bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021‒02‒21
27 papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Nat Commun. 2021 02 18. 12(1): 1117
    Karkampouna S, La Manna F, Benjak A, Kiener M, De Menna M, Zoni E, Grosjean J, Klima I, Garofoli A, Bolis M, Vallerga A, Theurillat JP, De Filippo MR, Genitsch V, Keller D, Booij TH, Stirnimann CU, Eng K, Sboner A, Ng CKY, Piscuoglio S, Gray PC, Spahn M, Rubin MA, Thalmann GN, Kruithof-de Julio M.
      Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.
  2. Proc Natl Acad Sci U S A. 2021 Feb 16. pii: e2020838118. [Epub ahead of print]118(7):
    Pienta KJ, Hammarlund EU, Brown JS, Amend SR, Axelrod RM.
      We present a unifying theory to explain cancer recurrence, therapeutic resistance, and lethality. The basis of this theory is the formation of simultaneously polyploid and aneuploid cancer cells, polyaneuploid cancer cells (PACCs), that avoid the toxic effects of systemic therapy by entering a state of cell cycle arrest. The theory is independent of which of the classically associated oncogenic mutations have already occurred. PACCs have been generally disregarded as senescent or dying cells. Our theory states that therapeutic resistance is driven by PACC formation that is enabled by accessing a polyploid program that allows an aneuploid cancer cell to double its genomic content, followed by entry into a nondividing cell state to protect DNA integrity and ensure cell survival. Upon removal of stress, e.g., chemotherapy, PACCs undergo depolyploidization and generate resistant progeny that make up the bulk of cancer cells within a tumor.
    Keywords:  drug resistance; evolution; metastasis; tumor microenvironment; whole-genome doubling
  3. Clin Cancer Res. 2021 Feb 15. pii: clincanres.3463.2020. [Epub ahead of print]
    Kelly G, Al-Ejeh F, McCuaig RD, Casciello F, Kamal N, Ferguson B, Pritchard AL, Ali S, Silva I, Wilmott JS, Long GV, Scolyer RA, Rao S, Hayward NK, Gannon F, Lee JS.
      PURPOSE: G9a histone methyltransferase exerts oncogenic effects in several tumor-types and its inhibition promotes anti-cancer effects. However, the impact on checkpoint inhibitor blockade response and the utility of G9a or its target genes as a biomarker is poorly studied. We aimed to examine whether G9a inhibition can augment the efficacy of checkpoint inhibitor blockade and whether LC3B, a G9a target gene can predict treatment response.EXPERIMENTAL DESIGN: Clinical potential of LC3B as a biomarker of checkpoint inhibitor blockade was assessed using patient samples including tumor biopsies and circulating tumor cells from liquid biopsies. Efficacy of G9a inhibition to enhance checkpoint inhibitor blockade was examined using a mouse model.
    RESULTS: Melanoma patients that responded to checkpoint inhibitor blockade were associated with not only a higher level of tumor LC3B but also a higher proportion of cells expressing LC3B. A higher expression of MAP1LC3B or LC3B protein was associated with longer survival and lower incidence of acquired resistance to checkpoint inhibitor blockade suggesting LC3B as a potential predictive biomarker. We demonstrate G9a histone methyltransferase inhibition is able to not only robustly induce LC3B level to augment the efficacy of checkpoint inhibitor blockade, but also induces melanoma cell death.
    CONCLUSIONS: Checkpoint inhibitor blockade response is limited to a subset of patient population. These results have implications for the development of LC3B as a predictive biomarker of checkpoint inhibitor blockade to guide patient selection, as well as G9a inhibition as a strategy to extend the proportion of patients responding to immunotherapy.
  4. Semin Cancer Biol. 2021 Feb 11. pii: S1044-579X(21)00024-9. [Epub ahead of print]
    Werner S, Heidrich I, Pantel K.
      Clinical tumor dormancy is specified as an extended latency period between removal of the primary tumor and subsequent relapse in a cancer patient who has been clinically disease-free. In particular, patients with estrogen receptor-positive breast cancer can undergo extended periods of more than five years before they relapse with overt metastatic disease. Recent studies have shown that minimal residual disease in breast cancer patients can be monitored by different liquid biopsy approaches like analysis of circulating tumor cells or cell-free tumor DNA. Even though the biological principles underlying tumor dormancy in breast cancer patients remain largely unknown, clinical observations and experimental studies have identified emerging mechanisms that control the state of tumor dormancy. In this review, we illustrate the latest discoveries on different molecular aspects that contribute to the control of tumor dormancy and distant metastatic relapse, then discuss current treatments affecting minimal residual disease and dormant cancer cells, and finally highlight how novel liquid biopsy based diagnostic methodologies can be integrated into the detection and molecular characterization of minimal residual disease.
