bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒10‒04
twenty-one papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Cancer Res. 2020 Oct 01. 80(19): 4103-4113
      Breast cancer relapse can develop over the course of years as a result of dormant cancer cells that disseminate to secondary sites. These dormant cells are often resistant to conventional hormone and chemotherapy. Although recurrence is the main cause of death from cancer, microenvironmental factors that may influence resistance to therapy and duration of dormancy are largely unknown. Breast cancer relapse is often detected in tissues that are softer than the normal mammary gland or the primary breast tumor, such as bone marrow, brain, and lung. We therefore explored how stiffness of the microenvironment at secondary sites regulates tumor dormancy and the response of breast cancer cells to hormone and chemotherapy. In soft microenvironments reminiscent of metastatic sites, breast cancer cells were more resistant to the estrogen receptor modulator tamoxifen as a result of increased autophagy and decreased expression of estrogen receptor-α. Consistently, pharmacologic inhibition or genetic downregulation of autophagy increased the response of breast cancer cells to tamoxifen on soft substrata. In addition, autophagy was decreased downstream of integrin-linked kinase on stiff substrata. Altogether, our data show that tissue mechanics regulates therapeutic outcome and long-term survival of breast cancer cells by influencing autophagy. SIGNIFICANCE: These findings characterize the persistence of dormant cells at metastatic sites, where soft microenvironments downregulate estrogen receptor expression and upregulate autophagy, thereby promoting therapy resistance in breast cancer cells. GRAPHICAL ABSTRACT:
  2. Nature. 2020 Sep 30.
      Blood vessels support tumours by providing nutrients and oxygen, while also acting as conduits for the dissemination of cancer1. Here we use mouse models of breast and lung cancer to investigate whether endothelial cells also have active 'instructive' roles in the dissemination of cancer. We purified genetically tagged endothelial ribosomes and their associated transcripts from highly and poorly metastatic tumours. Deep sequencing revealed that metastatic tumours induced expression of the axon-guidance gene Slit2 in endothelium, establishing differential expression between the endothelial (high Slit2 expression) and tumoural (low Slit2 expression) compartments. Endothelial-derived SLIT2 protein and its receptor ROBO1 promoted the migration of cancer cells towards endothelial cells and intravasation. Deleting endothelial Slit2 suppressed metastatic dissemination in mouse models of breast and lung cancer. Conversely, deletion of tumoural Slit2 enhanced metastatic progression. We identified double-stranded RNA derived from tumour cells as an upstream signal that induces expression of endothelial SLIT2 by acting on the RNA-sensing receptor TLR3. Accordingly, a set of endogenous retroviral element RNAs were upregulated in metastatic cells and detected extracellularly. Thus, cancer cells co-opt innate RNA sensing to induce a chemotactic signalling pathway in endothelium that drives intravasation and metastasis. These findings reveal that endothelial cells have a direct instructive role in driving metastatic dissemination, and demonstrate that a single gene (Slit2) can promote or suppress cancer progression depending on its cellular source.
  3. Cell. 2020 Sep 25. pii: S0092-8674(20)31087-4. [Epub ahead of print]
      Collective metastasis is defined as the cohesive migration and metastasis of multicellular tumor cell clusters. Disrupting various cell adhesion genes markedly reduces cluster formation and colonization efficiency, yet the downstream signals transmitted by clustering remain largely unknown. Here, we use mouse and human breast cancer models to identify a collective signal generated by tumor cell clusters supporting metastatic colonization. We show that tumor cell clusters produce the growth factor epigen and concentrate it within nanolumina-intercellular compartments sealed by cell-cell junctions and lined with microvilli-like protrusions. Epigen knockdown profoundly reduces metastatic outgrowth and switches clusters from a proliferative to a collective migratory state. Tumor cell clusters from basal-like 2, but not mesenchymal-like, triple-negative breast cancer cell lines have increased epigen expression, sealed nanolumina, and impaired outgrowth upon nanolumenal junction disruption. We propose that nanolumenal signaling could offer a therapeutic target for aggressive metastatic breast cancers.
