bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒10‒25
twenty-five papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Cancer Res. 2020 Oct 19. pii: canres.4036.2019. [Epub ahead of print]
    Smalley M, Natarajan SK, Mondal J, Goldman D, Shanthappa B, Pellowe M, Dash C, Saha T, Khiste S, Ramadurai N, Eton EO, Smalley JL, Brown A, Thayakumar A, Rahman M, Arai K, Kohandel M, Sengupta S, Goldman A.
      Drug-induced resistance, or tolerance, is an emerging yet poorly understood failure of anticancer therapy. The interplay between drug-tolerant cancer cells and innate immunity within the tumor, the consequence on tumor growth, and therapeutic strategies to address these challenges remain undescribed. Here we elucidate the role of taxane-induced resistance on natural killer (NK) cell tumor immunity in triple-negative breast cancer (TNBC) and the design of spatio-temporally controlled nanomedicines, which boost therapeutic efficacy and invigorate 'disabled' NK. Drug tolerance limited NK cell immune surveillance via drug-induced depletion of the NK-activating ligand receptor axis, NKG2D and MHC class I polypeptide-related sequence A, B (MICA/B). Systems biology supported by empirical evidence revealed the heat shock protein 90 (Hsp90) simultaneously controls immune surveillance and persistence of drug-treated tumor cells. Based on this evidence, we engineered a 'chimeric' nano-therapeutic tool comprising taxanes and a cholesterol-tethered Hsp90 inhibitor, radicicol, which targets the tumor, reduces tolerance, and optimally re-primes NK cells via prolonged induction of NK-activating ligand receptors via temporal control of drug release in vitro and in vivo. A human ex-vivo TNBC model confirmed the importance of NK cells in drug-induced death under pressure of clinically-approved agents. These findings highlight a convergence between drug-induced resistance, the tumor-immune contexture, and engineered approaches that considers the tumor and microenvironment to improve the success of combinatorial therapy.
  2. Cancer Res. 2020 Oct 21. pii: canres.3717.2019. [Epub ahead of print]
    Parashar D, Nair B, Geethadevi A, George J, Nair A, Tsaih SW, Kadamberi IP, Gopinadhan Nair GK, Lu Y, Ramchandran R, Uyar DS, Rader JS, Ram PT, Mills GB, Pradeep S, Chaluvally-Raghavan P.
      Peritoneal spread is the primary mechanism of metastasis of ovarian cancer, and survival of ovarian cancer cells in the peritoneal cavity as non-adherent spheroids and their adherence to the mesothelium of distant organs lead to cancer progression, metastasis and mortality. However, the mechanisms that govern this metastatic process in ovarian cancer cells remain poorly understood. In this study, we cultured ovarian cancer cell lines in adherent (AD) and in non-adherent (NAD) conditions in vitro and analyzed changes in mRNA and protein levels to identify mechanisms of tumor cell survival and proliferation in AD and NAD cells. EGFR or ERBB2 upregulated ZEB1 in NAD cells, which caused resistance to cell death and increased tumor-initiating capacity. Conversely, Forkhead box M1 (FOXM1) was required for the induction of Integrin Beta 1 (ITGB1), Integrin-α V (ITGAV), and Integrin-α 5 (ITGA5) for adhesion of cancer cells. FOXM1 also upregulated ZEB1, which could act as a feedback inhibitor of FOXM1 and caused the transition of AD cells to NAD cells. Strikingly, the combinatorial treatment with Lapatinib (dual kinase inhibitor of EGFR (ERBB1) and ERBB2) and Thiostrepton (FOXM1 inhibitor) reduced growth and peritoneal spread of ovarian cancer cells more effectively than either single agent treatment in vivo. In conclusion, these results demonstrate that FOXM1 and EGFR/ERBB2 pathways are key points of vulnerability for therapy to disrupt peritoneal spread and adhesion of ovarian cancer cells.
  3. Clin Cancer Res. 2020 Oct 22. pii: clincanres.2475.2020. [Epub ahead of print]
    Gao CF, Wisniewski LB, Liu Y, Staal B, Beddows I, Plenker D, Aldakkak M, Hall J, Barnett D, Kheir Gouda M, Allen PJ, Drake RR, Zureikat AH, Huang Y, Evans DB, Singhi AD, Brand RE, Tuveson DA, Tsai S, Haab BB.
      PURPOSE: A subset of pancreatic ductal adenocarcinomas (PDACs) is highly resistant to systemic chemotherapy, but no markers are available in clinical settings to identify this subset. We hypothesized that a glycan biomarker for PDAC called sTRA could be used for this purpose.EXPERIMENTAL DESIGN: We tested for differences between PDACs classified by glycan expression in multiple systems: sets of cell lines, organoids, and isogenic cell lines; primary tumors; and blood plasma from human subjects.