    Keywords:  Breast cancer; Circulating cell-free tumor DNA; Circulating tumor cells; Metastatic relapse; Minimal residual disease; Tumor dormancy
  5. Oncogene. 2021 Feb 18.
    Yoon H, Tang CM, Banerjee S, Yebra M, Noh S, Burgoyne AM, Torre J, Siena M, Liu M, Klug LR, Choi YY, Hosseini M, Delgado AL, Wang Z, French RP, Lowy A, DeMatteo RP, Heinrich MC, Molinolo AA, Gutkind JS, Harismendy O, Sicklick JK.
      Targeted therapies for gastrointestinal stromal tumor (GIST) are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors. In this study, we sought to identify new therapeutic targets in GIST by investigating the tumor microenvironment. Here, we identified a paracrine signaling network by which cancer-associated fibroblasts (CAFs) drive GIST growth and metastasis. Specifically, CAFs isolated from human tumors were found to produce high levels of platelet-derived growth factor C (PDGFC), which activated PDGFC-PDGFRA signal transduction in GIST cells that regulated the expression of SLUG, an epithelial-mesenchymal transition (EMT) transcription factor and downstream target of PDGFRA signaling. Together, this paracrine induce signal transduction cascade promoted tumor growth and metastasis in vivo. Moreover, in metastatic GIST patients, SLUG expression positively correlated with tumor size and mitotic index. Given that CAF paracrine signaling modulated GIST biology, we directly targeted CAFs with a dual PI3K/mTOR inhibitor, which synergized with imatinib to increase tumor cell killing and in vivo disease response. Taken together, we identified a previously unappreciated cellular target for GIST therapy in order to improve disease control and cure rates.
  6. Cancer Discov. 2021 Feb 15. pii: candisc.1098.2020. [Epub ahead of print]
    Pitarresi JR, Norgard RJ, Chiarella AM, Suzuki K, Bakir B, Sahu V, Li J, Zhao J, Marchand B, Wengyn MD, Hsieh A, Kim IK, Zhang A, Sellin K, Lee V, Takano S, Miyahara Y, Ohtsuka M, Maitra A, Notta F, Kremer R, Stanger BZ, Rustgi AK.
      Pancreatic cancer metastasis is a leading cause of cancer-related deaths, yet very little is understood regarding the underlying biology. As a result, targeted therapies to inhibit metastasis are lacking. Here, we report that the parathyroid hormone-related protein (PTHrP encoded by PTHLH) is frequently amplified as part of the KRAS amplicon in pancreatic cancer patients. PTHrP upregulation drives the growth of both primary and metastatic tumors in mice and is highly enriched in PDAC metastases. Loss of PTHrP - either genetically or pharmacologically - dramatically reduces tumor burden, eliminates metastasis, and enhances overall survival. These effects are mediated in part through a reduction in epithelial-to-mesenchymal transition, which reduces the tumor cells' ability to initiate the metastatic cascade. Spp1, which encodes Osteopontin, is revealed to be a downstream effector of PTHrP. Our results establish a new paradigm in pancreatic cancer whereby PTHrP is a driver of disease progression and emerges as a novel therapeutic vulnerability.
  7. Cancer Res. 2021 Feb 18. pii: canres.CAN-20-3044-A.2020. [Epub ahead of print]
    Bi L, Ren Y, Feng M, Meng P, Wang Q, Chen W, Jiao Q, Wang Y, Du L, Zhou F, Jiang Y, Chen F, Wang C, Tang B, Wang Y.
      Hepatocellular carcinoma (HCC) contains a subset of cancer stem cells (CSC) that cause tumor recurrence, metastasis, and chemical resistance. Histone deacetylase 11 (HDAC11) mediates diverse immune functions and metabolism, yet little is known about its role in HCC CSCs. In this study, we report that HDAC11 is highly expressed in HCC and is closely related to disease prognosis. Depletion of HDAC11 in a conditional knockout (KO) mouse model reduced hepatocellular tumorigenesis and prolonged survival. Loss of HDAC11 increased transcription of LKB1 by promoting histone acetylation in its promoter region, thereby activating the AMPK signaling pathway and inhibiting the glycolysis pathway, which in turn leads to the suppression of cancer stemness and HCC progression. Furthermore, HDAC11 overexpression reduced HCC sensitivity to sorafenib. Collectively, these data propose HDAC11 as a new target for combination therapy in patients with kinase-resistant HCC.
  8. Cancer Res. 2021 Feb 18. pii: canres.2642.2020. [Epub ahead of print]
    Yu R, Longo J, van Leeuwen JE, Zhang C, Branchard E, Elbaz M, Cescon DW, Drake RR, Dennis JW, Penn LZ.
