bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒03‒22
twenty-one papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology


  1. Front Cell Dev Biol. 2020 ;8 37
    Montagner M, Sahai E.
      Delayed relapses at distant sites are a common clinical observation for certain types of cancers after removal of primary tumor, such as breast and prostate cancer. This evidence has been explained by postulating a long period during which disseminated cancer cells (DCCs) survive in a foreign environment without developing into overt metastasis. Because of the asymptomatic nature of this phenomenon, isolation, and analysis of disseminated dormant cancer cells from clinically disease-free patients is ethically and technically highly problematic and currently these data are largely limited to the bone marrow. That said, detecting, profiling and treating indolent metastatic lesions before the onset of relapse is the imperative. To overcome this major limitation many laboratories developed in vitro models of the metastatic niche for different organs and different types of cancers. In this review we focus specifically on in vitro models designed to study metastatic dormancy of breast cancer cells (BCCs). We provide an overview of the BCCs employed in the different organotypic systems and address the components of the metastatic microenvironment that have been shown to impact on the dormant phenotype: tissue architecture, stromal cells, biochemical environment, oxygen levels, cell density. A brief description of the organ-specific in vitro models for bone, liver, and lung is provided. Finally, we discuss the strategies employed so far for the validation of the different systems.
    Keywords:  breast cancer; cancer dormancy; cancer metastasis; in vitro models cancer; metastasis biology; metastatic dormancy
    DOI:  https://doi.org/10.3389/fcell.2020.00037
  2. Nat Commun. 2020 Mar 20. 11(1): 1494
    Pein M, Insua-Rodríguez J, Hongu T, Riedel A, Meier J, Wiedmann L, Decker K, Essers MAG, Sinn HP, Spaich S, Sütterlin M, Schneeweiss A, Trumpp A, Oskarsson T.
      Metastatic colonization relies on interactions between disseminated cancer cells and the microenvironment in secondary organs. Here, we show that disseminated breast cancer cells evoke phenotypic changes in lung fibroblasts, forming a supportive metastatic niche. Colonization of the lungs confers an inflammatory phenotype in metastasis-associated fibroblasts. Specifically, IL-1α and IL-1β secreted by breast cancer cells induce CXCL9 and CXCL10 production in lung fibroblasts via NF-κB signaling, fueling the growth of lung metastases. Notably, we find that the chemokine receptor CXCR3, that binds CXCL9/10, is specifically expressed in a small subset of breast cancer cells, which exhibits tumor-initiating ability when co-transplanted with fibroblasts and has high JNK signaling that drives IL-1α/β expression. Importantly, disruption of the intercellular JNK-IL-1-CXCL9/10-CXCR3 axis reduces metastatic colonization in xenograft and syngeneic mouse models. These data mechanistically demonstrate an essential role for the molecular crosstalk between breast cancer cells and their fibroblast niche in the progression of metastasis.
    DOI:  https://doi.org/10.1038/s41467-020-15188-x
  3. Nat Commun. 2020 Mar 19. 11(1): 1456
    Li Q, Qin T, Bi Z, Hong H, Ding L, Chen J, Wu W, Lin X, Fu W, Zheng F, Yao Y, Luo ML, Saw PE, Wulf GM, Xu X, Song E, Yao H, Hu H.
      Resistance development to one chemotherapeutic reagent leads frequently to acquired tolerance to other compounds, limiting the therapeutic options for cancer treatment. Herein, we find that overexpression of Rac1 is associated with multi-drug resistance to the neoadjuvant chemotherapy (NAC). Mechanistically, Rac1 activates aldolase A and ERK signaling which up-regulates glycolysis and especially the non-oxidative pentose phosphate pathway (PPP). This leads to increased nucleotides metabolism which protects breast cancer cells from chemotherapeutic-induced DNA damage. To translate this finding, we develop endosomal pH-responsive nanoparticles (NPs) which deliver Rac1-targeting siRNA together with cisplatin and effectively reverses NAC-chemoresistance in PDXs from NAC-resistant breast cancer patients. Altogether, our findings demonstrate that targeting Rac1 is a potential strategy to overcome acquired chemoresistance in breast cancer.
