CAN-22-0909. [Epub ahead of print]
    An alternatively spliced p62 isoform confers resistance to chemotherapy in breast cancer.
    Qianying Guo, Hao Wang, Jiahao Duan, Wenwu Luo, Rong Rong Zhao, Yuting Shen, Bijun Wang, Siqi Tao, Yi Sun, Qian Ye, Xiaomin Bi, Hui Yuan, Qiang Wu, Peter E Lobie, Tao Zhu, Sheng Tan, Xing Huang, Zhengsheng Wu.
      Resistance to chemotherapy remains a major obstacle to the successful treatment of breast cancer. More than 80% of patients who receive neoadjuvant chemotherapy (NAC) do not achieve a pathological complete response. In this study, we report a novel p62 mRNA isoform with a short 3'-UTR (p62-SU, 662-nt) that is associated with chemoresistance in breast cancer cells and tissue specimens. The p62 mRNA isoform was identified by RNA sequencing with qRT-PCR, 3'-RACE, and northern blot analysis. In vitro and in vivo, ectopic expression of p62-SU promoted breast cancer cell proliferation, migration, invasion, and chemoresistance compared with the p62 mRNA isoform with a full-length 3'-UTR (p62-LU, 1,485-nt). Mechanistically, CPSF1 modulated the 3'-UTR of p62 through alternative polyadenylation. In addition, p62-SU escaped miR-124-3p-mediated repression and upregulated p62-SU protein expression, thereby inducing p62-dependent chemoresistance. These data suggest that a CPSF1-p62-miR-124-3p signaling axis is responsible for reduced sensitivity of breast cancer to chemotherapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0909
  9. Cancer Discov. 2022 Sep 02. 12(9): 2023-2025
    Pumping Iron: Ferritinophagy Promotes Survival and Therapy Resistance in Pancreatic Cancer.
    Vaibhav Jain, Ravi K Amaravadi.
       SUMMARY: Autophagy is an adaptive response to metabolic and therapeutic stress, especially in treatment-refractory cancers such as pancreatic cancer. In this issue of Cancer Discovery, two groups establish ferritinophagy, a selective autophagy program that could become a drug target, as the mechanism that pumps iron into mitochondria via the lysosome, enabling survival and therapy resistance in pancreas cancer. See related article by Santana-Codina et al., p. 2180 (3). See related article by Ravichandran et al., p. 2198 (4).
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0734
  10. J Clin Invest. 2022 Sep 01. pii: e160152. [Epub ahead of print]
    Targeting acetylcholine signaling modulates persistent drug tolerance in EGFR-mutant lung cancer and impedes tumor relapse.
    Meng Nie, Na Chen, Huanhuan Pang, Tao Jiang, Wei Jiang, Panwen Tian, LiAng Yao, Yangzi Chen, Ralph J DeBerardinis, Weimin Li, Qitao Yu, Caicun Zhou, Zeping Hu.
      Although first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is effective for treating EGFR-mutant non-small cell lung cancer (NSCLC), it is now understood that drug-tolerant persister (DTP) cells escaping from initial treatment eventually drives drug resistance. Here, through integration of metabolomics and transcriptomics, we found that the neurotransmitter acetylcholine (ACh) was specifically accumulated in DTP cells, and illustrated that treatment with EGFR-TKI heightens the expression of the rate-limiting enzyme choline acetyltransferase (ChAT) in ACh biosynthesis via YAP mediation. Genetic and pharmacological manipulation of ACh biosynthesis or ACh signaling could predictably regulate the extent of DTP formation in vitro and in vivo. Strikingly, pharmacologically targeting ACh/M3R signaling with an FDA-approved drug, Darifenacin, retarded tumor relapse in vivo. Mechanistically, upregulated ACh metabolism mediated drug tolerance in part through activating WNT signaling via ACh muscarinic receptor-3 (M3R). Importantly, aberrant ACh metabolism in NSCLC patients represented a potential role in predicting EGFR-TKI response rate and progression-free survival. Our study therefore defines a new therapeutic strategy-targeting ACh-M3R-WNT axis-for manipulating EGFR TKI drug tolerance in the treatment of NSCLC.