      Aberrant N-glycan Golgi remodeling and metabolism are associated with epithelial-mesenchymal transition (EMT) and metastasis in breast cancer patients. Despite this association, the N-glycosylation pathway has not been successfully targeted in cancer. Here we show that inhibition of the mevalonate pathway with fluvastatin, a clinically approved drug, reduces both N-glycosylation and N-glycan-branching, essential components of the EMT program and tumor metastasis. This indicates novel crosstalk between N-glycosylation at the endoplasmic reticulum (ER) and N-glycan remodeling at the Golgi. Consistent with this cooperative model between the two spatially separated levels of protein N-glycosylation, fluvastatin-induced tumor cell death was enhanced by loss of Golgi-associated N-acetylglucosaminyltransferases MGAT1 or MGAT5. In a mouse model of post-surgical metastatic breast cancer, adjuvant fluvastatin treatment reduced metastatic burden and improved overall survival. Collectively, these data support the immediate repurposing of fluvastatin as an adjuvant therapeutic to combat metastatic recurrence in breast cancer by targeting protein N-glycosylation at both the ER and Golgi.
  9. Cancer Res. 2021 Feb 15. pii: canres.2370.2020. [Epub ahead of print]
    Yang B, Li X, Fu Y, Guo E, Ye Y, Li F, Liu S, Xiao R, Liu C, Lu F, Huang J, Qin T, Han L, Peng G, Mills GB, Sun C, Chen G.
      Mutant KRAS tumors are associated with poor outcomes at least in part due to decreased therapeutic sensitivity. Here we show that KRAS mutations are associated with resistance to monotherapy and combination therapy with Poly-(ADP-ribose) polymerase inhibitors (PARPi) and immune checkpoint blockade with anti-PD-L1 antibodies. In mutant KRAS tumors, inhibition of KRAS signaling with MEK inhibitors (MEKi) triggered and amplified PARPi-induced DNA damage, cytosolic double-stranded DNA accumulation, STING pathway activation and CD8+ T cell recruitment. Moreover, MEKi decreased myeloid-derived suppressor cell infiltration in part by inhibiting IL-6 and GM-CSF production. Importantly, addition of MEKi to PARPi and anti-PD-L1 resulted in marked tumor inhibition in immunocompetent mutant KRAS tumor models. These studies provide the underlying mechanistic data to support evaluation of PARPi, MEKi, and anti-PD-L1 combination in clinical trials of mutant KRAS tumors.
  10. EMBO Rep. 2021 Feb 15. e50852
    Melixetian M, Bossi D, Mihailovich M, Punzi S, Barozzi I, Marocchi F, Cuomo A, Bonaldi T, Testa G, Marine JC, Leucci E, Minucci S, Pelicci PG, Lanfrancone L.
      Transition from proliferative-to-invasive phenotypes promotes metastasis and therapy resistance in melanoma. Reversion of the invasive phenotype, however, is challenged by the poor understanding of mechanisms underlying its maintenance. Here, we report that the lncRNA TINCR is down-regulated in metastatic melanoma and its silencing increases the expression levels of invasive markers, in vitro migration, in vivo tumor growth, and resistance to BRAF and MEK inhibitors. The critical mediator is ATF4, a central player of the integrated stress response (ISR), which is activated in TINCR-depleted cells in the absence of starvation and eIF2α phosphorylation. TINCR depletion increases global protein synthesis and induces translational reprogramming, leading to increased translation of mRNAs encoding ATF4 and other ISR proteins. Strikingly, re-expression of TINCR in metastatic melanoma suppresses the invasive phenotype, reduces numbers of tumor-initiating cells and metastasis formation, and increases drug sensitivity. Mechanistically, TINCR interacts with mRNAs associated with the invasive phenotype, including ATF4, preventing their binding to ribosomes. Thus, TINCR is a suppressor of the melanoma invasive phenotype, which functions in nutrient-rich conditions by repressing translation of selected ISR RNAs.
    Keywords:  ATF4; integrated stress response; lncRNAs; melanoma; translational reprogramming
  11. Proc Natl Acad Sci U S A. 2021 Feb 23. pii: e2025840118. [Epub ahead of print]118(8):
    Zhou Y, Bastian IN, Long MD, Dow M, Li W, Liu T, Ngu RK, Antonucci L, Huang JY, Phung QT, Zhao XH, Banerjee S, Lin XJ, Wang H, Dang B, Choi S, Karin D, Su H, Ellisman MH, Jamieson C, Bosenberg M, Cheng Z, Haybaeck J, Kenner L, Fisch KM, Bourgon R, Hernandez G, Lill JR, Liu S, Carter H, Mellman I, Karin M, Shalapour S.
      Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I-dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I-expressing tumors by reinvigorated CD8+ CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had "epigenetically down-regulated," but had not permanently lost MHC-I AgPP activity.
    Keywords:  MHC-I; NF-κB; antigen presentation; histone acetylation; immune checkpoint inhibitors
  12. J Exp Med. 2021 Jan 04. pii: e20190218. [Epub ahead of print]218(1):
    Abdul Pari AA, Singhal M, Augustin HG.
