bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2022‒01‒16
thirty-one papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Nat Rev Cancer. 2022 Jan 10.
      Resistance to therapeutic treatment and metastatic progression jointly determine a fatal outcome of cancer. Cancer metastasis and therapeutic resistance are traditionally studied as separate fields using non-overlapping strategies. However, emerging evidence, including from in vivo imaging and in vitro organotypic culture, now suggests that both programmes cooperate and reinforce each other in the invasion niche and persist upon metastatic evasion. As a consequence, cancer cell subpopulations exhibiting metastatic invasion undergo multistep reprogramming that - beyond migration signalling - supports repair programmes, anti-apoptosis processes, metabolic adaptation, stemness and survival. Shared metastasis and therapy resistance signalling are mediated by multiple mechanisms, such as engagement of integrins and other context receptors, cell-cell communication, stress responses and metabolic reprogramming, which cooperate with effects elicited by autocrine and paracrine chemokine and growth factor cues present in the activated tumour microenvironment. These signals empower metastatic cells to cope with therapeutic assault and survive. Identifying nodes shared in metastasis and therapy resistance signalling networks should offer new opportunities to improve anticancer therapy beyond current strategies, to eliminate both nodular lesions and cells in metastatic transit.
  2. Cancer Discov. 2022 Jan 14.
      Metabolic diversity and plasticity in HER2+ brain-tropic breast cancer cells shape metastatic fitness.
  3. Gut. 2022 Jan 12. pii: gutjnl-2021-325272. [Epub ahead of print]
      OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease and cytotoxic chemotherapy is the standard of care treatment for patients with advanced disease. Here, we investigate how the microenvironment in PDAC liver metastases reacts to chemotherapy and its role in metastatic disease progression post-treatment, an area which is poorly understood.DESIGN: The impact of chemotherapy on metastatic disease progression and immune cell infiltrates was characterised using flow and mass cytometry combined with transcriptional and histopathological analysis in experimental PDAC liver metastases mouse models. Findings were validated in patient derived liver metastases and in an autochthonous PDAC mouse model. Human and murine primary cell cocultures and ex vivo patient-derived liver explants were deployed to gain mechanistical insights on whether and how chemotherapy affects the metastatic tumour microenvironment.
    RESULTS: We show that in vivo, chemotherapy induces an initial infiltration of proinflammatory macrophages into the liver and activates cytotoxic T cells, leading only to a temporary restraining of metastatic disease progression. However, after stopping treatment, neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth. Disruption of neutrophil infiltration or inhibition of the Gas6/AXL signalling axis in combination with chemotherapy inhibits metastatic growth. Chemotherapy increases Gas6 expression in circulating neutrophils from patients with metastatic pancreatic cancer and recombinant Gas6 is sufficient to promote tumour cell proliferation ex vivo, in patient-derived metastatic liver explants.
    CONCLUSION: Combining chemotherapy with Gas6/AXL or neutrophil targeted therapy could provide a therapeutic benefit for patients with metastatic pancreatic cancer.
    Keywords:  immune response; liver metastases; macrophages; pancreatic cancer
  4. EMBO Mol Med. 2022 Jan 13. e14903
      Entering a drug-tolerant persister (DTP) state of cancer cells is a transient self-adaptive mechanism by which a residual cell subpopulation accelerates tumor progression. Here, we identified the acquisition of a DTP phenotype in multidrug-resistant (MDR) cancer cells as a tolerance response to routine combination treatment. Characterization of MDR cancer cells with a DTP state by RNA-seq revealed that these cells partially prevented chemotherapy-triggered oxidative stress by promoting NPC1L1-regulated uptake of vitamin E. Treatment with the NPC1L1 inhibitor ezetimibe further enhanced the therapeutic effect of combinatorial therapy by inducing methuosis. Mechanistically, we demonstrated that NRF2 was involved in transcriptional regulation of NPC1L1 by binding to the -205 to -215 bp site on its promoter. Decreased DNA methylation was also related partially to this process. Furthermore, we confirmed that a triple-combination of chemotherapeutic agents, verapamil, and ezetimibe, had a significant anti-tumor effect and prevented tumor recurrence in mice. Together, our study provides a novel insight into the role of DTP state and emphasizes the importance of disrupting redox homeostasis during cancer therapy.