    Keywords:  Drug therapy; Lung cancer; Metabolism; Oncology; Tolerance
    DOI:  https://doi.org/10.1172/JCI160152
  11. Cancer Immunol Res. 2022 Aug 30. pii: CIR-21-1120. [Epub ahead of print]
    Reciprocal interactions between the gut microbiome and mammary tissue mast cells promote metastatic dissemination of HR+ breast tumors.
    Tzu-Yu Feng, Francesca N Azar, Sally A Dreger, Claire Buchta Rosean, Mitchell T McGinty, Audrey M Putelo, Sree H Kolli, Maureen A Carey, Stephanie Greenfield, Wesley J Fowler, Stephen D Robinson, Melanie R Rutkowski.
      Establishing commensal dysbiosis, defined as an inflammatory gut microbiome with low biodiversity, prior to breast tumor initiation, enhances early dissemination of hormone-receptor-positive (HR+) mammary tumor cells. Here, we sought to determine whether cellular changes occurring in normal mammary tissues, prior to tumor initiation and in response to dysbiosis, enhanced dissemination of HR+ tumors. Commensal dysbiosis increased both the frequency and pro-fibrogenicity of mast cells in normal, non-tumor-bearing mammary tissues, a phenotypic change that persisted after tumor implantation. Pharmacological and adoptive transfer approaches demonstrated that pro-fibrogenic mammary tissue mast cells from dysbiotic animals were sufficient to enhance dissemination of HR+ tumor cells. Using archival HR+ patient samples, we determined that enhanced collagen levels in tumor-adjacent mammary tissue positively correlated with mast cell abundance and HR+ breast cancer recurrence. Together, these data demonstrate that mast cells programmed by commensal dysbiosis activate mammary tissue fibroblasts and orchestrate early dissemination of HR+ breast tumors.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-21-1120
  12. Mol Cancer. 2022 Sep 01. 21(1): 173
    CircSMARCC1 facilitates tumor progression by disrupting the crosstalk between prostate cancer cells and tumor-associated macrophages via miR-1322/CCL20/CCR6 signaling.
    Tao Xie, Du-Jiang Fu, Zhi-Min Li, Dao-Jun Lv, Xian-Lu Song, Yu-Zhong Yu, Chong Wang, Kang-Jin Li, Baoqian Zhai, Jiacheng Wu, Ning-Han Feng, Shan-Chao Zhao.
       BACKGROUND: Circular RNAs (circRNAs) mediate the infiltration of tumor-associated macrophages (TAMs) to facilitate carcinogenesis and development of various types of cancers. However, the role of circRNAs in regulating macrophages in prostate cancer (PCa) remains uncertain.
    METHODS: Differentially expressed circRNAs in PCa were identified by RNA sequencing. The expression of circSMARCC1 was recognized and evaluated using fluorescence in situ hybridization and quantitative real-time PCR. The oncogenic role of circSMARCC1 in PCa tumor proliferation and metastasis was investigated through a series of in vitro and in vivo assays. Finally, Western blot, biotin-labeled RNA pulldown, luciferase assay, rescue experiments, and co-culture experiments with TAMs were conducted to reveal the mechanistic role of circSMARCC1.
    RESULTS: CircSMARCC1 was dramatically up-regulated in PCa cells, plasma and tissues. Overexpression of circSMARCC1 promotes tumor proliferation and metastasis both in vitro and in vivo, whereas knockdown of circSMARCC1 exerts the opposite effects. Mechanistically, circSMARCC1 regulates the expression of CC-chemokine ligand 20 (CCL20) via sponging miR-1322 and activate PI3K-Akt signaling pathway involved in the proliferation and epithelial mesenchymal transformation. More importantly, high expression of circSMARCC1 was positively associated with colonization of CD68+/CD163+/CD206+ TAMs in tumor microenvironment. In addition, overexpression of circSMARCC1 facilitates the expression of CD163 in macrophages through the CCL20-CCR6 axis, induces TAMs infiltration and M2 polarization, thereby leading to PCa progression.