    Keywords:  CTC clusters; basal-like 2 breast cancer; collective invasion; collective metastasis; collective signaling; epigen; nanolumenal signaling; nanolumina; triple-negative breast cancer; tumor cell clusters
  4. Cancer Res. 2020 Sep 30. pii: canres.2199.2020. [Epub ahead of print]
      Lipid rafts are tightly packed, cholesterol- and sphingolipid-enriched microdomains within the plasma membrane that play important roles in many pathophysiological processes. Rafts have been strongly implicated as master regulators of signal transduction in cancer, where raft compartmentalization can promote transmembrane receptor oligomerization, shield proteins from enzymatic degradation, and act as scaffolds to enhance intracellular signaling cascades. Cancer cells have been found to exploit these mechanisms to initiate oncogenic signaling and promote tumor progression. This review highlights the roles of lipid rafts within the metastatic cascade, specifically within tumor angiogenesis, cell adhesion, migration, EMT, and transendothelial migration. Additionally, the interplay between lipid rafts and different modes of cancer cell death, including necrosis, apoptosis, and anoikis will be described. The clinical role of lipid raft-specific proteins caveolin and flotillin in assessing patient prognosis and evaluating metastatic potential of various cancers will be presented. Collectively, elucidation of the complex roles of lipid rafts and raft components within the metastatic cascade may be instrumental for therapeutic discovery to curb pro-metastatic processes.
  5. Cancer Discov. 2020 Oct;10(10): 1445-1447
      In this issue of Cancer Discovery, Cai and colleagues delineate a new mechanism that links cell of origin, the transcription factor EVI1, apoptotic priming, and therapeutic susceptibility in mixed lineage leukemia-rearranged acute myeloid leukemia. These findings establish a cell of origin-dependent program that may be leveraged by therapeutic combinations to overcome drug resistance in chemoresistant leukemias.See related article by Cai et al., p. 1500.
  6. Cancer Lett. 2020 Sep 25. pii: S0304-3835(20)30487-0. [Epub ahead of print]
      Metastasis is the major cause of cancer-related deaths. Invasive primary cancers often metastasize after circulating tumor cells (CTCs) enter the bloodstream or lymph node to colonize adjacent tissue or distant anatomical locations. CTCs interact with immune cells and metastatic microenvironments, survival signaling, and chemotherapeutic resistance. Among immune cells, natural killer (NK) cells can, directly and indirectly, interact with CTCs to control cancer metastasis. Understanding the molecular mechanisms that drive NK cells mediated recognition and elimination of CTCs may pave the way for a new generation of anti-CTC molecularly targeted immunotherapies. In this review, we will discuss i) the role of CTCs in metastases, ii) CTCs in the context of the tumor microenvironment, iii) CTCs immune escape, and finally, iv) the potentials of NK cell-based therapies alone, or in combination with nanomedicine for targeted-immunotherapies of metastatic diseases.
    Keywords:  Cancer stem cell; Chimeric antigen receptor; Disseminated tumor cell; Immune resistance; Nanoimmunotherapy
  7. Stem Cells. 2020 Sep 27.
      Combinations of metabolic blockers (incl. fenofibrate) with chemotherapeutic drugs interfere with the drug-resistance of prostate cancer cells. However, their effect on cancer stem cells-dependent microevolution of prostate cancer malignancy remains unaddressed. Here, we hypothesize that the combined docetaxel/fenofibrate treatment prompts the selective expansion of cancer stem cells that affects the microevolution of their progenies. Accordingly, we adapted a combined in vitro/in vivo approach to identify biological and therapeutic consequences of this process. Minute subpopulations of docetaxel-resistant CD133high and/or CD44high cancer stem cell-like (SCL) cells were found in prostate cancer DU145 and PC3 cell populations. When pretreated with docetaxel, they readily differentiated into docetaxel-resistant CD44negative "bulk" cells, thus accounting for the microevolution of drug-resistant cell lineages. Combined docetaxel/fenofibrate treatment induced the generation of poly(morpho)nuclear giant cells and drug-resistant CD44high SCL cells. However, the CD44negative offspring of docetaxel- and docetaxel/fenofibrate-treated SCLs remained relatively sensitive to the combined treatment, while retaining enhanced resistance to docetaxel. Long-term propagation of drug-resistant SCL-derived lineages in the absence of docetaxel/fenofibrate resulted in their reverse microevolution toward the drug-sensitivity and invasive phenotype. Consequently, prostate tumors were able to recover from the combined docetaxel/fenofibrate stress after the initial arrest of their expansion in vivo. In conclusion, we have confirmed the potential of fenofibrate for the metronomic treatment of drug-resistant prostate tumors. However, docetaxel/fenofibrate-induced selective expansion of hyper-resistant CD44high SCL prostate cells and their "bulk" progenies prompts the microevolution of prostate tumor drug-resistance. This process can limit the implementation of metabolic chemotherapy in prostate cancer treatment.