    DOI:  https://doi.org/10.1038/s41467-020-15308-7
  4. Proc Natl Acad Sci U S A. 2020 Mar 19. pii: 201912617. [Epub ahead of print]
    Sharma S, Zhang T, Michowski W, Rebecca VW, Xiao M, Ferretti R, Suski JM, Bronson RT, Paulo JA, Frederick D, Fassl A, Boland GM, Geng Y, Lees JA, Medema RH, Herlyn M, Gygi SP, Sicinski P.
      The cyclin-dependent kinase 5 (CDK5), originally described as a neuronal-specific kinase, is also frequently activated in human cancers. Using conditional CDK5 knockout mice and a mouse model of highly metastatic melanoma, we found that CDK5 is dispensable for the growth of primary tumors. However, we observed that ablation of CDK5 completely abrogated the metastasis, revealing that CDK5 is essential for the metastatic spread. In mouse and human melanoma cells CDK5 promotes cell invasiveness by directly phosphorylating an intermediate filament protein, vimentin, thereby inhibiting assembly of vimentin filaments. Chemical inhibition of CDK5 blocks the metastatic spread of patient-derived melanomas in patient-derived xenograft (PDX) mouse models. Hence, inhibition of CDK5 might represent a very potent therapeutic strategy to impede the metastatic dissemination of malignant cells.
    Keywords:  CDK5; cyclin-dependent kinases; metastasis; mouse cancer models
    DOI:  https://doi.org/10.1073/pnas.1912617117
  5. Proc Natl Acad Sci U S A. 2020 Mar 19. pii: 201914786. [Epub ahead of print]
    Yi Y, Chen D, Ao J, Zhang W, Yi J, Ren X, Fei J, Li F, Niu M, Chen H, Luo Y, Luo Z, Xiao ZJ.
      AMP-activated protein kinase (AMPK) functions as an energy sensor and is pivotal in maintaining cellular metabolic homeostasis. Numerous studies have shown that down-regulation of AMPK kinase activity or protein stability not only lead to abnormality of metabolism but also contribute to tumor development. However, whether transcription regulation of AMPK plays a critical role in cancer metastasis remains unknown. In this study, we demonstrate that AMPKα1 expression is down-regulated in advanced human breast cancer and is associated with poor clinical outcomes. Transcription of AMPKα1 is inhibited on activation of PI3K and HER2 through ΔNp63α. Ablation of AMPKα1 expression or inhibition of AMPK kinase activity leads to disruption of E-cadherin-mediated cell-cell adhesion in vitro and increased tumor metastasis in vivo. Furthermore, restoration of AMPKα1 expression significantly rescues PI3K/HER2-induced disruption of cell-cell adhesion, cell invasion, and cancer metastasis. Together, these results demonstrate that the transcription control is another layer of AMPK regulation and suggest a critical role for AMPK in regulating cell-cell adhesion and cancer metastasis.
    Keywords:  AMPK; cancer metastasis; cell adhesion; oncogenic signaling; ΔNp63α
    DOI:  https://doi.org/10.1073/pnas.1914786117
  6. Mol Cancer. 2020 Mar 19. 19(1): 62
    Wei L, Sun J, Zhang N, Zheng Y, Wang X, Lv L, Liu J, Xu Y, Shen Y, Yang M.