    CONCLUSIONS: CircSMARCC1 up-regulates the chemokine CCL20 secretion by sponging miR-1322, which is involved in the crosstalk between tumor cells and TAMs by targeting CCL20/CCR6 signaling to promote progression of PCa.
    Keywords:  CC-chemokine ligand 20; CircSMARCC1; Epithelial mesenchymal transformation; Prostate cancer; Tumor-associated macrophage
    DOI:  https://doi.org/10.1186/s12943-022-01630-9
  13. STAR Protoc. 2022 Sep 16. 3(3): 101600
    Coupling live-cell imaging and in situ isolation of the same single cell to profile the transient states of predicted drug-tolerant cells.
    Benjamin Bian, Agnès Paquet, Marie-Jeanne Arguel, Mickael Meyer, Ludovic Peyre, Asma Chalabi, Marielle Péré, Kevin Lebrigand, Rainer Waldmann, Pascal Barbry, Paul Hofman, Jérémie Roux.
      Cell response variability is a starting point in cancer drug resistance that has been difficult to analyze because the tolerant cell states are short lived. Here, we present fate-seq, an approach to isolate single cells in their transient states of drug sensitivity or tolerance before profiling. The drug response is predicted in live cells, which are laser-captured by microdissection before any drug-induced change can alter their states. This framework enables the identification of the cell-state signatures causing differential cell decisions upon treatment. For complete details on the use and execution of this protocol, please refer to Meyer et al. (2020).
    Keywords:  Cell isolation; Cell-based Assays; Microscopy; Single Cell; Systems biology
    DOI:  https://doi.org/10.1016/j.xpro.2022.101600
  14. Cancer Res. 2022 Sep 02. 82(17): 3016-3031
    Gain of Chromosome 1q Perturbs a Competitive Endogenous RNA Network to Promote Melanoma Metastasis.
    Xiaonan Xu, Kaizhen Wang, Olga Vera, Akanksha Verma, Neel Jasani, Ilah Bok, Olivier Elemento, Dongliang Du, Xiaoqing Yu, Florian A Karreth.
      Somatic copy-number alterations (CNA) promote cancer, but the underlying driver genes may not be comprehensively identified if only the functions of the encoded proteins are considered. mRNAs can act as competitive endogenous RNAs (ceRNA), which sponge miRNAs to posttranscriptionally regulate gene expression in a protein coding-independent manner. We investigated the contribution of ceRNAs to the oncogenic effects of CNAs. Chromosome 1q gains promoted melanoma progression and metastasis at least in part through overexpression of three mRNAs with ceRNA activity: CEP170, NUCKS1, and ZC3H11A. These ceRNAs enhanced melanoma metastasis by sequestering tumor suppressor miRNAs. Orthogonal genetic assays with miRNA inhibitors and target site blockers, along with rescue experiments, demonstrated that miRNA sequestration is critical for the oncogenic effects of CEP170, NUCKS1, and ZC3H11A mRNAs. Furthermore, chromosome 1q ceRNA-mediated miRNA sequestration alleviated the repression of several prometastatic target genes. This regulatory RNA network was evident in other cancer types, suggesting chromosome 1q ceRNA deregulation as a common driver of cancer progression. Taken together, this work demonstrates that ceRNAs mediate the oncogenicity of somatic CNAs.
    SIGNIFICANCE: The function of CEP170, NUCKS1, and ZC3H11A mRNAs as competitive endogenous RNAs that sequester tumor suppressor microRNAs underlies the oncogenic activity of chromosome 1q gains.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0283
  15. Sci Adv. 2022 Sep 02. 8(35): eabo7792
    Genome-wide in vivo screen of circulating tumor cells identifies SLIT2 as a regulator of metastasis.