    Keywords:  NPC1L1; cancer therapy; drug-tolerant persister state; multidrug resistance; oxidative stress
  5. Oncogene. 2022 Jan 08.
      Metastasis-initiating cells (MICs) display stem cell-like features, cause metastatic recurrences and defy chemotherapy, which leads to patients' demise. Here we show that prostate and breast cancer patients harbor contingents of tumor cells with high expression of CX3CR1, OCT4a (POU5F1), and NANOG. Impairing CX3CR1 expression or signaling hampered the formation of tumor spheroids by cell lines from which we isolated small subsets co-expressing CX3CR1 and stemness-related markers, similarly to patients' tumors. These rare CX3CR1High cells show transcriptomic profiles enriched in pathways that regulate pluripotency and endowed with metastasis-initiating behavior in murine models. Cancer cells lacking these features (CX3CR1Low) were capable of re-acquiring CX3CR1-associated features over time, implying that MICs can continuously emerge from non-stem cancer cells. CX3CR1 expression also conferred resistance to docetaxel, and prolonged treatment with docetaxel selected CX3CR1High phenotypes with de-enriched transcriptomic profiles for apoptotic pathways. These findings nominate CX3CR1 as a novel marker of stem-like tumor cells and provide conceptual ground for future development of approaches targeting CX3CR1 signaling and (re)expression as therapeutic means to prevent or contain metastasis initiation.
  6. Dev Cell. 2022 Jan 10. pii: S1534-5807(21)00996-5. [Epub ahead of print]57(1): 32-46.e8
      We test the hypothesis that glioblastoma harbors quiescent cancer stem cells that evade anti-proliferative therapies. Functional characterization of spontaneous glioblastomas from genetically engineered mice reveals essential quiescent stem-like cells that can be directly isolated from tumors. A derived quiescent cancer-stem-cell-specific gene expression signature is enriched in pre-formed patient GBM xenograft single-cell clusters that lack proliferative gene expression. A refined human 118-gene signature is preserved in quiescent single-cell populations from primary and recurrent human glioblastomas. The F3 cell-surface receptor mRNA, expressed in the conserved signature, identifies quiescent tumor cells by antibody immunohistochemistry. F3-antibody-sorted glioblastoma cells exhibit stem cell gene expression, enhance self-renewal in culture, drive tumor initiation and serial transplantation, and reconstitute tumor heterogeneity. Upon chemotherapy, the spared cancer stem cell pool becomes activated and accelerates transition to proliferation. These results help explain conventional treatment failure and lay a conceptual framework for alternative therapies.
    Keywords:  F3 receptor; cancer stem cells; chemoresistance; glioblastoma; heterogeneity; quiescence; recurrence; single-cell RNA sequencing; temozolomide
  7. EMBO Mol Med. 2022 Jan 11. e14764
      Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, we show that the ER membrane-associated protein THEM6 regulates intracellular levels of ether lipids and is essential to trigger the induction of the ER stress response (UPR). Consequently, THEM6 loss in CRPC cells significantly alters ER function, reducing de novo sterol biosynthesis and preventing lipid-mediated activation of ATF4. Finally, we demonstrate that high THEM6 expression is associated with poor survival and correlates with high levels of UPR activation in PCa patients. Altogether, our results highlight THEM6 as a novel driver of therapy resistance in PCa as well as a promising target for the treatment of CRPC.
    Keywords:  ATF4; ER stress; lipid metabolism; prostate cancer; therapy resistance
  8. Cell Rep Med. 2021 Dec 21. 2(12): 100471
      Resistance to platinum compounds is a major determinant of patient survival in high-grade serous ovarian cancer (HGSOC). To understand mechanisms of platinum resistance and identify potential therapeutic targets in resistant HGSOC, we generated a data resource composed of dynamic (±carboplatin) protein, post-translational modification, and RNA sequencing (RNA-seq) profiles from intra-patient cell line pairs derived from 3 HGSOC patients before and after acquiring platinum resistance. These profiles reveal extensive responses to carboplatin that differ between sensitive and resistant cells. Higher fatty acid oxidation (FAO) pathway expression is associated with platinum resistance, and both pharmacologic inhibition and CRISPR knockout of carnitine palmitoyltransferase 1A (CPT1A), which represents a rate limiting step of FAO, sensitize HGSOC cells to platinum. The results are further validated in patient-derived xenograft models, indicating that CPT1A is a candidate therapeutic target to overcome platinum resistance. All multiomic data can be queried via an intuitive gene-query user interface (
    Keywords:  CPT1A; carboplatin; fatty acid oxidation; ovarian cancer; oxidative phosphorylation; proteogenomic; proteomic; reactive oxygen species; resistance