      Gastric cancer is the fourth most common malignancy and the third leading cause of cancer-related deaths worldwide. Advanced gastric cancer patients can notably benefit from chemotherapy including adriamycin, platinum drugs, 5-fluorouracil, vincristine, and paclitaxel as well as targeted therapy drugs. Nevertheless, primary drug resistance or acquisition drug resistance eventually lead to treatment failure and poor outcomes of the gastric cancer patients. The detailed mechanisms involved in gastric cancer drug resistance have been revealed. Interestingly, different noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), are critically involved in gastric cancer development. Multiple lines of evidences demonstrated that ncRNAs play a vital role in gastric cancer resistance to chemotherapy reagents and targeted therapy drugs. In this review, we systematically summarized the emerging role and detailed molecular mechanisms of ncRNAs impact drug resistance of gastric cancer. Additionally, we propose the potential clinical implications of ncRNAs as novel therapeutic targets and prognostic biomarkers for gastric cancer.
    Keywords:  Circular RNA; Drug resistance; Gastric cancer; Long non-coding RNA; MicroRNA
    DOI:  https://doi.org/10.1186/s12943-020-01185-7
  7. Mol Cancer. 2020 Mar 18. 19(1): 60
    Han K, Wang FW, Cao CH, Ling H, Chen JW, Chen RX, Feng ZH, Luo J, Jin XH, Duan JL, Li SM, Ma NF, Yun JP, Guan XY, Pan ZZ, Lan P, Xu RH, Xie D.
      BACKGROUND: Metastasis causes the vast majority of colorectal carcinoma (CRC)-related deaths. However, little is known about the specific traits and underlying mechanisms of metastasis-initiating cells in primary CRC. And whether or not circular RNAs (circRNAs) take part in this particular event remain not adequately stated yet.METHODS: A screening method based on Transwell assay was first applied to build CRC subgroups with different metastatic potential. High throughput RNA sequencing was used to find out novel metastatic drivers in CRC metastasis-initiating step. A series of in vitro and in vivo assays were further applied to elucidate the functions and underlying molecular mechanisms of circRNAs in CRC metastasis.
    RESULTS: A circRNA consisting of exon 8-11 of LONP2, termed as circLONP2, was upregulated in metastasis-initiating CRC subgroups. Aberrant higher expression of circLONP2 was observed in primary CRC tissues with established metastasis, and along the invasive margin in metastatic site. High expression of circLONP2 predicted unfavorable overall survival. Functional studies revealed that circLONP2 could enhance the invasiveness of CRC cells in vitro, and targeting circLONP2 through anti-sense oligonucleotide (ASO) dramatically reduced the penetrance of metastasis to foreign organs in vivo. Mechanically, circLONP2 directly interacted with and promoted the processing of primary microRNA-17 (pri-miR-17), through recruiting DiGeorge syndrome critical region gene 8 (DGCR8) and Drosha complex in DDX1-dependent manner. Meanwhile, upregulated mature miR-17-5p could be assembled into exosomes and internalized by neighboring cells to enhance their aggressiveness.
    CONCLUSIONS: Our data indicate that circLONP2 acts as key metastasis-initiating molecule during CRC progression through modulating the intracellular maturation and intercellular transfer of miR-17, resulting in dissemination of metastasis-initiating ability in primary site and acceleration of metastasis formation in foreign organs. circLONP2 could serve as an effective prognostic predictor and/or novel anti-metastasis therapeutic target in CRC treatment.
    Keywords:  Colorectal carcinoma; Metastasis; circLONP2; microRNA-17
    DOI:  https://doi.org/10.1186/s12943-020-01184-8
  8. Cancer Discov. 2020 Mar 18. pii: CD-19-1299. [Epub ahead of print]
    Yuan S, Natesan R, Sanchez-Rivera FJ, Li J, Bhanu NV, Yamazoe T, Lin JH, Merrell AJ, Sela Y, Thomas SK, Jiang Y, Plesset JB, Miller EM, Shi J, Garcia BA, Lowe SW, Asangani IA, Stanger BZ.