    Keywords:  CD44, prostate cancer; cancer microevolution; cancer stem cells; drug-resistance; fenofibrate
  8. Gastroenterology. 2020 Sep 29. pii: S0016-5085(20)35147-7. [Epub ahead of print]
      BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibroblast-rich desmoplastic stroma. Cancer-associated fibroblasts (CAFs) have been shown to display a high degree of interconvertible states including quiescent, inflammatory and myofibroblastic phenotypes, however, the mechanisms by which this plasticity is achieved are poorly understood. Here, we aim to elucidate the role of CAF plasticity and its impact on PDAC biology.METHODS: To investigate the role of mesenchymal plasticity in PDAC progression, we generated a PDAC mouse model in which CAF plasticity is modulated by genetical depletion of the transcription factor Prrx1. Primary pancreatic fibroblasts from this mouse model were further characterized by functional in vitro assays. To characterize the impact of CAFs on tumor differentiation and response to chemotherapy various co-culture experiments were performed. In vivo, tumors were characterized by morphology, extracellular matrix composition as well as tumor dissemination and metastasis.
    RESULTS: Our in vivo findings demonstrated that Prrx1-deficient CAFs remain constitutively activated. Importantly, this CAF phenotype determines tumor differentiation and disrupts systemic tumor dissemination. Mechanistically, co-culture experiments of tumor organoids and CAFs revealed that CAFs shape the epithelial-to-mesenchymal phenotype and confer gemcitabine resistance of PDAC cells induced by CAF-derived hepatocyte growth factor. Furthermore, gene expression analysis revealed that pancreatic cancer patients with high stromal expression of Prrx1 display the squamous, most aggressive, subtype of PDAC.
    CONCLUSION: Here, we define that the Prrx1 transcription factor is critical for tuning CAF activation, allowing a dynamic switch between a dormant and an activated state. This work demonstrates that Prrx1-mediated CAF plasticity has significant impact on PDAC biology and therapeutic resistance.
    Keywords:  Cancer-associated fibroblasts; extracellular matrix proteins; myofibroblasts; pancreatic ductal adenocarcinoma
  9. Oncogene. 2020 Sep 28.
      While mechanisms for metastasis were extensively studied in cancer cells from patients with detectable tumors, pathways underlying metastatic dissemination from early lesions before primary tumors appear are poorly understood. Her2 promotes breast cancer early dissemination by suppressing p38, but how Her2 downregulates p38 is unclear. Here, we demonstrate that in early lesion breast cancer models, Her2 inhibits p38 by inducing Skp2 through Akt-mediated phosphorylation, which promotes ubiquitination and proteasomal degradation of Tpl2, a p38 MAP3K. The early disseminating cells are Her2+Skp2highTpl2lowp-p38lowE-cadherinlow in the MMTV-Her2 breast cancer model. In human breast carcinoma, high Skp2 and low Tpl2 expression are associated with the Her2+ status; Tpl2 expression positively correlates with that of activated p38; Skp2 expression negatively correlates with that of Tpl2 and activated p38. Moreover, the Her2-Akt-Skp2-Tpl2-p38 axis plays a key role in the disseminating phenotypes in early lesion breast cancer cells; inhibition of Tpl2 enhances early dissemination in vivo. These findings identify the Her2-Akt-Skp2-Tpl2-p38 cascade as a novel mechanism mediating breast cancer early dissemination and a potential target for novel therapies targeting early metastatic dissemination.