    Fan Xia, Yuan Ma, Kangfu Chen, Bill Duong, Sharif Ahmed, Randy Atwal, David Philpott, Troy Ketela, Jennifer Pantea, Sichun Lin, Stephane Angers, Shana O Kelley.
      Circulating tumor cells (CTCs) break free from primary tumors and travel through the circulation system to seed metastatic tumors, which are the major cause of death from cancer. The identification of the major genetic factors that enhance production and persistence of CTCs in the bloodstream at a whole genome level would enable more comprehensive molecular mechanisms of metastasis to be elucidated and the identification of novel therapeutic targets, but this remains a challenging task due to the heterogeneity and extreme rarity of CTCs. Here, we describe an in vivo genome-wide CRISPR knockout screen using CTCs directly isolated from a mouse xenograft. This screen elucidated SLIT2-a gene encoding a secreted protein acting as a cellular migration cue-as the most significantly represented gene knockout in the CTC population. SLIT2 knockout cells are highly metastatic with hypermigratory and mesenchymal phenotype, resulting in enhanced cancer progression in xenograft models.
    DOI:  https://doi.org/10.1126/sciadv.abo7792
  16. Clin Cancer Res. 2022 Aug 31. pii: CCR-22-1332. [Epub ahead of print]
    High-dimensional and spatial analysis reveals immune landscape dependent progression in cutaneous squamous cell carcinoma.
    Angela L Ferguson, Ashleigh R Sharman, Ruth O Allen, Thomas Ye, Jenny H Lee, Tsu-Hui H Low, Sydney Ch'ng, Carsten E Palme, Bruce Ashford, Marie Ranson, Jonathan R Clark, Ellis Patrick, Ruta Gupta, Umaimainthan Palendira.
       PURPOSE: The tumour immune microenvironment impacts the biological behaviour of the tumour but its effect on clinical outcomes in head and neck cutaneous squamous cell carcinomas (HNcSCC) is largely unknown.
    EXPERIMENTAL DESIGN: We compared the immune milieu of high-risk HNcSCC that never progressed to metastasis with those that metastasised using multi-parameter imaging mass cytometry. The cohort included both immunosuppressed patients (IS) and patients with an absence of clinical immune-suppression (ACIS). Spatial analyses were used to identify cellular interactions that were associated with tumour behaviour.
    RESULTS: Non-progressing primary HNcSCC were characterised by higher CD8+ and CD4+ T cell responses, including numerically increased Regulatory T cells. By contrast, primary lesions from HNcSCC patients who progressed were largely devoid of T cells with lower numbers of innate immune cells and increased expression of checkpoint receptors and in the metastatic lesions were characterised by an accumulation of B cells. Spatial analysis reveals multiple cellular interactions associated with non-progressing primary tumours that were distinct in primary tumours of disease progressing patients. Cellular regional analysis of the tumour microenvironment also shows squamous cell-enriched tumour regions associated with primary non-progressing tumours.
    CONCLUSIONS: Effective responses from both CD8+ and CD4+ T cells in the tumour microenvironment are essential for immune control of primary HNcSCC. Our findings indicate that the early events that shape the immune responses in primary tumours dictate progression and disease outcomes in HNcSCC.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-1332
  17. Cell Rep. 2022 Aug 30. pii: S2211-1247(22)01115-9. [Epub ahead of print]40(9): 111295
    Tumor-infiltrated activated B cells suppress liver metastasis of colorectal cancers.
    Yuqiu Xu, Zhuang Wei, Mei Feng, Dexiang Zhu, Shenglin Mei, Zhongen Wu, Qingyang Feng, Wenju Chang, Meiling Ji, Chenglong Liu, Yuanyuan Zhu, Lian Shen, Fan Yang, Yijiao Chen, Yuxiong Feng, Jianmin Xu, Di Zhu.