  9. Oncogene. 2022 Jan 14.
      Metastatic outgrowth is supported by metabolic adaptations that may differ from the primary tumor of origin. However, it is unknown if such adaptations are therapeutically actionable. Here we report a novel aminopyridine compound that targets a unique Phosphogluconate Dehydrogenase (PGD)-dependent metabolic adaptation in distant metastases from pancreatic cancer patients. Compared to structurally similar analogs, 6-aminopicolamine (6AP) potently and selectively reversed PGD-dependent metastatic properties, including intrinsic tumorigenic capacity, excess glucose consumption, and global histone hyperacetylation. 6AP acted as a water-soluble prodrug that was converted into intracellular bioactive metabolites that inhibited PGD in vitro, and 6AP monotherapy demonstrated anti-metastatic efficacy with minimal toxicity in vivo. Collectively, these studies identify 6AP and possibly other 6-aminopyridines as well-tolerated prodrugs with selectivity for metastatic pancreatic cancers. If unique metabolic adaptations are a common feature of metastatic or otherwise aggressive human malignancies, then such dependencies could provide a largely untapped pool of druggable targets for patients with advanced cancers.
  10. Nat Commun. 2022 Jan 10. 13(1): 182
      Combining immune checkpoint therapy (ICT) and targeted therapy holds great promises for broad and long-lasting anti-cancer therapies. However, combining ICT with anti-PI3K inhibitors have been challenging because the multifaceted effects of PI3K on both cancer cells and immune cells within the tumor microenvironment. Here we find that intermittent but not daily dosing of a PI3Kα/β/δ inhibitor, BAY1082439, on Pten-null prostate cancer models could overcome ICT resistance and unleash CD8+ T cell-dependent anti-tumor immunity in vivo. Mechanistically, BAY1082439 converts cancer cell-intrinsic immune-suppression to immune-stimulation by promoting IFNα/IFNγ pathway activation, β2-microglubin expression and CXCL10/CCL5 secretion. With its preferential regulatory T cell inhibition activity, BAY1082439 promotes clonal expansion of tumor-associated CD8+ T cells, most likely via tertiary lymphoid structures. Once primed, tumors remain T cell-inflamed, become responsive to anti-PD-1 therapy and have durable therapeutic effect. Our data suggest that intermittent PI3K inhibition can alleviate Pten-null cancer cell-intrinsic immunosuppressive activity and turn "cold" tumors into T cell-inflamed ones, paving the way for successful ICT.
  11. J Clin Invest. 2022 Jan 13. pii: e149473. [Epub ahead of print]
      Cancer metastasis is the cause of the majority of cancer-related deaths. In this study, we demonstrated that no/low expression of ATP11B in conjunction with high expression of PTDSS2, which was negatively regulated by BRCA1, markedly accelerates tumor metastasis. Further analysis revealed that low ATP11B-expressing and high PTDSS2-expressing (ATP11Blow/PTDSS2high) cells were associated with poor prognosis and enhanced metastasis in breast cancer patients in general. Mechanistically, an ATP11Blow/PTDSS2high phenotype was associated with increased levels of nonapoptotic phosphatidylserine (PS) on the outer leaflet of the cell membrane. This PS increase serves as a global immunosuppressive signal to promote breast cancer metastasis through an enriched tumor microenvironment with the accumulation of myeloid-derived suppressive cells (MDSCs) and reduced activity of cytotoxic T cells. The metastatic processes associated with ATP11Blow/PTDSSi2hgh cancer cells can be effectively overcome by changing the expression phenotype to ATP11Bhigh/PTDSS2low through a combination of anti-PS antibody with either paclitaxel or docetaxel. Thus, blocking the ATP11Blow/PTDSS2high axis provided a new selective therapeutic strategy to prevent metastasis in breast cancer patients.
    Keywords:  Breast cancer; Cancer immunotherapy; Oncology; Tumor suppressors
  12. Nat Commun. 2022 Jan 10. 13(1): 141
      Prostate cancer is the second most common malignancy in men worldwide and consists of a mixture of tumor and non-tumor cell types. To characterize the prostate cancer tumor microenvironment, we perform single-cell RNA-sequencing on prostate biopsies, prostatectomy specimens, and patient-derived organoids from localized prostate cancer patients. We uncover heterogeneous cellular states in prostate epithelial cells marked by high androgen signaling states that are enriched in prostate cancer and identify a population of tumor-associated club cells that may be associated with prostate carcinogenesis. ERG-negative tumor cells, compared to ERG-positive cells, demonstrate shared heterogeneity with surrounding luminal epithelial cells and appear to give rise to common tumor microenvironment responses. Finally, we show that prostate epithelial organoids harbor tumor-associated epithelial cell states and are enriched with distinct cell types and states from their parent tissues. Our results provide diagnostically relevant insights and advance our understanding of the cellular states associated with prostate carcinogenesis.