      Epithelial plasticity - reversible modulation of a cell's epithelial and mesenchymal features - is associated with tumor metastasis and chemoresistance, leading causes of cancer mortality. While different master transcription factors and epigenetic modifiers have been implicated in this process in various contexts, the extent to which a unifying, generalized mechanism of transcriptional regulation underlies epithelial plasticity remains largely unknown. Here, through targeted CRISPR-Cas9 screening, we discovered two histone-modifying enzymes involved in the writing and erasing of H3K36me2 that act reciprocally to regulate epithelial-mesenchymal identity, tumor differentiation, and metastasis. Using a K-to-M histone mutant to directly inhibit H3K36me2, we found that global modulation of the mark is a conserved mechanism underlying the mesenchymal state in various contexts. Mechanistically, regulation of H3K36me2 reprograms enhancers associated with master regulators of epithelial-mesenchymal state. Our results thus outline a unifying epigenome-scale mechanism by which a specific histone modification regulates cellular plasticity and metastasis in cancer.
    DOI:  https://doi.org/10.1158/2159-8290.CD-19-1299
  9. Cancer Res. 2020 Mar 19. pii: canres.3819.2019. [Epub ahead of print]
    Starrett JH, Guernet AA, Cuomo ME, Poels KE, van Alderwerelt van Rosenburgh IK, Nagelberg A, Farnsworth D, Price KS, Khan H, Ashtekar KD, Gaefele M, Ayeni D, Stewart TF, Kuhlmann A, Kaech S, Unni AM, Homer R, Lockwood WW, Michor F, Goldberg SB, Lemmon MA, Smith PD, Cross DA, Politi K.
      Osimertinib, a mutant-specific third generation EGFR TKI, is emerging as the preferred first-line therapy for EGFR mutant lung cancer, yet resistance inevitably develops in patients. We modeled acquired resistance to osimertinib in transgenic mouse models of EGFR L858R-induced lung adenocarcinoma and found that it is mediated largely through secondary mutations in EGFR - either C797S or L718V/Q. Analysis of circulating free DNA data from patients revealed that L718Q/V mutations almost always occur in the context of an L858R driver mutation. Therapeutic testing in mice revealed that both erlotinib and afatinib caused regression of osimertinib-resistant C797S-containing tumors, whereas only afatinib was effective on L718Q mutant tumors. Combination first-line osimertinib plus erlotinib treatment prevented the emergence of secondary mutations in EGFR. These findings highlight how knowledge of the specific characteristics of resistance mutations are important for determining potential subsequent treatment approaches and suggest strategies to overcome or prevent osimertinib resistance in vivo.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-3819
  10. Cancer Discov. 2020 Mar 20.
      LGR5- cells seed colorectal cancer metastases and produce stemlike LGR5+ outgrowth-promoting cells.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-042
  11. Mol Cancer. 2020 Mar 14. 19(1): 58
    Cui C, Yang J, Li X, Liu D, Fu L, Wang X.
      Circular RNAs (circRNAs), one type of non-coding RNA, were initially misinterpreted as nonfunctional products of pre-mRNA mis-splicing. Currently, circRNAs have been proven to manipulate the functions of diverse molecules, including non-coding RNAs, mRNAs, DNAs and proteins, to regulate cell activities in physiology and pathology. Accumulating evidence indicates that circRNAs play critical roles in tumor genesis, development, and sensitivity to radiation and chemotherapy. Radiotherapy and chemotherapy are two primary types of intervention for most cancers, but their therapeutic efficacies are usually retarded by intrinsic and acquired resistance. Thus, it is urgent to develop new strategies to improve therapeutic responses. To achieve this, clarification of the underlying mechanisms affecting therapeutic responses in cancer is needed. This review summarizes recent progress and mechanisms of circRNAs in cancer resistance to radiation and chemotherapy, and it discusses the limitations of available knowledge and potential future directions.