      Historically, therapy of metastatic disease has essentially been limited to using strategies that were identified and established to shrink primary tumors. The limited efficacy of such treatments on overall patient survival stems from diverging intrinsic and extrinsic characteristics of a primary tumor and metastases originating therefrom. To develop better therapeutic strategies to treat metastatic disease, there is an urgent need to shift the paradigm in preclinical metastasis research by conceptualizing metastatic dissemination, colonization, and growth as spatiotemporally dynamic processes and identifying rate-limiting vulnerabilities of the metastatic cascade. Clinically, while metastatic colonization remains the most attractive therapeutic avenue, comprehensive understanding of earlier steps may unravel novel metastasis-restricting therapies for presurgical neoadjuvant application. Moving beyond a primary tumor-centric view, this review adopts a holistic approach to understanding the spatial and temporal progression of metastasis. After reviewing recent developments in metastasis research, we highlight some of the grand challenges and propose a framework to expedite mechanism-based discovery research feeding the translational pipeline.
  13. Oncogene. 2021 Feb 18.
    Lin CC, Yang WH, Lin YT, Tang X, Chen PH, Ding CC, Qu DC, Alvarez JV, Chi JT.
      Recurrent breast cancer presents significant challenges with aggressive phenotypes and treatment resistance. Therefore, novel therapeutics are urgently needed. Here, we report that murine recurrent breast tumor cells, when compared with primary tumor cells, are highly sensitive to ferroptosis. Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2), the receptor for collagen I, is highly expressed in ferroptosis-sensitive recurrent tumor cells and human mesenchymal breast cancer cells. EMT regulators, TWIST and SNAIL, significantly induce DDR2 expression and sensitize ferroptosis in a DDR2-dependent manner. Erastin treatment induces DDR2 upregulation and phosphorylation, independent of collagen I. Furthermore, DDR2 knockdown in recurrent tumor cells reduces clonogenic proliferation. Importantly, both the ferroptosis protection and reduced clonogenic growth may be compatible with the compromised YAP/TAZ upon DDR2 inhibition. Collectively, these findings identify the important role of EMT-driven DDR2 upregulation in recurrent tumors in maintaining growth advantage but activating YAP/TAZ-mediated ferroptosis susceptibility, providing potential strategies to eradicate recurrent breast cancer cells with mesenchymal features.
  14. Cancer Discov. 2021 Feb 15. pii: candisc.0812.2020. [Epub ahead of print]
    Gu SS, Zhang W, Wang X, Jiang P, Traugh N, Li Z, Meyer C, Stewig B, Xie Y, Bu X, Manos MP, Font-Tello A, Gjini E, Lako A, Lim K, Conway J, Tewari AK, Zeng Z, Das Sahu A, Tokheim C, Weirather JL, Fu J, Zhang Y, Kroger B, Liang JH, Cejas P, Freeman GJ, Rodig S, Long HW, Gewurz BE, Hodi FS, Brown M, Liu XS.
      Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Here, we combined FACS-based genome-wide CRISPR screens with a data-mining approach to identify drugs that can upregulate MHC-I without inducing PD-L1. CRISPR screening identified TRAF3, a suppressor of the NF-kB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout (Traf3-KO) gene expression signature is associated with better survival in ICB-naive cancer patients and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified SMAC mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T-cell-dependent killing, and adds to ICB efficacy. Our findings provide preclinical rationale for treating tumors expressing low MHC-I expression with SMAC mimetics to enhance sensitivity to immunotherapy. The approach used in this study can be generalized to identify other drugs that enhance immunotherapy efficacy.
  15. Clin Cancer Res. 2021 Jan 27. pii: clincanres.3444.2020. [Epub ahead of print]
    Vidula N, Niemierko A, Malvarosa G, Yuen M, Lennerz JK, Iafrate AJ, Wander SA, Spring LM, Juric D, Isakoff SJ, Younger J, Moy B, Ellisen LW, Bardia A.
      PURPOSE: Actionable mutations can guide genotype-directed matched therapy. We evaluated the utility of tissue-based and plasma-based genotyping for the identification of actionable mutations and selection of matched therapy in patients with metastatic breast cancer (MBC).METHODS: Patients with MBC who underwent tissue genotyping (institutional platform, 91 gene assay) or plasma based cell-free DNA (cfDNA, Guardant360®, 73 gene assay) between January 2016 and December 2017 were included. A chart review of records to identify subtype, demographics, treatment, outcomes, and tissue genotyping or cfDNA results was performed. The incidence of actionable mutationsand the selection of matched therapy in tissue genotyping or cfDNA cohorts was determined. The impact of matched therapy status on overall survival (OS) in tissue genotyping or cfDNA subgroups was determined with Cox regression analysis.