  13. Mol Ther. 2022 Jan 08. pii: S1525-0016(22)00014-4. [Epub ahead of print]
      Endocytosis of cell surface receptors is essential for cell migration and cancer metastasis. Rab5, a small GTPases of Rab family, is a key regulator of endosome dynamics and thus cell migration, however, how its activity is regulated yet remains to be addressed. Here, we identified a Rab5 inhibitor, a long non-coding RNA namely HITT (HIF-1α inhibitor at translation level). Our data show that HITT expression is inversely associated with advanced stages and poorly prognosis of lung adenocarcinoma patients with area under receiver operating characteristics (ROC) curve (AUC) 0.6473. Further study reveals that both endogenous and exogenous HITT inhibits single cell migration by repressing β1 integrin endocytosis in lung adenocarcinoma. Mechanistically, HITT is physically associated with Rab5 at switch I via 1248-1347nt and suppresses β1 integrin endocytosis and subsequent cancer metastasis by interfering with guanine nucleotide exchange factors (GEFs) for Rab5 binding. Collectively, these findings suggest that HITT directly participates in the regulation of Rab5 activity, leading to a decreased integrin internalization and cancer metastasis, which provides important insights into a mechanistic understanding of endocytosis and cancer metastasis.
  14. Gut. 2022 Jan 10. pii: gutjnl-2021-324994. [Epub ahead of print]
      OBJECTIVE: Intratumor heterogeneity drives cancer progression and therapy resistance. However, it has yet to be determined whether and how subpopulations of cancer cells interact and how this interaction affects the tumour.DESIGN: We have studied the spontaneous flow of extracellular vesicles (EVs) between subpopulations of cancer cells: cancer stem cells (CSC) and non-stem cancer cells (NSCC). To determine the biological significance of the most frequent communication route, we used pancreatic ductal adenocarcinoma (PDAC) orthotopic models, patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMMs).
    RESULTS: We demonstrate that PDAC tumours establish an organised communication network between subpopulations of cancer cells using EVs called the EVNet). The EVNet is plastic and reshapes in response to its environment. Communication within the EVNet occurs preferentially from CSC to NSCC. Inhibition of this communication route by impairing Rab27a function in orthotopic xenographs, GEMMs and PDXs is sufficient to hamper tumour growth and phenocopies the inhibition of communication in the whole tumour. Mechanistically, we provide evidence that CSC EVs use agrin protein to promote Yes1 associated transcriptional regulator (YAP) activation via LDL receptor related protein 4 (LRP-4). Ex vivo treatment of PDXs with antiagrin significantly impairs proliferation and decreases the levels of activated YAP.Patients with high levels of agrin and low inactive YAP show worse disease-free survival. In addition, patients with a higher number of circulating agrin+ EVs show a significant increased risk of disease progression.
    CONCLUSION: PDAC tumours establish a cooperation network mediated by EVs that is led by CSC and agrin, which allows tumours to adapt and thrive. Targeting agrin could make targeted therapy possible for patients with PDAC and has a significant impact on CSC that feeds the tumour and is at the centre of therapy resistance.
    Keywords:  carcinogenesis; cell biology; molecular carcinogenesis; pancreatic cancer
  15. Cancer Discov. 2022 Jan;12(1): 20-22
      PIK3CA, which encodes the p110α catalytic subunit of PI3Kα, is one of the most frequently genetically activated kinases in solid tumors. In this issue of Cancer Discovery, Song and colleagues report that the related PI3Kα inhibitors taselisib and inavolisib trigger receptor tyrosine kinase (RTK)-dependent degradation of the mutant p110α protein in breast cancer cells that are positive for HER2 RTK, limiting feedback-mediated drug resistance and potentially widening the therapeutic index of PI3Kα inhibition.See related article by Song et al., p. 204.
  16. Nat Commun. 2022 Jan 11. 13(1): 245
      About 15-20% of breast cancer (BCa) is triple-negative BCa (TNBC), a devastating disease with limited therapeutic options. Aberrations in the PI3K/PTEN signaling pathway are common in TNBC. However, the therapeutic impact of PI3K inhibitors in TNBC has been limited and the mechanism(s) underlying this lack of efficacy remain elusive. Here, we demonstrate that a large subset of TNBC expresses significant levels of MAPK4, and this expression is critical for driving AKT activation independent of PI3K and promoting TNBC cell and xenograft growth. The ability of MAPK4 to bypass PI3K for AKT activation potentially provides a direct mechanism regulating tumor sensitivity to PI3K inhibition. Accordingly, repressing MAPK4 greatly sensitizes TNBC cells and xenografts to PI3K blockade. Altogether, we conclude that high MAPK4 expression defines a large subset or subtype of TNBC responsive to MAPK4 blockage. Targeting MAPK4 in this subset/subtype of TNBC both represses growth and sensitizes tumors to PI3K blockade.
