bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021‒03‒14
28 papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Nat Cancer. 2020 Jul;1(7): 672-680
      Disseminated tumor cells (DTCs) are known to enter a state of dormancy that is achieved via growth arrest of DTCs and/or a form of population equilibrium state, strongly influenced by the organ microenvironment. During this time, expansion of residual disseminated cancer is paused and DTCs survive to fuel relapse, sometimes decades later. This notion has opened a new window of opportunity for intervening and preventing relapse. Here we review recent data that have further augmented the understanding of cancer dormancy and discuss how this is leading to new strategies for monitoring and targeting dormant cancer.
  2. Cancer Cell. 2021 Mar 10. pii: S1535-6108(21)00117-3. [Epub ahead of print]
      Immune checkpoint blockade (ICB) results in durable disease control in a subset of patients with advanced renal cell carcinoma (RCC), but mechanisms driving resistance are poorly understood. We characterize the single-cell transcriptomes of cancer and immune cells from metastatic RCC patients before or after ICB exposure. In responders, subsets of cytotoxic T cells express higher levels of co-inhibitory receptors and effector molecules. Macrophages from treated biopsies shift toward pro-inflammatory states in response to an interferon-rich microenvironment but also upregulate immunosuppressive markers. In cancer cells, we identify bifurcation into two subpopulations differing in angiogenic signaling and upregulation of immunosuppressive programs after ICB. Expression signatures for cancer cell subpopulations and immune evasion are associated with PBRM1 mutation and survival in primary and ICB-treated advanced RCC. Our findings demonstrate that ICB remodels the RCC microenvironment and modifies the interplay between cancer and immune cell populations critical for understanding response and resistance to ICB.
    Keywords:  cancer; immunotherapy; kidney; resistance; single cell
  3. Nat Commun. 2021 Mar 12. 12(1): 1623
      The signalling pathways underpinning cell growth and invasion use overlapping components, yet how mutually exclusive cellular responses occur is unclear. Here, we report development of 3-Dimensional culture analyses to separately quantify growth and invasion. We identify that alternate variants of IQSEC1, an ARF GTPase Exchange Factor, act as switches to promote invasion over growth by controlling phosphoinositide metabolism. All IQSEC1 variants activate ARF5- and ARF6-dependent PIP5-kinase to promote PI(3,4,5)P3-AKT signalling and growth. In contrast, select pro-invasive IQSEC1 variants promote PI(3,4,5)P3 production to form invasion-driving protrusions. Inhibition of IQSEC1 attenuates invasion in vitro and metastasis in vivo. Induction of pro-invasive IQSEC1 variants and elevated IQSEC1 expression occurs in a number of tumour types and is associated with higher-grade metastatic cancer, activation of PI(3,4,5)P3 signalling, and predicts long-term poor outcome across multiple cancers. IQSEC1-regulated phosphoinositide metabolism therefore is a switch to induce invasion over growth in response to the same external signal. Targeting IQSEC1 as the central regulator of this switch may represent a therapeutic vulnerability to stop metastasis.
  4. Cancer Res. 2021 Mar 08. pii: canres.3232.2020. [Epub ahead of print]
      PI3Kα inhibitors have shown clinical activity in PIK3CA-mutated estrogen receptor-positive (ER+) breast cancer patients. Using whole genome CRISPR/Cas9 sgRNA knockout screens, we identified and validated several negative regulators of mTORC1 whose loss confers resistance to PI3Kα inhibition. Among the top candidates were TSC1, TSC2, TBC1D7, AKT1S1, STK11, MARK2, PDE7A, DEPDC5, NPRL2, NPRL3, C12orf66, SZT2 and ITFG2. Loss of these genes invariably results in sustained mTOR signaling under pharmacological inhibition of the PI3K-AKT pathway. Moreover, resistance could be prevented or overcome by mTOR inhibition, confirming the causative role of sustained mTOR activity in limiting the sensitivity to PI3Kα inhibition. Cumulatively, genomic alterations affecting these genes are identified in about 15% of PIK3CA-mutated breast tumors and appear to be mutually exclusive. This study improves our understanding of the role of mTOR signaling restoration in leading to resistance to PI3Kα inhibition and proposes therapeutic strategies to prevent or revert this resistance.