      More than 40% of patients with late-stage colorectal cancer (CRC) develop liver metastasis (LM). Which immune cells play important roles in CRC-LM and contribute to the difference between left-sided CRC (LCC) and right-sided CRC (RCC) remain unclear. By single-cell RNA sequencing (scRNA-seq), we not only find that activated B cells are significantly depleted in CRC with LM, but also find a subtype of B cells developed from activated B cells, namely immature plasma cell population alpha (iMPA), highly correlated with metastasis. Mechanistically, inhibition of the Wnt and transforming growth factor β (TGF-β) pathways in cancer cell promotes activated B cell migration via the SDF-1-CXCR4 axis. This study reveals that B cell subpopulations in the tumor immune microenvironment (TIME) play a key role in CRC-LM as well as in LCC and RCC. The preventive effects of modulating B cell subpopulations in CRC may provide a rationale for subsequent drug development and CRC-LM management.
    Keywords:  CP: Cancer; SDF-1-CXCR4; Wnt signaling; activated B cells; colorectal cancer; liver metastasis; scRNA-seq; tumor immune microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2022.111295
  18. Mol Cancer. 2022 Sep 02. 21(1): 174
    The m6A demethylase ALKBH5-mediated upregulation of DDIT4-AS1 maintains pancreatic cancer stemness and suppresses chemosensitivity by activating the mTOR pathway.
    Yi Zhang, Xiaomeng Liu, Yan Wang, Shihui Lai, Zhiqian Wang, Yudie Yang, Wenhui Liu, Hongquan Wang, Bo Tang.
       BACKGROUND: Chemoresistance is a major factor contributing to the poor prognosis of patients with pancreatic cancer, and cancer stemness is one of the most crucial factors associated with chemoresistance and a very promising direction for cancer treatment. However, the exact molecular mechanisms of cancer stemness have not been completely elucidated.
    METHODS: m6A-RNA immunoprecipitation and sequencing were used to screen m6A-related mRNAs and lncRNAs. qRT-PCR and FISH were utilized to analyse DDIT4-AS1 expression. Spheroid formation, colony formation, Western blot and flow cytometry assays were performed to analyse the cancer stemness and chemosensitivity of PDAC cells. Xenograft experiments were conducted to analyse the tumour formation ratio and growth in vivo. RNA sequencing, Western blot and bioinformatics analyses were used to identify the downstream pathway of DDIT4-AS1. IP, RIP and RNA pulldown assays were performed to test the interaction between DDIT4-AS1, DDIT4 and UPF1. Patient-derived xenograft (PDX) mouse models were generated to evaluate chemosensitivities to GEM.
    RESULTS: DDIT4-AS1 was identified as one of the downstream targets of ALKBH5, and recruitment of HuR onto m6A-modified sites is essential for DDIT4-AS1 stabilization. DDIT4-AS1 was upregulated in PDAC and positively correlated with a poor prognosis. DDIT4-AS1 silencing inhibited stemness and enhanced chemosensitivity to GEM (Gemcitabine). Mechanistically, DDIT4-AS1 promoted the phosphorylation of UPF1 by preventing the binding of SMG5 and PP2A to UPF1, which decreased the stability of the DDIT4 mRNA and activated the mTOR pathway. Furthermore, suppression of DDIT4-AS1 in a PDX-derived model enhanced the antitumour effects of GEM on PDAC.
    CONCLUSIONS: The ALKBH5-mediated m6A modification led to DDIT4-AS1 overexpression in PDAC, and DDIT-AS1 increased cancer stemness and suppressed chemosensitivity to GEM by destabilizing DDIT4 and activating the mTOR pathway. Approaches targeting DDIT4-AS1 and its pathway may be an effective strategy for the treatment of chemoresistance in PDAC.
    Keywords:  ALKBH5; Chemosensitivity; DDIT4-AS1; Stemness; UPF1
    DOI:  https://doi.org/10.1186/s12943-022-01647-0
  19. Cancer Discov. 2022 Sep 02. OF1
    Transcriptomic Profiling Highlights Rectal Tumors with Improved Prognosis.