  17. Cancer Res. 2022 Jan 13. pii: canres.1843.2021. [Epub ahead of print]
      Mutations in SF3B1 have been identified across several cancer types. This key spliceosome component promotes the efficient mRNA splicing of thousands of genes including those with crucial roles in the cellular response to DNA damage. Here, we demonstrate that depletion of SF3B1 specifically compromises homologous recombination (HR) and is epistatic with loss of BRCA1. More importantly, the most prevalent cancer-associated mutation in SF3B1, K700E, also affects HR efficiency and as a consequence, increases the cellular sensitivity to ionising radiation and a variety of chemotherapeutic agents, including PARP inhibitors. Additionally, the SF3B1 K700E mutation induced unscheduled R-loop formation, replication fork stalling, increased fork degradation and defective replication fork restart. Taken together, these data suggest that tumour-associated mutations in SF3B1 induce a BRCA-like cellular phenotype that confers synthetic lethality to DNA damaging agents and PARP inhibitors, which can be exploited therapeutically.
  18. Nat Commun. 2022 Jan 10. 13(1): 116
      Glioblastoma is an aggressive form of brain cancer with well-established patterns of intra-tumoral heterogeneity implicated in treatment resistance and progression. While regional and single cell transcriptomic variations of glioblastoma have been recently resolved, downstream phenotype-level proteomic programs have yet to be assigned across glioblastoma's hallmark histomorphologic niches. Here, we leverage mass spectrometry to spatially align abundance levels of 4,794 proteins to distinct histologic patterns across 20 patients and propose diverse molecular programs operational within these regional tumor compartments. Using machine learning, we overlay concordant transcriptional information, and define two distinct proteogenomic programs, MYC- and KRAS-axis hereon, that cooperate with hypoxia to produce a tri-dimensional model of intra-tumoral heterogeneity. Moreover, we highlight differential drug sensitivities and relative chemoresistance in glioblastoma cell lines with enhanced KRAS programs. Importantly, these pharmacological differences are less pronounced in transcriptional glioblastoma subgroups suggesting that this model may provide insights for targeting heterogeneity and overcoming therapy resistance.
  19. Nat Commun. 2022 Jan 10. 13(1): 42
      Owing to a lack of response to the anti-PD1 therapy for most cancer patients, we develop a network approach to infer genes, pathways, and potential therapeutic combinations that are associated with tumor response to anti-PD1. Here, our prediction identifies genes and pathways known to be associated with anti-PD1, and is further validated by 6 CRISPR gene sets associated with tumor resistance to cytotoxic T cells and targets of the 36 compounds that have been tested in clinical trials for combination treatments with anti-PD1. Integration of our top prediction and TCGA data identifies hundreds of genes whose expression and genetic alterations that could affect response to anti-PD1 in each TCGA cancer type, and the comparison of these genes across cancer types reveals that the tumor immunoregulation associated with response to anti-PD1 would be tissue-specific. In addition, the integration identifies the gene signature to calculate the MHC I association immunoscore (MIAS) that shows a good correlation with patient response to anti-PD1 for 411 melanoma samples complied from 6 cohorts. Furthermore, mapping drug target data to the top genes in our association prediction identifies inhibitors that could potentially enhance tumor response to anti-PD1, such as inhibitors of the encoded proteins of CDK4, GSK3B, and PTK2.
  20. Proc Natl Acad Sci U S A. 2022 Jan 18. pii: e2105898119. [Epub ahead of print]119(3):
      Drugs that block the activity of the methyltransferase EZH2 are in clinical development for the treatment of non-Hodgkin lymphomas harboring EZH2 gain-of-function mutations that enhance its polycomb repressive function. We have previously reported that EZH2 can act as a transcriptional activator in castration-resistant prostate cancer (CRPC). Now we show that EZH2 inhibitors can also block the transactivation activity of EZH2 and inhibit the growth of CRPC cells. Gene expression and epigenomics profiling of cells treated with EZH2 inhibitors demonstrated that in addition to derepressing gene expression, these compounds also robustly down-regulate a set of DNA damage repair (DDR) genes, especially those involved in the base excision repair (BER) pathway. Methylation of the pioneer factor FOXA1 by EZH2 contributes to the activation of these genes, and interaction with the transcriptional coactivator P300 via the transactivation domain on EZH2 directly turns on the transcription. In addition, CRISPR-Cas9-mediated knockout screens in the presence of EZH2 inhibitors identified these BER genes as the determinants that underlie the growth-inhibitory effect of EZH2 inhibitors. Interrogation of public data from diverse types of solid tumors expressing wild-type EZH2 demonstrated that expression of DDR genes is significantly correlated with EZH2 dependency and cellular sensitivity to EZH2 inhibitors. Consistent with these findings, treatment of CRPC cells with EZH2 inhibitors dramatically enhances their sensitivity to genotoxic stress. These studies reveal a previously unappreciated mechanism of action of EZH2 inhibitors and provide a mechanistic basis for potential combination cancer therapies.