    RESULTS: Of 252 patients who underwent cfDNA testing, 232 (92%) had detectable mutations, 196 (78%) had actionable mutations, and 86 (34%) received matched therapy. Of 118 patients who underwent tissue genotyping, 90 (76%) had detectable mutations, 59 (50%) had actionable mutations, and 13 (11%) received matched therapy. For cfDNA patients with actionable mutations, matched versus non-matched therapy was associated with better OS (HR 0.41, 95% CI: 0.23-0.73, p=0.002), and this remained significant in a multivariable analysis correcting for age, subtype, visceral metastases, and brain metastases (HR = 0.46, 95% CI: 0.26-0.83, p = 0.010).
    CONCLUSION: Plasma-based genotyping identified high rates of actionable mutations, which was associated with significant application of matched therapy and better OS in patients with MBC.
  16. Cancer Res. 2021 Feb 15. pii: canres.3665.2020. [Epub ahead of print]
    Zhou J, Li Q, Cao Y.
      The sum of target lesions is routinely used to evaluate patient objective responses to treatment in the RECIST criteria, but it fails to address response heterogeneity across metastases. This study argues that spatiotemporal heterogeneity across metastases and organ-specific response is informative for drug efficacy and patient survival. We analyzed the longitudinal data of 11,404 metastatic lesions in 2,802 colorectal cancer patients from five Phase III clinical trials. Initially, a metric Gower distance was applied to quantify response heterogeneity across metastases. Next, the spatiotemporal response heterogeneity across anatomical sites, therapies, and KRAS mutation status were assessed and examined for their association with drug efficacy and long-term patient survival. The response of metastatic lesions broadly differed across anatomical sites and therapies. About 60% of patients had at least one lesion respond contrarily from total tumor size. High inter-lesion heterogeneity was associated with shorter progression-free survival and overall survival. Targeted therapies (bevacizumab or panitumumab) combined with standard chemotherapy reduced inter-lesion heterogeneity and elicited more favorable effects from liver lesions (p<0.001) than chemotherapy alone. Moreover, the favorable responses in liver metastases (> 30% shrinkage) were associated with extended patient overall survival (p < 0.001), in contrast to lesions in the lungs and lymph nodes. Altogether, the spatiotemporal response heterogeneity across metastases informed drug efficacy and patient survival, which could improve the current methods for treatment evaluation and patient prognosis.
  17. Mol Cancer Res. 2021 Feb 19. pii: molcanres.1026.2020. [Epub ahead of print]
    Li M, Deng Y, Zhang W.
      Medulloblastoma (MB) is the most common malignant brain cancer in pediatrics consisting of four molecular subgroups, namely wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4. One of the biggest challenges in the clinical management of this disease is the leptomeningeal dissemination (LMD) of tumor cells with high morbidity and mortality. Many molecular regulators to date have been identified to participate in MB metastasis. In the SHH subgroup, the co-upregulation of CXCR4 and PDGFR, as well as the activation of c-MET, show significant pro-migratory effects on MB cells. Amplification or overexpression of genes on the long arm of chromosome 17, such as LASP1 and WIP1, facilitates tumor invasion in both Group 3 and Group 4 MBs. PRUNE1, NOTCH1, and MYC interactor JPO2 are more specific genetic drivers of metastatic Group 3 tumors. The RAS/MAPK and PI3K/AKT pathways are two crucial signal transduction pathways that may work as the convergent downstream mechanism of various metastatic drivers. Extracellular signals and cellular components in the tumor microenvironment also play a vital role in promoting the spread and colonization of MB cells. For instance, the stromal granule cells and astrocytes support tumor growth and dissemination by secreting PlGF and CCL2, respectively. Importantly, the genetic divergence has been determined between the matched primary and metastatic MB samples. However, the difficulty of obtaining metastatic MB tissue hinders more profound studies of LMD. Therefore, identifying and analyzing the subclone with the metastatic propensity in the primary tumor is essential for future investigation.
  18. Cancer Res. 2021 Feb 18. pii: canres.1890.2020. [Epub ahead of print]
    Dong Z, Yeo KS, Lopez G, Zhang C, Dankert Eggum EN, Rokita JL, Ung CY, Levee TM, Her ZP, Howe CJ, Hou X, van Ree JH, Li S, He S, Tao T, Fritchie K, Torres-Mora J, Lehman JS, Meves A, Razidlo GL, Rathi KS, Weroha SJ, Look AT, van Deursen JM, Li H, Westendorf JJ, Maris JM, Zhu S.