    RESULTS: The sTRA-expressing models tended to have stem-like gene expression and the capacity for mesenchymal differentiation, in contrast to the non-expressing models. The sTRA cell lines also had significantly increased resistance to seven different chemotherapeutics commonly used against pancreatic cancer. Patients with primary tumors that were positive for a gene-expression classifier for sTRA received no statistically significant benefit from adjuvant chemotherapy, in contrast to those negative for the signature. In another cohort, based on direct measurements of sTRA in tissue microarrays, the patients who were high in sTRA again had no statistically significant benefit from adjuvant chemotherapy. Furthermore, a blood-plasma test for the sTRA glycan identified the PDACs that showed rapid relapse following neoadjuvant chemotherapy.
    CONCLUSIONS: This research demonstrates that a glycan biomarker could have value to detect chemotherapy-resistant PDAC in clinical settings. This capability could aid in the development of stratified treatment plans and facilitate biomarker-guided trials targeting resistant PDAC.
  4. Nat Commun. 2020 10 20. 11(1): 5315
    Rodriguez-Hernandez I, Maiques O, Kohlhammer L, Cantelli G, Perdrix-Rosell A, Monger J, Fanshawe B, Bridgeman VL, Karagiannis SN, Penin RM, Marcolval J, Marti RM, Matias-Guiu X, Fruhwirth GO, Orgaz JL, Malanchi I, Sanz-Moreno V.
      Melanoma is a highly aggressive tumour that can metastasize very early in disease progression. Notably, melanoma can disseminate using amoeboid invasive strategies. We show here that high Myosin II activity, high levels of ki-67 and high tumour-initiating abilities are characteristic of invasive amoeboid melanoma cells. Mechanistically, we find that WNT11-FZD7-DAAM1 activates Rho-ROCK1/2-Myosin II and plays a crucial role in regulating tumour-initiating potential, local invasion and distant metastasis formation. Importantly, amoeboid melanoma cells express both proliferative and invasive gene signatures. As such, invasive fronts of human and mouse melanomas are enriched in amoeboid cells that are also ki-67 positive. This pattern is further enhanced in metastatic lesions. We propose eradication of amoeboid melanoma cells after surgical removal as a therapeutic strategy.
  5. J Clin Invest. 2020 Oct 20. pii: 133525. [Epub ahead of print]
    Peng JM, Lin SH, Yu MC, Hsieh SY.
      Membrane protrusion and adhesion to the extracellular matrix, which involves the extension of actin filaments and formation of adhesion complexes, are the fundamental processes for cell migration, tumor invasion, and metastasis. How cancer cells efficiently coordinate these processes remains unclear. Here, we showed that membrane-targeted CLIC1 spatiotemporally regulates the formation of cell-matrix adhesions and membrane protrusions through the recruitment of PIP5Ks to the plasma membrane. Comparative proteomics identified CLIC1 upregulated in human hepatocellular carcinoma (HCC) and associated with tumor invasiveness, metastasis, and poor prognosis. In response to migration-related stimuli, CLIC1 recruited PIP5K1A and PIP5K1C from the cytoplasm to the leading edge of the plasma membrane, where PIP5Ks generate a PIP2-rich microdomain to induce the formation of integrin-mediated cell-matrix adhesions and the signaling for cytoskeleon extension. CLIC1 silencing inhibited the attachment of tumor cells to culture plates and the adherence and extravasation in the lung alveoli resulting in suppressed lung metastasis in mice. This study reveals an unrecognized mechanism that spatiotemporally coordinates the formation of both lamellipodium/invadopodia and nascent cell-matrix adhesions for directional migration and tumor invasion/metastasis. The unique traits of upregulation and membrane targeting of CLIC1 in cancer cells make it an excellent therapeutic target for tumor metastasis.
    Keywords:  Cell Biology; Cell migration/adhesion; Chloride channels; Hepatology; Liver cancer
  6. Cancers (Basel). 2020 Oct 21. pii: E3067. [Epub ahead of print]12(10):
    Kesh K, Gupta VK, Durden B, Garrido V, Mateo-Victoriano B, Lavania SP, Banerjee S.