  5. Cancer Res. 2021 Mar 09. pii: canres.3222.2020. [Epub ahead of print]
      Surgical removal of malignant tumors is a mainstay in controlling most solid cancers. However, surgical insult also increases the risk of tumor recurrence and metastasis. Tissue trauma activates the innate immune system locally and systemically, mounting an inflammatory response. Platelets and neutrophils are two crucial players in the early innate immune response that heals tissues, but their actions may also contribute to cancer cell dissemination and distant metastasis. Here we report that surgical stress-activated platelets enhance the formation of platelet-tumor cell aggregates, facilitating their entrapment by neutrophil extracellular traps (NET) and subsequent distant metastasis. A murine hepatic ischemia/reperfusion (I/R) injury model of localized surgical stress showed that I/R promotes capturing of aggregated circulating tumor cells (CTC) by NETs and eventual metastasis to the lungs, which are abrogated when platelets are depleted. Hepatic I/R also increased deposition of NETs within the lung microvasculature, but depletion of platelets had no effect. TLR4 was essential for platelet activation and platelet-tumor cell aggregate formation in an ERK5-GPIIb/IIIa integrin-dependent manner. Such aggregation facilitated NET-mediated capture of CTCs in vitro under static and dynamic conditions. Blocking platelet activation or knocking out TLR4 protected mice from hepatic I/R-induced metastasis with no CTC-entrapment by NETs. These results uncover a novel mechanism where platelets and neutrophils contribute to metastasis in the setting of acute inflammation. Targeted disruption of the interaction between platelets and NETs holds therapeutic promise to prevent post-operative distant metastasis.
  6. Oncogene. 2021 Mar 08.
      Pancreatic cancer is one of the deadliest forms of cancer, which is attributed to lack of effective treatment options and drug resistance. Mitochondrial inhibitors have emerged as a promising class of anticancer drugs, and several inhibitors of the electron transport chain (ETC) are being clinically evaluated. We hypothesized that resistance to ETC inhibitors from the biguanide class could be induced by inactivation of SMAD4, an important tumor suppressor involved in transforming growth factor β (TGFβ) signaling, and associated with altered mitochondrial activity. Here we show that, paradoxically, both TGFβ-treatment and the loss of SMAD4, a downstream member of TGFβ signaling cascade, induce resistance to biguanides, decrease mitochondrial respiration, and fragment the mitochondrial network. Mechanistically, the resistance of SMAD4-deficient cells is mediated by increased mitophagic flux driven by MAPK/ERK signaling, whereas TGFβ-induced resistance is autophagy-independent and linked to epithelial-to-mesenchymal transition (EMT). Interestingly, mitochondria-targeted tamoxifen, a complex I inhibitor under clinical trial, overcomes resistance mediated by SMAD4-deficiency or TGFβ signaling. Our data point to differential mechanisms underlying the resistance to treatment in PDAC arising from TGFβ signaling and SMAD4 loss, respectively. The findings will help the development of mitochondria-targeted therapy for pancreatic cancer patients with SMAD4 as a plausible predictive marker.
  7. Cancer Discov. 2021 Mar 11. pii: candisc.1385.2020. [Epub ahead of print]
      In lung adenocarcinoma, oncogenic EGFR mutations co-occur with many tumor suppressor gene alterations, however the extent to which these contribute to tumor growth and response to therapy in vivo remains largely unknown. By quantifying the effects of inactivating ten putative tumor suppressor genes in a mouse model of EGFR-driven Trp53-deficient lung adenocarcinoma, we found that Apc, Rb1, or Rbm10 inactivation strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2 - the strongest drivers of growth in a Kras-driven model - reduced EGFR-driven tumor growth. These results are consistent with mutational frequencies in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, Keap1 inactivation reduced the sensitivity of EGFR-driven tumors to the EGFR inhibitor osimertinib and mutations in the KEAP1 pathway were associated with decreased time on tyrosine kinase inhibitor treatment in patients. Our study highlights how the impact of genetic alterations differ across oncogenic contexts and that the fitness landscape shifts upon treatment.