    Keywords:  DNA damage repair; EZH2 inhibitors; cancer therapy; mechanism of drug action
  21. Cell Rep. 2022 Jan 11. pii: S2211-1247(21)01745-9. [Epub ahead of print]38(2): 110236
      We determine that type I interferon (IFN) response biomarkers are enriched in a subset of pancreatic ductal adenocarcinoma (PDAC) tumors; however, actionable vulnerabilities associated with IFN signaling have not been systematically defined. Integration of a phosphoproteomic analysis and a chemical genomics synergy screen reveals that IFN activates the replication stress response kinase ataxia telangiectasia and Rad3-related protein (ATR) in PDAC cells and sensitizes them to ATR inhibitors. IFN triggers cell-cycle arrest in S-phase, which is accompanied by nucleotide pool insufficiency and nucleoside efflux. In combination with IFN, ATR inhibitors induce lethal DNA damage and downregulate nucleotide biosynthesis. ATR inhibition limits the growth of PDAC tumors in which IFN signaling is driven by stimulator of interferon genes (STING). These results identify a cross talk between IFN, DNA replication stress response networks, and nucleotide metabolism while providing the rationale for targeted therapeutic interventions that leverage IFN signaling in tumors.
    Keywords:  STING; interferon; nucleotide metabolism; pancreas cancer; replication stress
  22. Cancer Cell. 2022 Jan 10. pii: S1535-6108(21)00661-9. [Epub ahead of print]40(1): 14-16
      In this issue of Cancer Cell, Newell et al. introduce whole-genome and methylome data to melanoma immunotherapy response analysis. Genome breaks are more frequent in resistant tumors, but the best response classifiers remain mutation burden and interferon-ɣ signature. Clinical translation will need aggregation of many such datasets.
  23. Mol Ther. 2022 Jan 11. pii: S1525-0016(22)00017-X. [Epub ahead of print]
      Extravasation of circulating tumor cells (CTCs) is critical for metastasis and initiated by adhesive interactions between glycoligands on CTCs and E-selectin on endothelia. Here we show that the clinically approved proteasome inhibitor bortezomib (BZM=Velcade®) counteracts the cytokine-dependent induction of E-selectin in the lung mediated by the primary tumor, thereby impairing endothelial adhesion and thus spontaneous lung metastasis in vivo. However, the efficacy of BZM crucially depends on the tumor cells' E-selectin ligands, which determine distinct adhesion patterns: The canonical ligands sialyl-Lewis A (sLeA) and sLeX mediate particularly high-affinity E-selectin binding, so that the incomplete E-selectin-reducing effect of BZM is not sufficient to disrupt adhesion or metastasis. In contrast, tumor cells lacking sLeA/X nevertheless bind E-selectin, but with low affinity, so that adhesion and lung metastasis are significantly diminished. Such low-affinity E-selectin ligands apparently consist of sialylated MGAT5 products on CD44. BZM no longer has anti-metastatic activity after CD44 knockdown in sLeA/X-negative tumor cells or E-selectin knockout in mice. sLeA/X can be determined by immunohistochemistry in cancer samples, which might aid patient stratification. These data suggest that BZM might act as a drug for inhibiting extravasation and hence distant metastasis formation in malignancies expressing low affinity E-selectin ligands.
  24. Oncogene. 2022 Jan 10.
      Poor prognosis of head and neck squamous cell carcinomas (HNSCCs) results from resistance to chemotherapy and radiotherapy. To uncover the drivers of HNSCC resistance, including stemness and hypoxia, in this study, we compared the gene expression between CD44+ and CD44- HNSCC cells and assessed the correlation of CD44 and hypoxia-inducible factor 1α (HIF-1α) expression with mouse features and outcomes of patients with HNSCC. We combined the knockdown or activation of HIF-1α with in vitro and in vivo assays to evaluate effects on stemness and resistance of HNSCC cells. Analysis of clinical data showed that activation of HIF-1α in CD44+ patients with HNSCC was correlated with worse prognosis. Functional assays showed that HIF-1α promoted stemness, resistance, and epithelial-mesenchymal transition in HNSCC CD44+ cells. HIF-1α activated NOTCH1 signaling in HNSCC stem-like cells characterized by CD44 expression. Moreover, inhibition of these signaling proteins using shRNA or Evofosfamide (Evo) development for cancer treatment, reversed chemoresistance in vitro and in vivo. Taken together, our results indicated that targeting HIF-1α attenuated NOTCH1-induced stemness, which regulates responses to chemotherapy or radiotherapy and malignancy in CD44+ HNSCCs. HIF-1α/NOTCH1 signaling may represent a target for HNSCC treatment.