      The extracellular matrix (ECM) has remained an enigmatic component of the tumor microenvironment. It drives metastasis via its interaction with the integrin signaling pathway, contributes to tumor progression and confers therapy resistance by providing a physical barrier around the tumor. The complexity of the ECM lies in its heterogeneous composition and complex glycosylation that can provide a support matrix as well as trigger oncogenic signaling pathways by interacting with the tumor cells. In this review, we attempt to dissect the role of the ECM in enriching for the treatment refractory cancer stem cell population and how it may be involved in regulating their metabolic needs. Additionally, we discuss how the ECM is instrumental in remodeling the tumor immune microenvironment and the potential ways to target this component in order to develop a viable therapy.
    Keywords:  cancer metabolism; cancer stem cells; extra cellular matrix
  7. Proc Natl Acad Sci U S A. 2020 Oct 23. pii: 202006445. [Epub ahead of print]
    Srijakotre N, Liu HJ, Nobis M, Man J, Yip HYK, Papa A, Abud HE, Anderson KI, Welch HCE, Tiganis T, Timpson P, McLean CA, Ooms LM, Mitchell CA.
      The Rac-GEF, P-Rex1, activates Rac1 signaling downstream of G protein-coupled receptors and PI3K. Increased P-Rex1 expression promotes melanoma progression; however, its role in breast cancer is complex, with differing reports of the effect of its expression on disease outcome. To address this we analyzed human databases, undertook gene array expression analysis, and generated unique murine models of P-Rex1 gain or loss of function. Analysis of PREX1 mRNA expression in breast cancer cDNA arrays and a METABRIC cohort revealed that higher PREX1 mRNA in ER+ve/luminal tumors was associated with poor outcome in luminal B cancers. Prex1 deletion in MMTV-neu or MMTV-PyMT mice reduced Rac1 activation in vivo and improved survival. High level MMTV-driven transgenic PREX1 expression resulted in apicobasal polarity defects and increased mammary epithelial cell proliferation associated with hyperplasia and development of de novo mammary tumors. MMTV-PREX1 expression in MMTV-neu mice increased tumor initiation and enhanced metastasis in vivo, but had no effect on primary tumor growth. Pharmacological inhibition of Rac1 or MEK1/2 reduced P-Rex1-driven tumoroid formation and cell invasion. Therefore, P-Rex1 can act as an oncogene and cooperate with HER2/neu to enhance breast cancer initiation and metastasis, despite having no effect on primary tumor growth.
    Keywords:  breast cancer; cell polarity; guanine nucleotide exchange factor (GEF); metastasis; transgenic mouse
  8. Cancer Discov. 2020 Oct 18. pii: CD-20-0282. [Epub ahead of print]
    Binkley MS, Jeon YJ, Nesselbush M, Moding EJ, Nabet BY, Almanza D, Kunder C, Stehr H, Yoo CH, Rhee S, Xiang M, Chabon JJ, Hamilton E, Kurtz DM, Gojenola L, Owen SG, Ko RB, Shin JH, Maxim PG, Lui NS, Backhus LM, Berry MF, Shrager JB, Ramchandran KJ, Padda SK, Das M, Neal JW, Wakelee HA, Alizadeh AA, Loo BW, Diehn M.
      Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in KEAP1/NFE2L2 mutation tumors, indicating they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1 mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations.
  9. Nat Commun. 2020 10 21. 11(1): 5321
    Cho YH, Ro EJ, Yoon JS, Mizutani T, Kang DW, Park JC, Il Kim T, Clevers H, Choi KY.
      5-Fluorouracil (5-FU) remains the first-line treatment for colorectal cancer (CRC). Although 5-FU initially de-bulks the tumor mass, recurrence after chemotherapy is the barrier to effective clinical outcomes for CRC patients. Here, we demonstrate that p53 promotes WNT3 transcription, leading to activation of the WNT/β-catenin pathway in ApcMin/+/Lgr5EGFP mice, CRC patient-derived tumor organoids (PDTOs) and patient-derived tumor cells (PDCs). Through this regulation, 5-FU induces activation and enrichment of cancer stem cells (CSCs) in the residual tumors, contributing to recurrence after treatment. Combinatorial treatment of a WNT inhibitor and 5-FU effectively suppresses the CSCs and reduces tumor regrowth after discontinuation of treatment. These findings indicate p53 as a critical mediator of 5-FU-induced CSC activation via the WNT/β-catenin signaling pathway and highlight the significance of combinatorial treatment of WNT inhibitor and 5-FU as a compelling therapeutic strategy to improve the poor outcomes of current 5-FU-based therapies for CRC patients.
  10. Cancer Lett. 2020 Oct 16. pii: S0304-3835(20)30542-5. [Epub ahead of print]497 100-111
    Bai X, Ni J, Beretov J, Graham P, Li Y.