      One of the greatest barriers to curative treatment of neuroblastoma (NB) is its frequent metastatic outgrowth prior to diagnosis, especially in cases driven by amplification of the MYCN oncogene. However, only a limited number of regulatory proteins that contribute to this complex MYCN-mediated process have been elucidated. Here we show that the growth arrest-specific 7 (GAS7) gene, located at chromosome band 17p13.1, is preferentially deleted in high-risk MYCN-driven NB. GAS7 expression was also suppressed in MYCN-amplified NB lacking 17p deletion. GAS7 deficiency led to accelerated metastasis in both zebrafish and mammalian models of NB with overexpression or amplification of MYCN. Analysis of expression profiles and the ultrastructure of zebrafish NB tumors with MYCN overexpression identified that GAS7 deficiency led to (i) downregulation of genes involved in cell-cell interaction, (ii) loss of contact among tumor cells as critical determinants of accelerated metastasis, and (iii) increased levels of MYCN protein. These results provide the first genetic evidence that GAS7 depletion is a critical early step in the cascade of events culminating in NB metastasis in the context of MYCN overexpression.
  19. Cancer Discov. 2021 Jan 27. pii: candisc.1211.2020. [Epub ahead of print]
    Dey P, Kimmelman AC, DePinho RA.
      Metabolic reprogramming enables cancer cell growth, proliferation, and survival. This reprogramming is driven by the combined actions of oncogenic alterations in cancer cells and host cell factors acting on cancer cells in the tumor microenvironment. Cancer cell intrinsic mechanisms activate signal transduction components that either directly enhance metabolic enzyme activity or upregulate transcription factors that in turn increase expression of metabolic regulators. Extrinsic signaling mechanisms involve host-derived factors that further promote and amplify metabolic reprogramming in cancer cells. This review describes intrinsic and extrinsic mechanisms driving cancer metabolism in the tumor microenvironment and how such mechanisms may be targeted therapeutically.
  20. Clin Cancer Res. 2021 Feb 16. pii: clincanres.3365.2020. [Epub ahead of print]
    Nguyen TT, Ramsay L, Ahanfeshar-Adams M, Lajoie M, Schadendorf D, Alain T, Watson IR.
      PURPOSE: Next-generation sequencing studies and CRISPR-Cas9 screens have established mutations in the interferon (IFN)γ-JAK-STAT pathway as an ICI resistance mechanism in a subset of melanoma patients. We hypothesized ICI resistance mutations in the IFNγ pathway would simultaneously render melanomas susceptible to oncolytic virus (OV) therapy.EXPERIMENTAL DESIGN: Cytotoxicity experiments were performed with a number of OVs on a matched melanoma cell line pair generated from a baseline biopsy and a progressing lesion with complete JAK2 loss from a patient that relapsed on anti-PD-1 therapy, in melanoma lines following JAK1/2 RNAi and pharmacological inhibition and in Jak2 KO B16-F10 mouse melanomas. Furthermore, we estimated the frequency of genetic alterations in the IFNγ-JAK-STAT pathway in human melanomas.
    RESULTS: The melanoma line from an anti-PD-1 progressing lesion was 7- and 22-fold more sensitive to the modified OVs, vesicular stomatitis virus (VSV-Δ51) and herpes simplex virus 1 (HSV1-dICP0), respectively, compared to the line from the baseline biopsy. RNAi, JAK1/2 inhibitor studies, and in vivo studies of Jak2 KOs B16-F10 melanomas revealed a significant increase in VSV-Δ51 sensitivity with JAK/STAT pathway inhibition. Our analysis of TCGA data estimated that ~11% of ICI-naïve cutaneous melanomas have alterations in IFNγ pathway genes that may confer OV susceptibility.
    CONCLUSION: We provide mechanistic support for the use of OVs as a precision-medicine strategy for both salvage therapy in ICI-resistant and first-line treatment in melanomas with IFNγ-JAK-STAT pathway mutations. Our study also supports JAK inhibitor-OV combination therapy for treatment-naive melanomas without IFN signaling defects.
  21. Nat Rev Cancer. 2021 Feb 15.
    Cox TR.
      The extracellular matrix is a fundamental, core component of all tissues and organs, and is essential for the existence of multicellular organisms. From the earliest stages of organism development until death, it regulates and fine-tunes every cellular process in the body. In cancer, the extracellular matrix is altered at the biochemical, biomechanical, architectural and topographical levels, and recent years have seen an exponential increase in the study and recognition of the importance of the matrix in solid tumours. Coupled with the advancement of new technologies to study various elements of the matrix and cell-matrix interactions, we are also beginning to see the deployment of matrix-centric, stromal targeting cancer therapies. This Review touches on many of the facets of matrix biology in solid cancers, including breast, pancreatic and lung cancer, with the aim of highlighting some of the emerging interactions of the matrix and influences that the matrix has on tumour onset, progression and metastatic dissemination, before summarizing the ongoing work in the field aimed at developing therapies to co-target the matrix in cancer and cancer metastasis.
  22. Semin Cancer Biol. 2021 Feb 11. pii: S1044-579X(21)00025-0. [Epub ahead of print]
    Corthay A, Bakacs T, Thangavelu G, Anderson CC.