  25. Nat Commun. 2022 Jan 10. 13(1): 173
      Mechanisms of drug-tolerance remain poorly understood and have been linked to genomic but also to non-genomic processes. 5-fluorouracil (5-FU), the most widely used chemotherapy in oncology is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways. Here, we show that 5-FU treatment leads to the production of fluorinated ribosomes exhibiting altered translational activities. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts, and human tumors. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs depending on the nature of their 5'-untranslated region. As a result, we find that sustained translation of IGF-1R mRNA, which encodes one of the most potent cell survival effectors, promotes the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that "man-made" fluorinated ribosomes favor the drug-tolerant cellular phenotype by promoting translation of survival genes.
  26. Nat Commun. 2022 Jan 10. 13(1): 97
      For many solid tumors, immune checkpoint blockade therapy has become first line treatment, yet a large proportion of patients with immunologically cold tumors do not benefit due to the paucity of tumor infiltrating lymphocytes. Here we show that the orphan G Protein-Coupled Receptor 182 (GPR182) contributes to immunotherapy resistance in cancer via scavenging chemokines that are important for lymphocyte recruitment to tumors. GPR182 is primarily upregulated in melanoma-associated lymphatic endothelial cells (LECs) during tumorigenesis, and this atypical chemokine receptor endocytoses chemokines promiscuously. In GPR182-deficient mice, T cell infiltration into transplanted melanomas increases, leading to enhanced effector T cell function and improved antitumor immunity. Ablation of GPR182 leads to increased intratumoral concentrations of multiple chemokines and thereby sensitizes poorly immunogenic tumors to immune checkpoint blockade and adoptive cellular therapies. CXCR3 blockade reverses the improved antitumor immunity and T cell infiltration characteristic of GPR182-deficient mice. Our study thus identifies GPR182 as an upstream regulator of the CXCL9/CXCL10/CXCR3 axis that limits antitumor immunity and as a potential therapeutic target in immunologically cold tumors.
  27. Cell Death Differ. 2022 Jan 08.
      As the most predominant RNA epigenetic regulation in eukaryotic cells, N6-methyladenosine (m6A) plays a critical role in human tumorigenesis and cancer progression. However, the biological function and molecular mechanism of m6A regulation in naso-pharyngeal carcinoma (NPC) remain elusive. Here, we showed that Wilms' tumor 1-associating protein (WTAP) expression was apparently upregulated in NPC, and increased WTAP was associated with poor prognosis. WTAP upregulated in NPC was fine-tuned by KAT3A-mediated H3K27 acetylation. Functionally, WTAP was required for the growth and metastasis of NPC. Mechanistically, lncRNA DIAPH1-AS1 was identified as a bona fide m6A target of WTAP. WTAP-mediated m6A modification of DIAPH1-AS1 enhanced its stability relying on the m6A reader IGF2BP2-dependent pathway. Furthermore, DIAPH1-AS1 acted as a molecular adaptor that promoted MTDH-LASP1 complex formation and upregulated LASP1 expression, ultimately facilitating NPC growth and metastasis. Thus, WTAP-mediated DIAPH1-AS1 m6A methylation is required for NPC tumorigenesis and metastasis.
  28. Neuro Oncol. 2022 Jan 06. pii: noac009. [Epub ahead of print]
      PURPOSE: The role of tumor genomic profiling is rapidly growing as it results in targeted, personalized, cancer therapy. Though routinely used in clinical practice, there are no data exploring the reliability of genomic data obtained from spine metastases samples often leading to multiple biopsies in clinical practice. This study compares the genomic tumor landscape between spinal metastases and the corresponding primary tumors as well as between spinal metastases and visceral metastases.PATIENTS AND METHODS: Spine tumor samples, obtained for routine clinical care from 2013 to 2019, were analyzed using MSK-IMPACT, a next generation sequencing assay. These samples were matched to primary or metastatic tumors from the corresponding patients. A concordance rate for genomic alterations was calculated for matching sample pairs within patients for the primary and spinal metastatic tumor samples as well as for the matching sample pairs within patients for the spinal and visceral metastases. For a more robust and clinically relevant estimate of concordance, a subgroup analyses of previously established driver mutations specific to the main primary tumor histologies was performed.