      Triple-negative breast cancer (TNBC) shows a higher response rate to systemic therapy compared with other breast cancer subtypes. However, the tumor differentiation of TNBC is poorer, with an early tendency to metastasis and a higher recurrence rate. Relapsed and metastatic TNBCs usually progress more rapidly, showing strong resistance to chemotherapy and radiotherapy. Due to the lack of combinatorial targeted drugs, alternative treatments fail to improve these patient's prognosis and the quality of life. Finding the Achilles' heel of TNBC is critical for patients with advanced TNBC. Here, we summarize the latest advances in the mechanisms underlying TNBC therapeutic resistance, consider how these mechanisms may affect the development and utilization of TNBC targeted drugs, and discuss the rationale of relevant signals as therapeutic targets. Also, we review the clinical trials registered in for TNBC patients, which comprehensively reveals current research and development of novel TNBC targeted drugs and future trends.
    Keywords:  Clinical trial; DNA repair; Immunotherapy; TNBC; Targeted drug; Therapeutic resistance; Tumor microenvironment
  11. Oncogene. 2020 Oct 24.
    Chen J, Xuan Z, Song W, Han W, Chen H, Du Y, Xie H, Zhao Y, Zheng S, Song P.
      Ether-à-go-go-1 (EAG1), one of the potassium channels, is involved in various physiological processes and plays an important role in the tumorigenesis of many kinds of cancer. EAG1 is highly expressed in hepatocarcinoma cells and is closely related to clinical prognosis, but the molecular mechanism remains elusive. In this study, we verified that EAG1 promotes the proliferation of hepatocellular carcinoma (HCC) both in vitro and in vivo. It promotes cell cycle progression by inhibiting the ubiquitination of SKP2. In addition, EAG1 promotes the migration and invasion of HCC by promoting cell pseudopod formation. Furthermore, in a high-pressure plasmid-injected mouse liver orthotopic carcinoma model, astemizole, an EAG family blocker, can significantly inhibit the formation of liver cancer. Meanwhile, liver-specific EAG1 knockout mice show resistance to hepatocarcinogenesis. This research demonstrated that EAG1 plays an important role in the progression of HCC, and could be a potential therapeutic target for HCC.
  12. Nat Med. 2020 Oct 19.
    Cerezo-Wallis D, Contreras-Alcalde M, Troulé K, Catena X, Mucientes C, Calvo TG, Cañón E, Tejedo C, Pennacchi PC, Hogan S, Kölblinger P, Tejero H, Chen AX, Ibarz N, Graña-Castro O, Martinez L, Muñoz J, Ortiz-Romero P, Rodriguez-Peralto JL, Gómez-López G, Al-Shahrour F, Rabadán R, Levesque MP, Olmeda D, Soengas MS.
      An open question in aggressive cancers such as melanoma is how malignant cells can shift the immune system to pro-tumorigenic functions. Here we identify midkine (MDK) as a melanoma-secreted driver of an inflamed, but immune evasive, microenvironment that defines poor patient prognosis and resistance to immune checkpoint blockade. Mechanistically, MDK was found to control the transcriptome of melanoma cells, allowing for coordinated activation of nuclear factor-κB and downregulation of interferon-associated pathways. The resulting MDK-modulated secretome educated macrophages towards tolerant phenotypes that promoted CD8+ T cell dysfunction. In contrast, genetic targeting of MDK sensitized melanoma cells to anti-PD-1/anti-PD-L1 treatment. Emphasizing the translational relevance of these findings, the expression profile of MDK-depleted tumors was enriched in key indicators of a good response to immune checkpoint blockers in independent patient cohorts. Together, these data reveal that MDK acts as an internal modulator of autocrine and paracrine signals that maintain immune suppression in aggressive melanomas.
  13. Oncogene. 2020 Oct 20.
    Zhang Q, Zhou W, Yu S, Ju Y, To SKY, Wong AST, Jiao Y, Poon TCW, Tam KY, Lee LTO.
      As a result of the hostile microenvironment, metabolic alterations are required to enable the malignant growth of cancer cells. To understand metabolic reprogramming during metastasis, we conducted shotgun proteomic analysis of highly metastatic (HM) and non-metastatic (NM) ovarian cancer cells. The results suggest that the genes involved in fatty-acid (FA) metabolism are upregulated, with consequent increases of phospholipids with relatively short FA chains (myristic acid, MA) in HM cells. Among the upregulated proteins, ACSL1 expression could convert the lipid profile of NM cells to that similar of HM cells and make them highly aggressive. Importantly, we demonstrated that ACSL1 activates the AMP-activated protein kinase and Src pathways via protein myristoylation and finally enhances FA beta oxidation. Patient samples and tissue microarray data also suggested that omentum metastatic tumours have higher ACSL1 expression than primary tumours and a strong association with poor clinical outcome. Overall, our data reveal that ACSL1 enhances cancer metastasis by regulating FA metabolism and myristoylation.