      Disseminated non-dividing (dormant) cancer cells as well as those in equilibrium with the immune response remain the major challenge for successful treatment of cancer. The equilibrium between disseminated dormant cancer cells and the immune system is reminiscent of states that can occur during infection or allogeneic tissue and cell transplantation. We discuss here the major competing models of how the immune system achieves a self nonself discrimination (pathogen/danger patterns, quorum, and coinhibition/tuning models), and suggest that taking advantage of a combination of the proposed mechanisms in each model may lead to increased efficacy in tackling cancer cell dormancy.
    Keywords:  Cancer dormancy; Coinhibitory; Hyperthermia; Immune tolerance; T cell activation
  23. Nat Commun. 2021 02 18. 12(1): 1137
    Garg M, Couturier DL, Nsengimana J, Fonseca NA, Wongchenko M, Yan Y, Lauss M, Jönsson GB, Newton-Bishop J, Parkinson C, Middleton MR, Bishop DT, McDonald S, Stefanos N, Tadross J, Vergara IA, Lo S, Newell F, Wilmott JS, Thompson JF, Long GV, Scolyer RA, Corrie P, Adams DJ, Brazma A, Rabbie R.
      Adjuvant systemic therapies are now routinely used following resection of stage III melanoma, however accurate prognostic information is needed to better stratify patients. We use differential expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature. This signature strongly associated with progression-free (HR = 1.63, p = 5.24 × 10-5) and overall survival (HR = 1.61, p = 1.67 × 10-4), was validated in 175 regional lymph nodes metastasis as well as two externally ascertained datasets. The machine learning classification models trained using the signature genes performed significantly better in predicting metastases than models trained with clinical covariates (pAUROC = 7.03 × 10-4), or published prognostic signatures (pAUROC < 0.05). The signature score negatively correlated with measures of immune cell infiltration (ρ = -0.75, p < 2.2 × 10-16), with a higher score representing reduced lymphocyte infiltration and a higher 5-year risk of death in stage II melanoma. Our expression signature identifies melanoma patients at higher risk of metastases and warrants further evaluation in adjuvant clinical trials.
  24. Clin Cancer Res. 2021 Feb 16. pii: clincanres.3113.2020. [Epub ahead of print]
    Sinn BV, Loibl S, Hanusch CA, Zahm DM, Sinn HP, Untch M, Weber K, Karn T, Becker C, Marme F, Schmitt WD, Müller V, Schem C, Treue D, Stickeler E, Klauschen F, Burchardi N, Furlanetto J, von Mackelenbergh M, Fasching PA, Schneeweiss A, Denkert C.
      PURPOSE: We evaluated mRNA signatures to predict response to neoadjuvant PD-L1 inhibition in combination with chemotherapy in early triple-negative breast cancer.EXPERIMENTAL DESIGN: Targeted mRNA sequencing of 2559 transcripts was performed in FFPE samples from 162 patients of the GeparNuevo trial. We focused on validation of four predefined gene-signatures and differential gene expression analyses for new predictive markers.
    RESULTS: Two signatures (G6-Sig, IFN-Sig) were predictive for treatment response in a multivariate model including treatment arm (G6-Sig: OR 1.558, 95 % CI 1.130-2.182; P = 0.008, IFN-Sig: OR 1.695, 95 % CI 1.234-2.376; P = 0.002), while the CYT metric predicted pCR in the durvalumab arm, and the Prolif-Sig in the placebo arm. Expression of PD-L1 mRNA was associated with better response on both arms, indicating that increased levels of PD-L1 are a general predictor of neoadjuvant therapy response. In an exploratory analysis, we identified seven genes that were higher expressed in responders in the durvalumab arm but not the placebo arm: HLA-A, HLA-B, TAP1, GBP1, CXCL10, STAT1, CD38. These genes were associated with cellular antigen processing and presentation and interferon signaling.
    CONCLUSIONS: Immune-associated signatures are associated with pCR after chemotherapy but might be of limited use for the prediction of response to additional immune-checkpoint blockade. Gene expression related to antigen presentation and interferon signaling might be interesting candidates for further evaluation.
  25. Cell. 2021 Feb 18. pii: S0092-8674(21)00012-X. [Epub ahead of print]184(4): 1064-1080.e20
    Hanna RE, Hegde M, Fagre CR, DeWeirdt PC, Sangree AK, Szegletes Z, Griffith A, Feeley MN, Sanson KR, Baidi Y, Koblan LW, Liu DR, Neal JT, Doench JG.