    RESULTS: Eighty-four patients contributed next generation sequencing from a spinal metastasis and at least one other site of disease: 54 from the primary tumor, 39 had genomic tumor data from another, non-spinal metastasis, 12 patients participated in both subsets. For the cohort of matched primary tumors and spinal metastases (n = 54) comprised of mixed histologies, we found an average concordance rate of 96.97% for all genetic events, 97.17% for mutations, 100% for fusions, 89.81% for deletions, and 97.01% for amplifications across all matched samples. Notably, >25% of patients harbored at least one genetic variant between samples tested, though not specifically for known driver mutations. The average concordance rate of driver mutations was 96.99% for prostate cancer, 95.69% (p = 0.0004513) for lung cancer and 96.43% for breast cancer. An average concordance of 99.02% was calculated for all genetic events between spine metastases and non-spinal metastases (n=41) and, more specifically, a concordance rate of 98.91% was calculated between spine metastases and liver metastases (n=12) which was the largest represented group of non-spine metastases.
    CONCLUSION: Sequencing data performed on spine tumor samples demonstrate a high concordance rate for genetic alterations between the primary tumor and spinal metastasis as well as between spinal metastases and other, visceral metastases, particularly for driver mutations. Spine tumor samples may be reliably used for genomic based decision making in cancer care, particularly for prostate, NSCLC and breast cancer.
  29. Cancer Metastasis Rev. 2022 Jan 14.
      Despite advancements in cancer management, tumor relapse and metastasis are associated with poor outcomes in many cancers. Over the past decade, oncogene-driven carcinogenesis, dysregulated cellular signaling networks, dynamic changes in the tissue microenvironment, epithelial-mesenchymal transitions, protein expression within regulatory pathways, and their part in tumor progression are described in several studies. However, the complexity of metabolic enzyme expression is considerably under evaluated. Alterations in cellular metabolism determine the individual phenotype and behavior of cells, which is a well-recognized hallmark of cancer progression, especially in the adaptation mechanisms underlying therapy resistance. In metabolic symbiosis, cells compete, communicate, and even feed each other, supervised by tumor cells. Metabolic reprogramming forms a unique fingerprint for each tumor tissue, depending on the cellular content and genetic, epigenetic, and microenvironmental alterations of the developing cancer. Based on its sensing and effector functions, the mechanistic target of rapamycin (mTOR) kinase is considered the master regulator of metabolic adaptation. Moreover, mTOR kinase hyperactivity is associated with poor prognosis in various tumor types. In situ metabolic phenotyping in recent studies highlights the importance of metabolic plasticity, mTOR hyperactivity, and their role in tumor progression. In this review, we update recent developments in metabolic phenotyping of the cancer ecosystem, metabolic symbiosis, and plasticity which could provide new research directions in tumor biology. In addition, we suggest pathomorphological and analytical studies relating to metabolic alterations, mTOR activity, and their associations which are necessary to improve understanding of tumor heterogeneity and expand the therapeutic management of cancer.
    Keywords:  Cancer; Metabolic heterogeneity; Metabolic phenotypes; Metabolic plasticity; mTOR hyperactivity
  30. Clin Cancer Res. 2022 Jan 12. pii: clincanres.2846.2021. [Epub ahead of print]
      PURPOSE: Loss of transforming growth factor β (TGFβ) signaling increases error-prone alternative end-joining (alt-EJ) DNA repair. We previously translated this mechanistic relationship as TGFβ and alt-EJ gene expression signatures, which are anti-correlated across cancer types. A score, βAlt, representing anti-correlation predicts patient outcome in response to genotoxic therapy. Here we sought to verify this biology in live specimens and additional datasets.EXPERIMENTAL DESIGN: Human head and neck squamous cell (HNSC) carcinoma explants were treated in vitro to test whether the signatures report TGFβ signaling, indicated by SMAD2 phosphorylation, and unrepaired DNA damage, indicated by persistent 53BP1 foci after irradiation or olaparib. A custom NanoString assay was implemented to analyze the signatures' expression in explants. Each signature gene was then weighted by its association with functional responses to define a modified score, βAltw, that was retested for association with response to genotoxic therapies in independent datasets.
    RESULTS: Most genes in each signature were positively correlated with the expected biological response in tumor explants. Anticorrelation of TGFβ and alt-EJ signatures measured by Nanostring was confirmed in explants. βAltw was significantly (P<0.001) better than βAlt in predicting overall survival in response to genotoxic therapy in TCGA pancancer patients and in independent HNSC and ovarian cancer patient datasets.
    CONCLUSION: Association of the TGFβ and alt-EJ signatures with their biological response validates TGFβ competency as a key mediator of DNA repair that can be readily assayed by gene expression. The predictive value of βAltw supports its development to assist in clinical decision-making.