  14. Clin Cancer Res. 2020 Oct 20. pii: clincanres.2278.2020. [Epub ahead of print]
    Rosen EY, Johnson ML, Clifford SE, Somwar R, Kherani JF, Son J, Bertram AA, Davare MA, Gladstone EG, Ivanova EV, Henry D, Kelley EM, Lin M, Milan MSD, Nair BC, Olek EA, Scanlon JE, Vojnic M, Ebata K, Hechtman JF, Li BT, Sholl LM, Taylor BS, Ladanyi M, Janne PA, Rothenberg SM, Drilon A, Oxnard GR.
      PURPOSE: The RET proto-oncogene encodes a receptor tyrosine kinase which is activated by gene fusion in 1-2% of non-small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating RET gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood.PATIENTS AND METHODS: We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have MET amplification associated with resistance to selpercatinib. We validated MET activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPPs).
    RESULTS: MET amplification was identified in post-treatment biopsies in four patients with RET fusion-positive NSCLC treated with selpercatinib. In at least one case, MET amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in RET fusion-positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months.
    CONCLUSIONS: Through the use of SPPs we were able to offer combination therapy targeting MET-amplified resistance identified on the first-in-human study of selpercatinib. These data provide suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.
  15. Cancers (Basel). 2020 Oct 16. pii: E3003. [Epub ahead of print]12(10):
    Zhang D, Iwabuchi S, Baba T, Hashimoto SI, Mukaida N, Sasaki SI.
      Patients with triple negative breast cancer (TNBC) is frequently complicated by bone metastasis, which deteriorates the life expectancy of this patient cohort. In order to develop a novel type of therapy for bone metastasis, we established 4T1.3 clone with a high capacity to metastasize to bone after orthotopic injection, from a murine TNBC cell line, 4T1.0. To elucidate the molecular mechanism underlying a high growth ability of 4T1.3 in a bone cavity, we searched for a novel candidate molecule with a focus on a transcription factor whose expression was selectively enhanced in a bone cavity. Comprehensive gene expression analysis detected enhanced Nfe2 mRNA expression in 4T1.3 grown in a bone cavity, compared with in vitro culture conditions. Moreover, Nfe2 gene transduction into 4T1.0 cells enhanced their capability to form intraosseous tumors. Moreover, Nfe2 shRNA treatment reduced tumor formation arising from intraosseous injection of 4T1.3 clone as well as another mouse TNBC-derived TS/A.3 clone with an augmented intraosseous tumor formation ability. Furthermore, NFE2 expression was associated with in vitro growth advantages of these TNBC cell lines under hypoxic condition, which mimics the bone microenvironment, as well as Wnt pathway activation. These observations suggest that NFE2 can potentially contribute to breast cancer cell survival in the bone microenvironment.
    Keywords:  Wnt pathway; bone metastasis; breast cancer; transcription factor
  16. Nat Cell Biol. 2020 Oct 19.
    Ros M, Nguyen AT, Chia J, Le Tran S, Le Guezennec X, McDowall R, Vakhrushev S, Clausen H, Humphries MJ, Saltel F, Bard FA.
      Tumour growth and invasiveness require extracellular matrix (ECM) degradation and are stimulated by the GALA pathway, which induces protein O-glycosylation in the endoplasmic reticulum (ER). ECM degradation requires metalloproteases, but whether other enzymes are required is unclear. Here, we show that GALA induces the glycosylation of the ER-resident calnexin (Cnx) in breast and liver cancer. Glycosylated Cnx and its partner ERp57 are trafficked to invadosomes, which are sites of ECM degradation. We find that disulfide bridges are abundant in connective and liver ECM. Cell surface Cnx-ERp57 complexes reduce these extracellular disulfide bonds and are essential for ECM degradation. In vivo, liver cancer cells but not hepatocytes display cell surface Cnx. Liver tumour growth and lung metastasis of breast and liver cancer cells are inhibited by anti-Cnx antibodies. These findings uncover a moonlighting function of Cnx-ERp57 at the cell surface that is essential for ECM breakdown and tumour development.