  10. Cancer Res. 2020 Sep 30. pii: canres.1228.2020. [Epub ahead of print]
      The majority of advanced prostate cancer therapies aim to inhibit androgen receptor (AR) signaling. However, AR reactivation inevitably drives disease progression to castration-resistant prostate cancer (CRPC). Here we demonstrate that protein arginine methyltransferase 5 (PRMT5) functions as an epigenetic activator of AR transcription in CRPC, requiring cooperation with a methylosome subunit pICln. In vitro and in xenograft tumors in mice, targeting PRMT5 or pICln suppressed growth of CRPC cells. Full-length AR and AR-V7 transcription activation required both PRMT5 and pICln but not MEP50. This activation of transcription was accompanied by PRMT5-mediated symmetric dimethylation of H4R3 at the proximal AR promoter. Further, knockdown of PRMT5 abolished the binding of pICln (but not vice versa) to the AR proximal promoter region, suggesting that PRMT5 recruits pICln to the AR promoter to activate AR transcription. Differential gene expression analysis in 22Rv1 cells confirmed that PRMT5 and pICln both regulate the androgen signaling pathway. Additionally, PRMT5 and pICln protein expression positively correlated with AR and AR-V7 protein expression in CRPC tissues and their expression was highly correlated at the mRNA level across multiple publicly available CRPC datasets. Our results suggest that targeting PRMT5 or pICln may be explored as a novel therapy for CRPC treatment by suppressing expression of AR and AR splice variants to circumvent AR reactivation.
  11. J Exp Med. 2020 Nov 02. pii: e20201259. [Epub ahead of print]217(11):
      Using macrophage morphology in human colorectal cancer liver metastasis, Donadon et al. in this issue of JEM ( provide a window into lipid metabolism and foamy macrophages, which accrue in numerous pathological states and here are shown to have clinical application.
  12. Cancers (Basel). 2020 Sep 24. pii: E2756. [Epub ahead of print]12(10):
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by a mostly immunosuppressive microenvironment. Tumor-draining lymph nodes (TDLN) are a major site for priming of tumor-reactive T cells and also tumor metastasis. However, the phenotype and function of T cells in TDLNs from PDAC patients is unknown. In this study, lymph nodes from the pancreatic head (PH), the hepatoduodenal ligament (HDL) and the interaortocaval (IAC) region were obtained from 25 patients with adenocarcinoma of the pancreatic head. Additionally, tumors and matched blood were analyzed from 16 PDAC patients. Using multicolor flow cytometry, we performed a comprehensive analysis of T cells. CD4+ T cells were the predominant T cell subset in PDAC-draining lymph nodes. Overall, lymph node CD4+ and CD8+ T cells had a similar degree of activation, as measured by CD69, inducible T cell co-stimulator (ICOS) and CD137 (4-1BB) expression and interferon-γ (IFNγ) secretion. Expression of the inhibitory receptor programmed death 1 (PD-1) by lymph node and tumor-infiltrating regulatory T cells (Tregs) correlated with lymph node metastasis. Collectively, Treg cells and PD-1 are two relevant components of the immunosuppressive network in PDAC-draining lymph nodes and may be particularly attractive targets for combinatorial immunotherapeutic strategies in selected patients with node-positive PDAC.
    Keywords:  PD-1; T cells; Treg cells; pancreatic cancer; tumor-draining lymph nodes
  13. Cancer Discov. 2020 Oct 01. pii: CD-20-0571. [Epub ahead of print]
      On-target resistance to next-generation TRK inhibitors in TRK fusion-positive cancers is largely uncharacterized. In patients with these tumors, we found that TRK xDFG mutations confer resistance to type I next-generation TRK inhibitors designed to maintain potency against several kinase domain mutations. Computational modeling and biochemical assays showed that TRKA G667 and TRKC G696 xDFG substitutions reduce drug binding by generating steric hindrance. Concurrently, these mutations stabilize the inactive (DFG-out) conformations of the kinases, thus sensitizing these kinases to type II TRK inhibitors. Consistently, type II inhibitors impede the growth and TRK-mediated signaling of xDFG-mutant isogenic and patient-derived models. Collectively, these data demonstrate that adaptive conformational resistance can be abrogated by shifting kinase engagement modes. Given the prior identification of paralogous xDFG resistance mutations in other oncogene-addicted cancers, these findings provide insights into rational type II drug design by leveraging inhibitor class affinity switching to address recalcitrant resistant alterations.