    Keywords:  Cancer therapy; Chemoresistance; Multidrug resistance; Radioresistance; Sensitivity; circRNAs
    DOI:  https://doi.org/10.1186/s12943-020-01180-y
  12. Cancer Res. 2020 Mar 19. pii: canres.2207.2019. [Epub ahead of print]
    Flach KD, Periyasamy M, Jadhav A, Dorjsuren D, Siefert JC, Hickey TE, Opdam M, Patel H, Canisius S, Wilson DM, Donaldson Collier M, Prekovic S, Nieuwland M, Kluin RJ, Zakharov AV, Wesseling J, Wessels LFA, Linn SC, Tilley WD, Simeonov A, Ali S, Zwart W.
      Estrogen receptor α (ERα) is a key transcriptional regulator in the majority of breast cancers. ERα-positive patients are frequently treated with tamoxifen, but resistance is common. In this study, we refined a previously identified 111-gene outcome prediction-classifier, revealing FEN1 as the strongest determining factor in ERα-positive patient prognostication. FEN1 levels were predictive of outcome in tamoxifen-treated patients, and FEN1played a causal role in ERα-driven cell growth. FEN1 impacted the transcriptional-activity of ERα by facilitating coactivator recruitment to the ERα transcriptional complex. FEN1 blockade induced proteasome-mediated degradation of activated ERα, resulting in loss of ERα-driven gene expression and eradicated tumor cell proliferation. Finally, a high-throughput 465,195 compound screen identified a novel FEN1 inhibitor, which effectively blocked ERα-function and inhibited proliferation of tamoxifen-resistant cell lines as well as ex-vivo cultured ERα-positive breast tumors. Collectively, these results provide therapeutic proof-of-principle for FEN1 blockade in tamoxifen-resistant breast cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-2207
  13. Signal Transduct Target Ther. 2020 ;5 28
    Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y.
      Metastasis is the hallmark of cancer that is responsible for the greatest number of cancer-related deaths. Yet, it remains poorly understood. The continuous evolution of cancer biology research and the emergence of new paradigms in the study of metastasis have revealed some of the molecular underpinnings of this dissemination process. The invading tumor cell, on its way to the target site, interacts with other proteins and cells. Recognition of these interactions improved the understanding of some of the biological principles of the metastatic cell that govern its mobility and plasticity. Communication with the tumor microenvironment allows invading cancer cells to overcome stromal challenges, settle, and colonize. These characteristics of cancer cells are driven by genetic and epigenetic modifications within the tumor cell itself and its microenvironment. Establishing the biological mechanisms of the metastatic process is crucial in finding open therapeutic windows for successful interventions. In this review, the authors explore the recent advancements in the field of metastasis and highlight the latest insights that contribute to shaping this hallmark of cancer.
    Keywords:  Metastasis
    DOI:  https://doi.org/10.1038/s41392-020-0134-x
  14. Cancer Res. 2020 Mar 19. pii: canres.0631.2019. [Epub ahead of print]
    Cho J, Lee HJ, Hwang SJ, Min HY, Kang HN, Park AY, Hyun SY, Sim JY, Lee HJ, Jang HJ, Suh YA, Hong S, Shin YK, Kim HR, Lee HY.
      Quiescent cancer cells are believed to cause cancer progression after chemotherapy through unknown mechanisms. We show here that human non-small-cell lung cancer (NSCLC) cell line-derived, quiescent-like, slow-cycling cancer cells (SCC) and residual patient-derived xenograft (PDX) tumors after chemotherapy experience activating transcription factor 6 (ATF6)-mediated upregulation of various cytokines, which acts in a paracrine manner to recruit fibroblasts. Cancer-associated fibroblasts (CAF) underwent transcriptional upregulation of COX2 and type I collagen (Col-I), which subsequently triggered a slow-to-active-cycling switch in SCC through prostaglandin E2 (PGE2)- and integrin/Src-mediated signaling pathways, leading to cancer progression. Both antagonism of ATF6 and cotargeting of Src/COX2 effectively suppressed cytokine production and slow-to-active cell cycling transition in SCC, withholding cancer progression. Expression of COX2 and Col-I and activation of Src were observed in NSCLC patients who progressed while receiving chemotherapy. Public data analysis revealed significant association between COL1A1 and SRC expression and NSCLC relapse. Overall, these findings indicate that a proinflammatory niche created by the interplay between SCC and CAF triggers tumor progression.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-0631
  15. Nature. 2020 Mar;579(7799): 323
      
    Keywords:  Cancer
    DOI:  https://doi.org/10.1038/d41586-020-00722-0
  16. Cancer Res. 2020 Mar 16. pii: canres.2914.2019. [Epub ahead of print]
    Girard CA, Lecacheur M, Ben Jouira R, Berestjuk I, Diazzi S, Prod'homme V, Mallavialle A, Larbret F, Gesson M, Schaub S, Pisano S, Audebert S, Mari B, Gaggioli C, Leucci E, Marine JC, Deckert M, Tartare-Deckert S.