  8. Clin Cancer Res. 2021 Mar 08. pii: clincanres.0032.2021. [Epub ahead of print]
      PURPOSE: Current standard initial therapy for advanced, ROS1 fusion-positive (ROS1+) non-small cell lung cancer (NSCLC) is crizotinib or entrectinib. Lorlatinib, a next-generation ALK/ROS1 inhibitor, recently demonstrated efficacy in ROS1+ NSCLC including in crizotinib-pretreated patients. However, mechanisms of lorlatinib resistance in ROS1+ disease remain poorly understood. Here, we assessed mechanisms of resistance to crizotinib and lorlatinib.EXPERIMENTAL DESIGN: Biopsies from ROS1+ NSCLC patients progressing on crizotinib or lorlatinib were profiled by genetic sequencing.
    RESULTS: From 55 patients, 47 post-crizotinib and 32 post-lorlatinib biopsies were assessed. Among 42 post-crizotinib and 28 post-lorlatinib biopsies analyzed at distinct timepoints, ROS1 mutations were identified in 38% and 46%, respectively. ROS1 G2032R was the most common occurring in approximately a third of cases. Additional ROS1 mutations included: D2033N (2.4%) and S1986F (2.4%) post-crizotinib; L2086F (3.6%), G2032R/L2086F (3.6%), G2032R/S1986F/L2086F (3.6%), and S1986F/L2000V (3.6%) post-lorlatinib. Structural modeling predicted ROS1L2086F causes steric interference to lorlatinib, crizotinib, and entrectinib, while it may accommodate cabozantinib. In Ba/F3 models, ROS1L2086F, ROS1G2032R/L2086F, and ROS1S1986F/G2032R/L2086F were refractory to lorlatinib but sensitive to cabozantinib. A patient with disease progression on crizotinib and lorlatinib and ROS1 L2086F received cabozantinib for nearly 11 months with disease control. Among lorlatinib-resistant biopsies, we also identified MET amplification (4%), KRAS G12C (4%), KRAS amplification (4%), NRAS mutation (4%), and MAP2K1 mutation (4%).
    CONCLUSIONS: ROS1 mutations mediate resistance to crizotinib and lorlatinib in over one-third of cases, underscoring the importance of developing next-generation ROS1 inhibitors with potency against these mutations including G2032R and L2086F. Continued efforts are needed to elucidate ROS1-independent resistance mechanisms.
  9. Blood. 2021 Mar 08. pii: blood.2020006765. [Epub ahead of print]
      Inhibitors of Bruton's tyrosine kinase (BTKi) and phosphatidylinositol 3-kinase delta (PI3Kδi) that target the B cell receptor (BCR) signaling pathway have revolutionized the treatment of chronic lymphocytic leukemia (CLL). While mutations associated with resistance to BTK inhibitors have been identified, limited data are available on mechanisms of resistance to PI3Kδi. Here we present findings from longitudinal whole-exome sequencing of multiply relapsed CLL patients (Ncases=28) enrolled in PI3Ki trials. The non-responder subgroup was characterized by baseline activating mutations in MAP2K1, BRAF and KRAS in 60% of patients. PI3Kδ inhibition failed to inhibit ERK phosphorylation (pERK) in non-responder CLL cells with and without mutations, while treatment with MEKi rescued ERK inhibition. Overexpression of MAP2K1 mutants in vitro led to increased basal and inducible pERK and resistance to idelalisib. These data demonstrate that MAPK/ERK activation plays a key role in resistance to PI3Kδi in CLL and provide rationale for combination therapy with PI3Kδ and ERK inhibitors.