  17. J Clin Invest. 2020 Oct 19. pii: 135528. [Epub ahead of print]
    Gauttier V, Pengam S, Durand J, Biteau K, Mary C, Morello A, Néel M, Porto G, Teppaz G, Thepenier V, Danger R, Vince N, Wilhelm E, Girault I, Abes R, Ruiz C, Trilleaud C, Ralph KL, Trombetta ES, Garcia A, Vignard V, Martinet B, Glémain A, Bruneau S, Haspot F, Dehmani S, Duplouye P, Miyasaka M, Labarrière N, Laplaud D, Le Bas-Bernardet S, Blanquart C, Catros V, Gouraud PA, Archambeaud I, Aublé H, Metairie S, Mosnier JF, Costantini D, Blancho G, Conchon S, Vanhove B, Poirier N.
      T cell exclusion causes resistance to cancer immunotherapies via immune checkpoint blockade (ICB). Myeloid cells contribute to resistance by expressing signal regulatory protein-α (SIRPα), an inhibitory membrane receptor that interacts with ubiquitous receptor CD47 to control macrophage phagocytosis in the tumor microenvironment. Although CD47/SIRPα-targeting drugs have been assessed in preclinical models, the therapeutic benefit of selectively blocking SIRPα, and not SIRPγ/CD47, in humans remains unknown. We report a potent synergy between selective SIRPα blockade and ICB in increasing memory T cell responses and reverting exclusion in syngeneic and orthotopic tumor models. Selective SIRPα blockade stimulated tumor nest T cell recruitment by restoring murine and human macrophage chemokine secretion and increased anti-tumor T cell responses by promoting tumor-antigen crosspresentation by dendritic cells. However, nonselective SIRPα/SIRPγ blockade targeting CD47 impaired human T cell activation, proliferation, and endothelial transmigration. Selective SIRPα inhibition opens an attractive avenue to overcoming ICB resistance in patients with elevated myeloid cell infiltration in solid tumors.
    Keywords:  Cancer immunotherapy; Immunology; Macrophages; T cells; Therapeutics
  18. Cancers (Basel). 2020 Oct 19. pii: E3042. [Epub ahead of print]12(10):
    Jeong YM, Cho H, Kim TM, Kim Y, Jeon S, Bychkov A, Jung CK.
      CD73 is involved in tumor immune escape and promotes the growth and progression of cancer cells. The functional role of CD73 expression in papillary thyroid carcinoma (PTC) has not yet been established. In 511 patients with PTC, immunohistochemistry for CD73 on tissue microarrays showed that the high expression of CD73 was associated with an aggressive histologic variant (p = 0.002), extrathyroidal extension (p < 0.001), lymph node metastasis (p < 0.001), and BRAFV600E mutation (p = 0.015). Survival analysis results showed that patients with high CD73 expression had worse recurrence-free survival (p = 0.023). CD73 inhibitors induced G1 cell cycle arrest and apoptosis, inhibited the migration and invasion of PTC cells, and suppressed tumor growth in PTC xenograft nude mice. High expression of CD73 (NT5E) mRNA was associated with unfavorable clinicopathologic characteristics, the abundance of Tregs and dendritic cells, depletion of natural killer (NK) cells, and high expression of immune checkpoint genes and epithelial-to-mesenchymal transition-related genes in The Cancer Genome Atlas (TCGA) dataset. Taken together, CD73 expression promotes tumor progression and predicts low recurrence-free survival. Targeting the CD73-adenosine axis in the tumor microenvironment offers an attractive pathway for therapeutic strategies aimed at advanced PTC.
    Keywords:  5′-Nucleotidase; CD73; epithelial–mesenchymal transition; thyroid cancer; tumor microenvironment
  19. Clin Cancer Res. 2020 Oct 21. pii: clincanres.2710.2020. [Epub ahead of print]
    Loree JM, Dowers A, Tu D, Jonker D, Edelstein DL, Quinn H, Holtrup F, Price T, Zalcberg JR, Moore MJ, Karapetis CS, O'Callaghan CJ, Waring P, Kennecke HF, Hamilton SR, Kopetz S.
      BACKGROUND: Expanded RAS/BRAF mutations have not been assessed as predictive for single-agent cetuximab in metastatic colorectal cancer (mCRC) and low mutant allele frequency (MAF) mutations are of unclear significance. We aimed to establish cetuximab efficacy in optimally selected patients using highly sensitive BEAMing, capable of detecting alterations below standard clinical assays.METHODS: CO.17 compared cetuximab versus best supportive care (BSC) in RAS/BRAF unselected mCRC. We performed RAS/BRAF analysis on micro-dissected tissue of 242 patients in CO.17 using BEAMing for KRAS/NRAS (codons 12/13/59/61/117/146) and BRAF V600E. Patients without BEAMing but with previous Sanger sequencing detected mutations were included.