      Aberrant extracellular matrix (ECM) deposition and stiffening is a physical hallmark of several solid cancers and is associated with therapy failure. BRAF-mutant melanomas treated with BRAF and MEK inhibitors almost invariably develop resistance that is frequently associated with transcriptional reprogramming and a de-differentiated cell state. Melanoma cells secrete their own ECM proteins, an event that is promoted by oncogenic BRAF inhibition. Yet, the contribution of cancer cell-derived ECM and tumor mechanics to drug adaptation and therapy resistance remains poorly understood. Here, we show that melanoma cells can adapt to targeted therapies through a mechanosignaling loop involving the autocrine remodeling of a drug-protective ECM. Analyses revealed that therapy resistant cells associated with a mesenchymal de-differentiated state displayed elevated responsiveness to collagen stiffening and force-mediated ECM remodeling through activation of actin-dependent mechanosensors Yes-associated protein (YAP) and Myocardin-related transcription factor (MRTF). Short-term inhibition of MAPK pathway also induced mechanosignaling associated with deposition and remodeling of an aligned fibrillar matrix. This provided a favored ECM reorganization that promoted tolerance to BRAF inhibition in a YAP and MRTF-dependent manner. Matrix remodeling and tumor stiffening were also observed in vivo upon exposure of BRAF-mutant melanoma cell lines or patient-derived xenograft models to MAPK pathway inhibition. Importantly, pharmacological targeting of YAP reversed treatment-induced excessive collagen deposition, leading to enhancement of BRAF inhibitor efficacy. We conclude that MAPK pathway targeting therapies mechanically reprogram melanoma cells to confer a drug-protective matrix environment. Preventing melanoma cell mechanical reprogramming might be a promising therapeutic strategy for patients on targeted therapies.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-2914
  17. Cancer Res. 2020 Mar 19. pii: canres.2739.2019. [Epub ahead of print]
    Luo ML, Zheng F, Chen W, Liang ZM, Chandramouly G, Tan J, Willis NA, Chen CH, de Oliveira Taveira M, Zhou XZ, Lu KP, Scully R, Wulf GM, Hu H.
      PARP inhibitor monotherapies effectively treat breast, ovary, prostate, and pancreatic cancer patients with BRCA1 mutations, but not the more frequent BRCA-wildtype cancers. Searching for strategies that would extend the use of PARP inhibitors to BRCA1-proficient tumors, we report here that the stability of BRCA1 protein following ionizing radiation (IR) is maintained by post-phosphorylational prolyl-isomerization adjacent to Ser1191 of BRCA1, which is catalyzed by prolyl-isomerase Pin1. Extinction of Pin1 decreased homologous recombination (HR) to the level of BRCA1-deficient cells. Pin1 stabilized BRCA1 by preventing ubiquitination of BRCA1 at Lys1037. Loss of Pin1 or introduction of a BRCA1 mutant refractory to Pin1 binding decreased the ability of BRCA1 to localize to repair foci and augmented IR-induced DNA damage. In vitro growth of HR-proficient breast, prostate, and pancreatic cancer cells was modestly repressed by Olaparib or Pin1 inhibition using all-trans retinoic acid (ATRA), while combination treatment resulted in near-complete block of cell proliferation. In MDA-MB 231 xenografts and triple-negative breast cancer PDX, either loss of Pin1 or ATRA treatment reduced BRCA1 expression and sensitized breast tumors to Olaparib. Together our study reveals that Pin1 inhibition with widely used ATRA acts as an effective HR disrupter that sensitizes BRCA1-proficient tumors to PARP inhibition.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-2739
  18. Lancet Oncol. 2020 Mar 12. pii: S1470-2045(20)30058-9. [Epub ahead of print]
    Lambertini M, Vaz-Luis I.