      Transcriptomic and immune features distinguish responses to neoadjuvant therapy in rectal cancer.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-160
  20. Clin Cancer Res. 2022 Sep 01. pii: CCR-22-0749. [Epub ahead of print]
    Mutational signature 3 detected from clinical panel sequencing is associated with responses to olaparib in breast and ovarian cancers.
    Felipe Batalini, Doga C Gulhan, Victor Mao, Antuan Tran, Madeline Polak, Niya Xiong, Nabihah Tayob, Nadine M Tung, Eric P Winer, Erica L Mayer, Stian Knappskog, Per Eystein Lønning, Ursula A Matulonis, Panagiotis A Konstantinopoulos, David B Solit, Helen Won, Hans Petter Eikesdal, Peter J Park, Gerburg M Wulf.
       BACKGROUND: The identification of patients with homologous recombination deficiency (HRD) beyond BRCA1/2 mutations is an urgent task, as they may benefit from PARP inhibitors. We have previously developed a method to detect mutational signature 3 (Sig3), termed SigMA, associated with HRD from clinical panel sequencing data, that is able to reliably detect HRD from the limited sequencing data derived from gene-focused panel sequencing.
    METHODS: We apply this method to patients from two independent datasets: (1) high-grade serous ovarian cancer and triple-negative breast cancer (TNBC) from a Phase 1b trial of the PARP inhibitor olaparib in combination with the PI3K inhibitor buparlisib (BKM120) (NCT01623349), and (2) TNBC patients who received neoadjuvant olaparib in the Phase II PETREMAC trial (NCT02624973).
    RESULTS: We find that Sig3 as detected by SigMA is positively associated with improved progression-free survival and objective responses. In addition, comparison of Sig3 detection in panel and exome sequencing data from the same patient samples demonstrated highly concordant results and superior performance in comparison with the genomic instability score.
    CONCLUSION: Our analyses demonstrate that HRD can be detected reliably from panel sequencing data that are obtained as part of routine clinical care, and that this approach can identify patients beyond those with germline BRCA12 mut who might benefit from PARP inhibitors. Prospective clinical utility testing is warranted.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-0749
  21. Autophagy. 2022 Aug 29.
    Genome-Scale CRISPR Screen Identifies LAPTM5 driving lenvatinib resistance in hepatocellular carcinoma.
    Jiaomeng Pan, Mao Zhang, Liangqing Dong, Shuyi Ji, Juan Zhang, Shu Zhang, Youpei Lin, Xiaoying Wang, Zhenbin Ding, Shuangjian Qiu, Daming Gao, Jian Zhou, Jia Fan, Qiang Gao.
      Drug resistance has greatly limited the clinical efficacy of lenvatinib in hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of lenvatinib resistance remain largely undetermined. Further in-depth exploration of mechanisms underlying lenvatinib resistance is still required for the majority of HCC patients. In this study, integrated unbiased whole-genome CRISPR-Cas9 screen with database analysis indicated LAPTM5 (lysosomal protein transmembrane 5) as the critical contributor to lenvatinib resistance in HCC. We revealed that LAPTM5 could promote intrinsic macroautophagic/autophagic flux by facilitating autolysosome formation to drive lenvatinib resistance. The upregulation of LAPTM5 in HCC was induced by both DNA hypomethylation and driver mutations like TP53. Inhibition of autolysosome formation by either hydroxychloroquine (HCQ) or LAPTM5 abrogation worked synergistically with lenvatinib to inhibit tumor growth. In HCC cell lines, patient-derived primary cell lines and organoids, as well as human HCC xenografts and immunocompetent mouse HCC model, the close association between LAPTM5 and sensitivity to lenvatinib was consistently verified. Importantly, in clinical HCC samples, where lenvatinib was used as the first line or adjuvant therapy, LAPTM5 expression positively correlated with lenvatinib sensitivity, implying it as a biomarker to predict patient response to lenvatinib. In conclusion, the combinational therapy targeting autophagy represented a promising strategy to overcome lenvatinib resistance in HCC, and LAPTM5 expression could provide potential guidance for clinical interference.