  10. Stem Cell Reports. 2021 Mar 02. pii: S2213-6711(21)00092-8. [Epub ahead of print]
      Metastasis is the major cause of cancer-related death, but whether metastatic lesions exhibit the same cellular composition as primary tumors has yet to be elucidated. To investigate the cellular heterogeneity of metastatic colorectal cancer (CRC), we established 72 patient-derived organoids (PDOs) from 21 patients. Combined bulk transcriptomic and single-cell RNA-sequencing analysis revealed decreased gene expression of markers for differentiated cells in PDOs derived from metastatic lesions. Paradoxically, expression of potential intestinal stem cell markers was also decreased. We identified OLFM4 as the gene most strongly correlating with a stem-like cell cluster, and found OLFM4+ cells to be capable of initiating organoid culture growth and differentiation capacity in primary PDOs. These cells were required for the efficient growth of primary PDOs but dispensable for metastatic PDOs. These observations demonstrate that metastatic lesions have a cellular composition distinct from that of primary tumors; patient-matched PDOs are a useful resource for analyzing metastatic CRC.
    Keywords:  colorectal cancer; metastasis; patient-derived organoids; scRNA-seq
  11. EMBO Mol Med. 2021 Mar 11. e13366
      Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A-priori identification of platinum resistance is therefore crucial to improve on standard first-line carboplatin-paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum-induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK-compliant study of pre-treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51-High tumours had shorter progression-free and overall survival compared to RAD51-Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR-proficient cancers (Myriad HRDscore < 42). Interestingly, overexpression of RAD51 modified expression of immune-regulatory pathways in vitro, while RAD51-High tumours showed exclusion of cytotoxic T cells in situ. Our findings highlight RAD51 expression as a determinant of platinum resistance and suggest possible roles for therapy to overcome immune exclusion in RAD51-High EOC. The qIHC approach is generalizable to other proteins with a continuum instead of discrete/bimodal expression.
    Keywords:  HRD; RAD51; immune exclusion; multiplexed IHC; ovarian cancer
  12. Nat Commun. 2021 Mar 12. 12(1): 1628
      Tyrosine kinase inhibitors were found to be clinically effective for treatment of patients with certain subsets of cancers carrying somatic mutations in receptor tyrosine kinases. However, the duration of clinical response is often limited, and patients ultimately develop drug resistance. Here, we use single-cell RNA sequencing to demonstrate the existence of multiple cancer cell subpopulations within cell lines, xenograft tumors and patient tumors. These subpopulations exhibit epigenetic changes and differential therapeutic sensitivity. Recurrently overrepresented ontologies in genes that are differentially expressed between drug tolerant cell populations and drug sensitive cells include epithelial-to-mesenchymal transition, epithelium development, vesicle mediated transport, drug metabolism and cholesterol homeostasis. We show analysis of identified markers using the LINCS database to predict and functionally validate small molecules that target selected drug tolerant cell populations. In combination with EGFR inhibitors, crizotinib inhibits the emergence of a defined subset of EGFR inhibitor-tolerant clones. In this study, we describe the spectrum of changes associated with drug tolerance and inhibition of specific tolerant cell subpopulations with combination agents.
  13. Cancer Res. 2021 Mar 08. pii: canres.1628.2020. [Epub ahead of print]
      Deferoxamine (DFO) represents a widely used iron chelator for the treatment of iron overload. Here we describe the use of mitochondrially targeted deferoxamine (mitoDFO) as a novel approach to preferentially target cancer cells. The agent showed marked cytostatic, cytotoxic, and migrastatic properties in vitro, and it significantly suppressed tumor growth and metastasis in vivo. The underlying molecular mechanisms included (I) impairment of [Fe-S] cluster/heme biogenesis, leading to destabilization and loss of activity of [Fe-S] cluster/heme containing enzymes, (II) inhibition of mitochondrial respiration leading to mitochondrial ROS production, resulting in dysfunctional mitochondria with markedly reduced supercomplexes, and (III) fragmentation of the mitochondrial network and induction of mitophagy. Mitochondrial targeting of DFO represents a way to deprive cancer cells of biologically active iron, which is incompatible with their proliferation and invasion, without disrupting systemic iron metabolism. Our findings highlight the importance of mitochondrial iron metabolism for cancer cells and demonstrate repurposing deferoxamine into an effective anti-cancer drug via mitochondrial targeting.