  14. Nat Commun. 2020 09 30. 11(1): 4909
      Effectively activating macrophages against cancer is promising but challenging. In particular, cancer cells express CD47, a 'don't eat me' signal that interacts with signal regulatory protein alpha (SIRPα) on macrophages to prevent phagocytosis. Also, cancer cells secrete stimulating factors, which polarize tumor-associated macrophages from an antitumor M1 phenotype to a tumorigenic M2 phenotype. Here, we report that hybrid cell membrane nanovesicles (known as hNVs) displaying SIRPα variants with significantly increased affinity to CD47 and containing M2-to-M1 repolarization signals can disable both mechanisms. The hNVs block CD47-SIRPα signaling axis while promoting M2-to-M1 repolarization within tumor microenvironment, significantly preventing both local recurrence and distant metastasis in malignant melanoma models. Furthermore, by loading a stimulator of interferon genes (STING) agonist, hNVs lead to potent tumor inhibition in a poorly immunogenic triple negative breast cancer model. hNVs are safe, stable, drug loadable, and suitable for genetic editing. These properties, combined with the capabilities inherited from source cells, make hNVs an attractive immunotherapy.
  15. Cancer Metastasis Rev. 2020 Oct 02.
      Environment surrounding tumours are now recognized to play an important role in tumour development and progression. Among the cells found in the tumour environment, adipocytes from adipose tissue establish a vicious cycle with cancer cells to promote cancer survival, proliferation, metastasis and treatment resistance. This cycle is particularly of interest in the context of obesity, which has been found as a cancer risk factor. Cancers cells can reprogram adipocyte physiology leading to an "activated" phenotype characterized by delipidation and secretion of inflammatory adipokines. The adipocyte secretions then influence tumour growth and metastasis which has been mainly attributed to interleukin 6 (IL-6) or leptin but also to the release of fatty acids which are able to change cancer cell metabolism and signalling pathways. The aim of this review is to report recent advances in the understanding of the molecular mechanisms linking adipose tissue with cancer progression in order to propose new therapeutic strategies based on pharmacological or nutritional intervention.
    Keywords:  Adipocyte; Adipokines; Cancer; Exosome; Fatty acid; Metabolism
  16. Cancer Discov. 2020 Oct 02.
      Lung mesenchymal cells promoted neutrophil lipid storage; lipids were transferred to tumor cells.
  17. Cancers (Basel). 2020 Sep 28. pii: E2784. [Epub ahead of print]12(10):
      Circulating tumor cells (CTCs) represent a unique population of cells that can be used to investigate the mechanistic underpinnings of metastasis. Unfortunately, current technologies designed for the isolation and capture of CTCs are inefficient. Existing literature for in vitro CTC cultures report low (6-20%) success rates. Here, we describe a new method for the isolation and culture of CTCs. Once optimized, we employed the method on 12 individual metastatic breast cancer patients and successfully established CTC cultures from all 12 samples. We demonstrate that cells propagated were of breast and epithelial origin. RNA-sequencing and pathway analysis demonstrated that CTC cultures were distinct from cells obtained from healthy donors. Finally, we observed that CTC cultures that were associated with CD45+ leukocytes demonstrated higher viability. The presence of CD45+ leukocytes significantly enhanced culture survival and suggests a re-evaluation of the methods for CTC isolation and propagation. Routine access to CTCs is a valuable resource for identifying genetic and molecular markers of metastasis, personalizing the treatment of metastatic cancer patients and developing new therapeutics to selectively target metastatic cells.
    Keywords:  Cancer metastasis; cell culture; circulating tumor cells; leukocytes; tumor-associated neutrophils
  18. Cancer Res. 2020 Sep 30. pii: canres.2339.2020. [Epub ahead of print]
      Tumor-derived secretory factors orchestrate splenic hematopoietic and stromal cells to fuel metastasis. The spleen acts as a reservoir site for hematopoietic stem and progenitor cells, which are rapidly exploited as myeloid-derived suppressor cells at the cost of tumor-reactive lymphoid cells. Splenic erythroid progenitor cells and mesenchymal stromal cells contribute directly and indirectly to both tumor immune escape and the metastatic cascade. Animal models provide valuable mechanistic insights, but their translation to a clinical setting highlights specific challenges and open issues. In this review, we envision the exploitation of the spleen as a source for novel biomarkers and therapeutic approaches.