    RESULTS: KRAS, NRAS, and BRAF mutations were present in 53%, 4%, and 3% of tumors, respectively. Cetuximab improved overall survival (OS) (HR 0.51, 95% CI 0.32-0.81, P=0.004) and progression free survival (PFS) (HR 0.25, 95% CI 0.15-0.41, P<0.0001) compared to BSC in RAS/BRAF wild type patients. Cetuximab did not improve OS/PFS for KRAS, NRAS, or BRAF mutated tumors and tests of interaction confirmed expanded KRAS (P=0.0002) and NRAS (P=0.006) as predictive, while BRAF mutations were not (P=0.089). BEAMing identified 14% more tumors as RAS mutant than Sanger sequencing and cetuximab lacked activity in these patients. Mutations at MAF<5% were noted in 6/242 patients (2%). One patient with a KRAS A59T mutation (MAF=2%) responded to cetuximab. More NRAS than KRAS mutations were low MAF (OR 20.50, 95% CI 3.88-96.85, P=0.0038).
    CONCLUSIONS: We establish single-agent cetuximab efficacy in optimally selected patients and show that subclonal RAS/BRAF alterations are uncommon and remain of indeterminate significance.
  20. Mol Cancer Res. 2020 Oct 21. pii: molcanres.0686.2020. [Epub ahead of print]
    Morton JJ, Alzofon N, Keysar SB, Chimed TS, Reisinger J, Perrenoud L, Le PN, Nieto C, Gomez K, Miller B, Yeager R, Gao D, Tan AC, Somerset H, Medina T, Wang XJ, Wang JH, Robinson W, Roop DR, Gonzalez R, Jimeno A.
      Resistance to immunotherapy is a significant challenge, and the scarcity of human models hinders the identification of the underlying mechanisms. To address this limitation, we constructed an autologous humanized mouse (aHM) model with hematopoietic stem and progenitor cells (HSPCs) and tumors from two melanoma patients progressing to immunotherapy. Unlike mismatched humanized mouse (mHM) models, generated from cord blood-derived HSPCs and tumors from different donors, the aHM recapitulates a patient-specific tumor microenvironment (TME). When patient tumors were implanted on aHM, mHM and NOD/SCID/IL2rg-/- (NSG) cohorts, tumors appeared earlier and grew faster on NSG and mHM cohorts. We observed that immune cells differentiating in the aHM were relatively more capable of circulating peripherally, invading into tumors and interacting with the TME. A heterologous, human leukocyte antigen (HLA-A) matched cohort also yielded slower growing tumors than non-HLA-matched mHM, indicating that a less permissive immune environment inhibits tumor progression. When the aHM, mHM, and NSG cohorts were treated with immunotherapies mirroring what the originating patients received, tumor growth in the aHM accelerated, similar to the progression observed in the patients. This rapid growth was associated with decreased immune cell infiltration, reduced interferon gamma (IFNγ)-related gene expression, and a reduction in STAT3 phosphorylation, events that were replicated in vitro using tumor-derived cell lines. Implications: Engrafted adult HSPCs give rise to more tumor infiltrative immune cells, increased HLA matching leads to slower tumor initiation and growth, and continuing immunotherapy past progression can paradoxically lead to increased growth.
  21. Cancers (Basel). 2020 Oct 15. pii: E2984. [Epub ahead of print]12(10):
    Archer M, Dogra N, Kyprianou N.
      Prostate cancer is the most common malignancy among men, and progression to metastasis and the emergence of therapeutically resistant disease confers a high mortality rate. Growing evidence implicates inflammation as a driver of prostate cancer development and progression, resulting in increased cancer risk for prostate cancer. Population-based studies revealed that the use of antinflammatory drugs led to a 23% risk reduction prostate cancer occurrence, a negative association that was stronger in men who specifically used COX-2 inhibitors. Furthermore, patients that were taking aspirin had a 21% reduction in prostate cancer risk, and further, long-term users of daily low dose aspirin had a 29% prostate cancer risk reduction as compared to the controls. Environmental exposure to bacterial and viral infections, exposure to mutagenic agents, and genetic variations predispose the prostate gland to inflammation, with a coordinated elevated expression of inflammatory cytokines (IL-6, TGF-β). It is the dynamics within the tumor microenvironment that empower these cytokines to promote survival and growth of the primary tumor and facilitate disease progression by navigating the immunoregulatory network, phenotypic epithelial-mesenchymal transition (EMT), angiogenesis, anoikis resistance, and metastasis. In this review, we discuss the sources of inflammation in the prostate, the functional contribution of the critical inflammatory effectors to prostate cancer initiation and metastatic progression, and the therapeutic challenges that they impose on treatment of advanced disease and overcoming therapeutic resistance. Growing mechanistic evidence supports the significance of inflammation in localized prostate cancer, and the systemic impact of the process within the tumor microenvironment on disease progression to advanced therapeutically-resistant prostate cancer. Rigorous exploitation of the role of inflammation in prostate cancer progression to metastasis and therapeutic resistance will empower the development of precise biomarker signatures and effective targeted therapeutics to reduce the clinical burden and lethal disease in the future.