  14. Dev Cell. 2021 Mar 02. pii: S1534-5807(21)00121-0. [Epub ahead of print]
      Beginning with the earliest studies of autophagy in cancer, there have been indications that autophagy can both promote and inhibit cancer growth and progression; autophagy regulation of organelle homeostasis is similarly complicated. In this review we discuss pro- and antitumor effects of organelle-targeted autophagy and how this contributes to several hallmarks of cancer, such as evading cell death, genomic instability, and altered metabolism. Typically, the removal of damaged or dysfunctional organelles prevents tumor development but can also aid in proliferation or drug resistance in established tumors. By better understanding how organelle-specific autophagy takes place and can be manipulated, it may be possible to go beyond the brute-force approach of trying to manipulate all autophagy in order to improve therapeutic targeting of this process in cancer.
    Keywords:  ER-phagy; autophagy; cancer; lysophagy; mitophagy
  15. J Clin Invest. 2021 Mar 09. pii: 140752. [Epub ahead of print]
      Melanomas commonly undergo a phenotype switch, from a proliferative to an invasive state. Such tumor cell plasticity contributes to immunotherapy resistance, however, the mechanisms are not completely understood and thus therapeutically unexploited. Using melanoma mouse models, we demonstrated that blocking the MNK1/2-eIF4E axis inhibited melanoma phenotype switching and sensitized melanoma to anti-PD-1 immunotherapy. We showed that phospho-eIF4E-deficient murine melanomas expressed high levels of melanocytic antigens, with similar results verified in patient melanomas. Mechanistically, we identified phospho-eIF4E-mediated translational control of NGFR, a critical effector of phenotype switching. Genetic ablation of phospho-eIF4E reprogrammed the immunosuppressive microenvironment, exemplified by lowered production of inflammatory factors, decreased PD-L1 expression on dendritic cells and MDSCs, and increased CD8+ T-cell infiltrates. Finally, dual blockade of the MNK1/2-eIF4E axis and the PD-1/PD-L1 immune checkpoint demonstrated efficacy in multiple melanoma models regardless of their genomic classification. An increase in the presence of intratumoral stem-like TCF1+PD-1+CD8+ T cells, a characteristic essential for durable anti-tumor immunity, was detected in mice administered a MNK1/2 inhibitor and anti-PD-1 therapy. Using MNK1/2 inhibitors to repress phospho-eIF4E thus offers a new strategy to inhibit melanoma plasticity and improve response to anti-PD-1 immunotherapy.