  19. Cancer Lett. 2020 Sep 29. pii: S0304-3835(20)30488-2. [Epub ahead of print]
      Mechanotransduction is the leading cellular process that mammalian cells adopted to receive and respond to various mechanical cues from their local microenvironment. Increasing evidence suggests that mechano-transduction is involved in many physiological and disease conditions, ranging from early embryonic development, organogenesis, to a variety of human diseases including cancer. Mechanotransduction is mediated through several classes of senor proteins on the cell surface, intracellular signaling mediators, and core transcriptional regulation networks. Dissecting the molecular mechanisms regulating mechanotransduction and their association with cancer metastasis has received much attention in recent years. RNA binding proteins (RBPs) are a special group of nucleic acid interacting factors that participate in many important cellular processes. In this review, we would like to summarize recent research progresses in understanding the role of RBPs-mediated regulation in mechanotransduction and cancer metastasis. Those intriguing findings will provide novel insights for the disease and guide the potential development of new therapeutic approaches.
    Keywords:  Mechanotransduction; Metastasis; Noncoding RNAs; RNA binding Proteins; Ribonucleocomplex; Transcriptional regulation
  20. Cancers (Basel). 2020 Sep 29. pii: E2801. [Epub ahead of print]12(10):
      This systematic review investigated the literature on acquired v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor resistance in patients with melanoma. We searched MEDLINE for articles on BRAF inhibitor resistance in patients with melanoma published since January 2010 in the following areas: (1) genetic basis of resistance; (2) epigenetic and transcriptomic mechanisms; (3) influence of the immune system on resistance development; and (4) combination therapy to overcome resistance. Common resistance mutations in melanoma are BRAF splice variants, BRAF amplification, neuroblastoma RAS viral oncogene homolog (NRAS) mutations and mitogen-activated protein kinase kinase 1/2 (MEK1/2) mutations. Genetic and epigenetic changes reactivate previously blocked mitogen-activated protein kinase (MAPK) pathways, activate alternative signaling pathways, and cause epithelial-to-mesenchymal transition. Once BRAF inhibitor resistance develops, the tumor microenvironment reverts to a low immunogenic state secondary to the induction of programmed cell death ligand-1. Combining a BRAF inhibitor with a MEK inhibitor delays resistance development and increases duration of response. Multiple other combinations based on known mechanisms of resistance are being investigated. BRAF inhibitor-resistant cells develop a range of 'escape routes', so multiple different treatment targets will probably be required to overcome resistance. In the future, it may be possible to personalize combination therapy towards the specific resistance pathway in individual patients.
    Keywords:  BRAF inhibitors; melanoma; metastasis; microenvironment; resistance; therapy
  21. Nat Cell Biol. 2020 Oct;22(10): 1276-1285
      Breast cancer brain metastasis (BCBM) is a devastating disease. Radiation therapy remains the mainstay for treatment of this disease. Unfortunately, its efficacy is limited by the dose that can be safely applied. One promising approach to overcoming this limitation is to sensitize BCBMs to radiation by inhibiting their ability to repair DNA damage. Here, we report a DNA repair suppressor, leucine-rich repeat-containing protein 31 (LRRC31), that was identified through a genome-wide CRISPR screen. We found that overexpression of LRRC31 suppresses DNA repair and sensitizes BCBMs to radiation. Mechanistically, LRRC31 interacts with Ku70/Ku80 and the ataxia telangiectasia mutated and RAD3-related (ATR) at the protein level, resulting in inhibition of DNA-dependent protein kinase, catalytic subunit (DNA-PKcs) recruitment and activation, and disruption of the MutS homologue 2 (MSH2)-ATR module. We demonstrate that targeted delivery of the LRRC31 gene via nanoparticles improves the survival of tumour-bearing mice after irradiation. Collectively, our study suggests LRRC31 as a major DNA repair suppressor that can be targeted for cancer radiosensitizing therapy.