      Understanding the functional consequences of single-nucleotide variants is critical to uncovering the genetic underpinnings of diseases, but technologies to characterize variants are limiting. Here, we leverage CRISPR-Cas9 cytosine base editors in pooled screens to scalably assay variants at endogenous loci in mammalian cells. We benchmark the performance of base editors in positive and negative selection screens, identifying known loss-of-function mutations in BRCA1 and BRCA2 with high precision. To demonstrate the utility of base editor screens to probe small molecule-protein interactions, we screen against BH3 mimetics and PARP inhibitors, identifying point mutations that confer drug sensitivity or resistance. We also create a library of single guide RNAs (sgRNAs) predicted to generate 52,034 ClinVar variants in 3,584 genes and conduct screens in the presence of cellular stressors, identifying loss-of-function variants in numerous DNA damage repair genes. We anticipate that this screening approach will be broadly useful to readily and scalably functionalize genetic variants.
    Keywords:  CRISPR; ClinVar; DNA damage; PARPi; apoptosis; base editing; genetic screens
  26. Cell Death Discov. 2021 Feb 17. 7(1): 33
    Chen X, Cheng B, Dai D, Wu Y, Feng Z, Tong C, Wang X, Zhao J.
      Heparanase (HPSE) is a kind of multifunctional extracellular hydrolase, and related to metastasis of hepatocellular carcinoma (HCC). Endothelial necroptosis promotes the metastasis of cancer cells. It is not clear whether HPSE could mediate necroptosis of microvascular endothelial cells (MVECs) to promote HCC metastasis. Here we found HPSE expression was up-regulated in HCC tissues and its over-expression was correlated with multiple tumor foci, microvascular invasion, and poor outcome of HCC patients. Non-contact co-culture experiments showed high-expressed HPSE in HCC cells mediated the necroptosis of human umbilical vein endothelial cells (HUVECs) and elevated the expression levels of syndecan-1 (SDC-1) and tumor necrosis factor-α (TNF-α) in vitro. As a result of necroptosis, trans-endothelial migration (TEM) of HCC cells was increased. Conversely, both HPSE and SDC-1 knockdowns reversed necroptosis and decreased TNF-α expression level, while HPSE over-expression increased SDC-1 and TNF-α expression and aggravated necroptosis. Animal experiments found that the nude mice, intraperitoneally injected with HPSE high expressing HCC cells, had obvious necroptosis of MVECs and high intrahepatic metastasis rate, which could be relieved by inhibitor of necroptosis. Morever, HPSE elevated the expression levels of p38 mitogen-activated protein kinase (p38 MAPK) rather than nuclear factor kappa B in vitro. Our data suggest that HPSE induces necroptosis of MVECs to promote the metastasis of HCC by activating HPSE/SDC-1/TNF-α axis and p38 MAPK pathway.
  27. Clin Cancer Res. 2021 Feb 16. pii: clincanres.4772.2020. [Epub ahead of print]
    Jones GD, Caso R, Tan KS, Mastrogiacomo B, Sanchez-Vega F, Liu Y, Connolly JG, Murciano-Goroff YR, Bott M, Adusumilli PS, Molena D, Rocco G, Rusch VW, Sihag S, Misale S, Yaeger R, Drilon A, Arbour KC, Riely GJ, Rosen N, Lito P, Zhang H, Lyden D, Rudin CM, Jones DR, Li BT, Isbell JM.
      PURPOSE: KRASG12C is the most common KRAS mutation in primary lung adenocarcinoma (LUAD). Phase I clinical trials have demonstrated encouraging clinical activity of KRASG12C inhibitors in the metastatic setting. We investigated disease-free survival (DFS) and tumor genomic features in patients with surgically resected KRASG12C-mutant LUAD.EXPERIMENTAL DESIGN: Patients who underwent resection of stage I-III LUAD and next-generation sequencing (NGS) were evaluated. Exclusion criteria were receipt of induction therapy, incomplete resection, and low-quality NGS. Mutations were classified as KRAS wild-type (KRASwt), G12C (KRASG12C), or non-G12C (KRASother). DFS was compared between groups using the log-rank test; factors associated with DFS were assessed using Cox regression. Mutual exclusivity and co-occurrence, tumor clonality, and mutational signatures were assessed.
    RESULTS: In total, 604 patients were included: 374 KRASwt (62%), 95 KRASG12C (16%), and 135 KRASother (22%). Three-year DFS was not different between KRAS-mutant and KRASwt tumors. However, 3-year DFS was worse in patients with KRASG12C than KRASother tumors (log-rank p=0.029). KRASG12C tumors had more lymphovascular invasion (51% vs. 37%; p=0.032) and higher tumor mutation burden (median [interquartile range], 7.0 [5.3-10.8] vs. 6.1 [3.5-9.7]; p=0.021), compared with KRASother tumors. KRASG12C mutation was independently associated with worse DFS on multivariable analysis. Our DFS findings were externally validated in an independent The Cancer Genome Atlas cohort.
    CONCLUSIONS: KRASG12C mutations are associated with worse DFS after complete resection of stage I-III LUAD. These tumors harbor more-aggressive clinicopathologic and genomic features than other KRAS-mutant tumors. We identify a high-risk group for whom KRASG12C inhibitors may be investigated to improve survival.