    Keywords:  Melanoma; Oncology
  16. Oncogene. 2021 Mar 12.
      Cisplatin-based chemoradiotherapy is the recommended treatment for local advanced cervical cancer, but radioresistance remains one of the most important and unresolved clinical problems. Investigations have revealed aberrant epigenetic modifications as one of the chief culprits for the development of radioresistance. Here, we attempt to identify a radiosensitizer from an epigenetic drug synergy screen and explore the underlying mechanism. We integrated epigenetic inhibitors and radiotherapy in cervical cancer cell lines to identify potential radiosensitizers. We further verified the sensitization effect of the drug and the function of its target gene both in vitro and in vivo. Finally, we validated the clinical significance of its target gene in clinical cervical cancer specimens. We identified JQ1, a BRD4 inhibitor, as a potent radiosensitizer. Functional assays demonstrated that repressing BRD4 activity led to significant radiosensitization and potentiation of DNA damage in cervical cancer cell lines. By using RNA-seq to determine JQ1-mediated changes in transcription, we identified RAD51AP1 as a major BRD4 target gene involved in radiosensitivity. A dual-luciferase reporter assay and ChIP-qPCR showed that BRD4 binds to the promoter region of RAD51AP1 and promotes its transcription, whereas this activity was attenuated by BRD4 inhibition. The in vivo experiments also suggested a synergy between BRD4 inhibition and radiotherapy. High BRD4 expression was found to be related to a worse prognosis and radiation resistance. BRD4 inhibition sensitizes cervical cancer to radiotherapy by inhibiting RAD51AP1 transcription. The combination of JQ1 with radiotherapy merits further evaluation as a therapeutic strategy for improving local control in cervical cancer.
  17. Lancet Oncol. 2021 Mar 04. pii: S1470-2045(21)00019-X. [Epub ahead of print]
  18. Cancer Discov. 2021 Mar 12.
      Enzalutamide-treated prostate cancer and small-cell carcinoma cells had distinct transcriptomes.
  19. Cancer Discov. 2021 Mar 11. pii: candisc.1144.2020. [Epub ahead of print]
      A number of cancer drugs activate innate immune pathways in tumor cells but unfortunately also compromise anti-tumor immune function. We discovered that inhibition of Carm1, an epigenetic enzyme and co-transcriptional activator, elicited beneficial anti-tumor activity in both cytotoxic T cells and tumor cells. In T cells, Carm1 inactivation substantially enhanced their anti-tumor function and preserved memory-like populations required for sustained anti-tumor immunity. In tumor cells, Carm1 inactivation induced a potent type 1 interferon response that sensitized resistant tumors to cytotoxic T cells. Substantially increased numbers of dendritic cells, CD8 T cells and NK cells were present in Carm1-deficient tumors, and infiltrating CD8 T cells expressed low levels of exhaustion markers. Targeting of Carm1 with a small molecule elicited potent anti-tumor immunity and sensitized resistant tumors to checkpoint blockade. Targeting of this co-transcriptional regulator thus offers an opportunity to enhance immune function while simultaneously sensitizing resistant tumor cells to immune attack.
  20. Nat Commun. 2021 03 08. 12(1): 1503
      Brain metastases are the most common tumor of the brain with a dismal prognosis. A fraction of patients with brain metastasis benefit from treatment with immune checkpoint inhibitors (ICI) and the degree and phenotype of the immune cell infiltration has been used to predict response to ICI. However, the anatomical location of brain lesions limits access to tumor material to characterize the immune phenotype. Here, we characterize immune cells present in brain lesions and matched cerebrospinal fluid (CSF) using single-cell RNA sequencing combined with T cell receptor genotyping. Tumor immune infiltration and specifically CD8+ T cell infiltration can be discerned through the analysis of the CSF. Consistently, identical T cell receptor clonotypes are detected in brain lesions and CSF, confirming cell exchange between these compartments. The analysis of immune cells of the CSF can provide a non-invasive alternative to predict the response to ICI, as well as identify the T cell receptor clonotypes present in brain metastasis.
  21. Sci Rep. 2021 Mar 12. 11(1): 5838
      Chemotherapy resistance is the main impediment in the treatment of acute myeloid leukaemia (AML). Despite rapid advances, the various mechanisms inducing resistance development remain to be defined in detail. Here we report that loss-of-function mutations (LOF) in the histone methyltransferase EZH2 have the potential to confer resistance against the chemotherapeutic agent cytarabine. We identify seven distinct EZH2 mutations leading to loss of H3K27 trimethylation via multiple mechanisms. Analysis of matched diagnosis and relapse samples reveal a heterogenous regulation of EZH2 and a loss of EZH2 in 50% of patients. We confirm that loss of EZH2 induces resistance against cytarabine in the cell lines HEK293T and K562 as well as in a patient-derived xenograft model. Proteomics and transcriptomics analysis reveal that resistance is conferred by upregulation of multiple direct and indirect EZH2 target genes that are involved in apoptosis evasion, augmentation of proliferation and alteration of transmembrane transporter function. Our data indicate that loss of EZH2 results in upregulation of its target genes, providing the cell with a selective growth advantage, which mediates chemotherapy resistance.