    Keywords:  Autophagy; LAPTM5; drug resistance; lenvatinib; liver cancer; whole-genome CRISPR-Cas9 screen
    DOI:  https://doi.org/10.1080/15548627.2022.2117893
  22. EMBO J. 2022 Sep 02. e109288
    Extracellular vesicles and particles impact the systemic landscape of cancer.
    Serena Lucotti, Candia M Kenific, Haiying Zhang, David Lyden.
      Intercellular cross talk between cancer cells and stromal and immune cells is essential for tumor progression and metastasis. Extracellular vesicles and particles (EVPs) are a heterogeneous class of secreted messengers that carry bioactive molecules and that have been shown to be crucial for this cell-cell communication. Here, we highlight the multifaceted roles of EVPs in cancer. Functionally, transfer of EVP cargo between cells influences tumor cell growth and invasion, alters immune cell composition and function, and contributes to stromal cell activation. These EVP-mediated changes impact local tumor progression, foster cultivation of pre-metastatic niches at distant organ-specific sites, and mediate systemic effects of cancer. Furthermore, we discuss how exploiting the highly selective enrichment of molecules within EVPs has profound implications for advancing diagnostic and prognostic biomarker development and for improving therapy delivery in cancer patients. Altogether, these investigations into the role of EVPs in cancer have led to discoveries that hold great promise for improving cancer patient care and outcome.
    Keywords:  biomarkers; cancer; extracellular vesicles and particles; metastasis; therapeutic deliverables
    DOI:  https://doi.org/10.15252/embj.2021109288
  23. EMBO J. 2022 Aug 30. e110046
    Suppression of Ca2+ signaling enhances melanoma progression.
    Scott Gross, Robert Hooper, Dhanendra Tomar, Alexander P Armstead, No'ad Shanas, Pranava Mallu, Hinal Joshi, Suravi Ray, Parkson Lee-Gau Chong, Igor Astsaturov, Jeffrey M Farma, Kathy Q Cai, Kumaraswamy Naidu Chitrala, John W Elrod, M Raza Zaidi, Jonathan Soboloff.
      The role of store-operated Ca2+ entry (SOCE) in melanoma metastasis is highly controversial. To address this, we here examined UV-dependent metastasis, revealing a critical role for SOCE suppression in melanoma progression. UV-induced cholesterol biosynthesis was critical for UV-induced SOCE suppression and subsequent metastasis, although SOCE suppression alone was both necessary and sufficient for metastasis to occur. Further, SOCE suppression was responsible for UV-dependent differences in gene expression associated with both increased invasion and reduced glucose metabolism. Functional analyses further established that increased glucose uptake leads to a metabolic shift towards biosynthetic pathways critical for melanoma metastasis. Finally, examination of fresh surgically isolated human melanoma explants revealed cholesterol biosynthesis-dependent reduced SOCE. Invasiveness could be reversed with either cholesterol biosynthesis inhibitors or pharmacological SOCE potentiation. Collectively, we provide evidence that, contrary to current thinking, Ca2+ signals can block invasive behavior, and suppression of these signals promotes invasion and metastasis.
    Keywords:  Orai1; STIM1; calcium; melanoma; metastasis
    DOI:  https://doi.org/10.15252/embj.2021110046
  24. Cancer Cell. 2022 Aug 26. pii: S1535-6108(22)00383-X. [Epub ahead of print]
    Cellular hierarchies predict drug response in acute myeloid leukemia.
    Simon Raffel, Lars Velten, Simon Haas.
      In a recent Nature Medicine study, Zeng and colleagues integrate both genomic and stem cell models of acute myeloid leukemia (AML) by deconvoluting cellular hierarchies of more than 1,000 AML samples. This work introduces a framework capable of predicting drug responses to targeted therapies in future clinical trials.
    DOI:  https://doi.org/10.1016/j.ccell.2022.08.019
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