    Keywords:  EMT phenotype; anoikis; macrophages; metastasis; survival signaling; treatment resistance; tumor microenvironment; vascularity
  22. Nat Rev Cancer. 2020 Oct 23.
    Bugter JM, Fenderico N, Maurice MM.
      Mutation-induced activation of WNT-β-catenin signalling is a frequent driver event in human cancer. Sustained WNT-β-catenin pathway activation endows cancer cells with sustained self-renewing growth properties and is associated with therapy resistance. In healthy adult stem cells, WNT pathway activity is carefully controlled by core pathway tumour suppressors as well as negative feedback regulators. Gene inactivation experiments in mouse models unequivocally demonstrated the relevance of WNT tumour suppressor loss-of-function mutations for cancer growth. However, in human cancer, a far more complex picture has emerged in which missense or truncating mutations mediate stable expression of mutant proteins, with distinct functional and phenotypic ramifications. Herein, we review recent advances and challenges in our understanding of how different mutational subsets of WNT tumour suppressor genes link to distinct cancer types, clinical outcomes and treatment strategies.
  23. Cancers (Basel). 2020 Oct 17. pii: E3017. [Epub ahead of print]12(10):
    Nocquet L, Juin PP, Souazé F.
      Resistance of solid cancer cells to chemotherapies and targeted therapies is not only due to the mutational status of cancer cells but also to the concurring of stromal cells of the tumor ecosystem, such as immune cells, vasculature and cancer-associated fibroblasts (CAFs). The reciprocal education of cancer cells and CAFs favors tumor growth, survival and invasion. Mitochondrial function control, including the regulation of mitochondrial metabolism, oxidative stress and apoptotic stress are crucial for these different tumor progression steps. In this review, we focus on how CAFs participate in cancer progression by modulating cancer cells metabolic functions and mitochondrial apoptosis. We emphasize that mitochondria from CAFs influence their activation status and pro-tumoral effects. We thus advocate that understanding mitochondria-mediated tumor-stroma interactions provides the possibility to consider cancer therapies that improve current treatments by targeting these interactions or mitochondria directly in tumor and/or stromal cells.
    Keywords:  BCL-2 family proteins; apoptosis; cancer; cancer-associated fibroblast; metabolism; mitochondria
  24. Cancers (Basel). 2020 Oct 16. pii: E3005. [Epub ahead of print]12(10):
    Nawrocki ST, Wang W, Carew JS.
      Autophagy is a mechanism of lysosomal proteolysis that is utilized to degrade damaged organelles, proteins, and other cellular components. Although key studies demonstrate that autophagy functions as a mechanism of tumor suppression via the degradation of defective pre-malignant cells, autophagy can also be used as a mechanism to break down cellular components under stress conditions to generate the required metabolic materials for cell survival. Autophagy has emerged as an important mediator of resistance to radiation, chemotherapy, and targeted agents. This series of articles highlight the role of autophagy in cancer progression and drug resistance and underscores the need for new and more effective agents that target this process.
    Keywords:  ROC-325; autophagy; cancer; drug resistance; lysosome
  25. Cancers (Basel). 2020 Oct 16. pii: E3001. [Epub ahead of print]12(10):
    Freitas MO, Gartner J, Rangel-Pozzo A, Mai S.
      Circulating tumor cells (CTCs) can promote distant metastases and can be obtained through minimally invasive liquid biopsy for clinical assessment in cancer patients. Having both genomic heterogeneity and instability as common features, the genetic characterization of CTCs can serve as a powerful tool for a better understanding of the molecular changes occurring at tumor initiation and during tumor progression/metastasis. In this review, we will highlight recent advances in the detection and quantification of tumor cell heterogeneity and genomic instability in CTCs. We will focus on the contribution of chromosome instability studies to genetic heterogeneity in CTCs at the single-CTC level by discussing data from different cancer subtypes and their impact on diagnosis and precision medicine.
    Keywords:  chromosome instability; circulating tumor cells (CTCs); tumor heterogeneity