  22. Cancer Cell. 2021 Mar 05. pii: S1535-6108(21)00119-7. [Epub ahead of print]
      Clinical implementation of anti-stromal therapies in pancreatic cancer has been delayed by unanticipated tumor-restraining properties of the desmoplastic stroma. In confronting these challenges, Chen et al. demonstrate in this issue of Cancer Cell that fibroblast-specific deletion of collagen I, in the background of oncogenic Kras-induced spontaneous murine pancreatic ductal adenocarcinoma, enhances immune suppression and accelerates progression of disease.
  23. Cell Rep. 2021 Mar 09. pii: S2211-1247(21)00130-3. [Epub ahead of print]34(10): 108816
      Significant changes in cell stiffness, contractility, and adhesion, i.e., mechanotype, are observed during a variety of biological processes. Whether cell mechanics merely change as a side effect of or driver for biological processes is still unclear. Here, we sort genotypically similar metastatic cancer cells into strongly adherent (SA) versus weakly adherent (WA) phenotypes to study how contractility and adhesion differences alter the ability of cells to sense and respond to gradients in material stiffness. We observe that SA cells migrate up a stiffness gradient, or durotax, while WA cells largely ignore the gradient, i.e., adurotax. Biophysical modeling and experimental validation suggest that differences in cell migration and durotaxis between weakly and strongly adherent cells are driven by differences in intra-cellular actomyosin activity. These results provide a direct relationship between cell phenotype and durotaxis and suggest how, unlike other senescent cells, metastatic cancer cells navigate against stiffness gradients.
    Keywords:  acto-mysoin contractility; carcinoma; catch bonds; durotaxis; focal adhesions; metastasis
  24. Cancer Cell. 2021 Mar 08. pii: S1535-6108(21)00110-0. [Epub ahead of print]39(3): 285-287
      March 8 is International Women's Day. Women, particularly women of color, are still underrepresented in science and medical careers and face severe health disparities. To commemorate this day, we asked female cancer researchers and oncologists to talk about their work experiences and their efforts to improve equity, representation, and leadership.
  25. Methods Mol Biol. 2021 ;2265 363-376
      The lymph node microenvironment is extremely dynamic and responds to immune stimuli in the host by reprogramming immune, stromal, and endothelial cells. In normal physiological conditions, the lymph node will initiate an appropriate immune response to clear external threats that the host may experience. However, in metastatic disease, cancer cells often colonize local lymph nodes, disrupt immune function, and even leave the lymph node to create additional metastases. Understanding how cancer cells enter, colonize, survive, proliferate, and interact with other cell types in the lymph node is challenging. Here, we describe the use of photoconvertible fluorescent proteins to label and trace the fate of cancer cells once they enter the lymph node.
    Keywords:  Circulating tumor cells; Confocal microscopy; Dendra2; Intravital imaging; Lymph node; Metastasis; Photoconvertible proteins; Photodiode
  26. Methods Mol Biol. 2021 ;2265 65-71
      Cell migration is a critical process involved in morphogenesis, inflammation, and cancer metastasis. Wound healing assay is a simple, non-expensive, and highly reproducible method to study cancer cell migration in vitro. It is based on the observation that cells growing in a monolayer migrate to re-establish cell contacts after the development of an artificial wound. The assay involves creation of a wound in a monolayer, image acquisition during wound closure, and comparison of migrated area at initial and final time points.
    Keywords:  Cell migration; Melanoma; Metastasis; Wound healing; Wound scratch