      
    DOI:  https://doi.org/10.1016/S1470-2045(20)30058-9
  19. Cancer Discov. 2020 Mar 19. pii: CD-19-1508. [Epub ahead of print]
    Sakamoto H, Attiyeh MA, Gerold JM, Makohon-Moore AP, Hayashi A, Hong J, Kappagantula R, Zhang L, Melchor JP, Reiter JG, Heyde A, Bielski CM, Penson AV, Gonen M, Chakravarty D, O'Reilly EM, Wood LD, Hruban RH, Nowak MA, Socci ND, Taylor BS, Iacobuzio-Donahue CA.
      Surgery is the only curative option for Stage I/II pancreatic cancer, nonetheless most patients will recur after surgery and die of their disease. To identify novel opportunities for management of recurrent pancreatic cancer we performed whole exome or targeted sequencing of 10 resected primary cancers and matched intrapancreatic recurrences or distant metastases. We identified that recurrent disease after adjuvant or first-line platinum therapy corresponds to an increased mutational burden. Recurrent disease is enriched for genetic alterations predicted to activate Mapk/Erk and PI3K/AKT signaling and develops from a monophyletic or polyphyletic origin. Treatment induced genetic bottlenecks lead to a modified genetic landscape and subclonal heterogeneity for driver gene alterations in part due to intermetastatic seeding. In one patient what was believed to be recurrent disease was an independent (second) primary tumor. These findings suggest routine post-treatment sampling may have value in the management of recurrent pancreatic cancer.
    DOI:  https://doi.org/10.1158/2159-8290.CD-19-1508
  20. Cancer Cell. 2020 Mar 16. pii: S1535-6108(20)30096-9. [Epub ahead of print]37(3): 265-267
    Fassl A, Sicinski P.
      Chemotherapy remains the main treatment option for patients with several tumor types. In this issue of Cancer Cell, Salvador-Barbero et al. demonstrate that treatment with CDK4/6 inhibitors after application of taxanes (or other chemotherapeutic compounds) strongly potentiates the anti-tumor effect due to repression of DNA repair machinery.
    DOI:  https://doi.org/10.1016/j.ccell.2020.02.007
  21. Cancer Res. 2020 Mar 19. pii: canres.2098.2018. [Epub ahead of print]
    Gerarduzzi C, Hartmann U, Leask A, Drobetsky E.
      The extracellular matrix (ECM) surrounding cells is indispensable for regulating their behavior. The dynamics of ECM signaling are tightly controlled throughout growth and development. During tissue remodeling, matricellular proteins (MCPs) are secreted into the ECM. These factors do not serve classical structural roles, but rather regulate matrix proteins and cell-matrix interactions to influence normal cellular functions. In the tumor microenvironment, it is becoming increasingly clear that aberrantly expressed MCPs can support multiple hallmarks of carcinogenesis by interacting with various cellular components that are coupled to an array of downstream signals. Moreover, MCPs also reorganize the biomechanical properties of the ECM to accommodate metastasis and tumor colonization. This realization is stimulating new research on MCPs as reliable and accessible biomarkers in cancer, as well as effective and selective therapeutic targets.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-18-2098