bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021‒09‒19
twenty-four papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Cancer Discov. 2021 Sep 14.
      Contrary to prior thought that they are dormant, some malignant cells that tolerate anticancer treatment, termed persister cells, actively proliferate even under the pressure of targeted therapy, potentially driving relapse.
  2. Cancer Res. 2021 Sep 16. pii: canres.1606.2021. [Epub ahead of print]
      Cancer is a complex disease and cancer cells typically harbor multiple genetic and epigenetic alterations. Large-scale sequencing of patient-derived cancer samples has identified several druggable driver oncogenes. Many of these oncogenes can be pharmacologically targeted to provide effective therapies for breast cancer, leukemia, lung cancer, melanoma, lymphoma, and other cancer types. Initial responses to these agents can be robust in many cancer types and some cancer patients experience sustained tumor inhibition. However, resistance to these targeted therapeutics frequently emerges, either from intrinsic or acquired mechanisms, posing a major clinical hurdle for effective treatment. Several resistance mechanisms, both cell autonomous and cell non-autonomous, have been identified in different cancer types. Here we describe how alterations of the transcriptome, transcription factors, DNA, and chromatin regulatory proteins confer resistance to targeted therapeutic agents. We also elaborate on how these studies have identified underlying epigenetic factors that drive drug resistance and oncogenic pathways, with direct implications for the prevention and treatment of drug-resistant cancer.
  3. Dev Cell. 2021 Sep 13. pii: S1534-5807(21)00677-8. [Epub ahead of print]
      Melanomas can have multiple coexisting cell states, including proliferative (PRO) versus invasive (INV) subpopulations that represent a "go or grow" trade-off; however, how these populations interact is poorly understood. Using a combination of zebrafish modeling and analysis of patient samples, we show that INV and PRO cells form spatially structured heterotypic clusters and cooperate in the seeding of metastasis, maintaining cell state heterogeneity. INV cells adhere tightly to each other and form clusters with a rim of PRO cells. Intravital imaging demonstrated cooperation in which INV cells facilitate dissemination of less metastatic PRO cells. We identified the TFAP2 neural crest transcription factor as a master regulator of clustering and PRO/INV states. Isolation of clusters from patients with metastatic melanoma revealed a subset with heterotypic PRO-INV clusters. Our data suggest a framework for the co-existence of these two divergent cell populations, in which heterotypic clusters promote metastasis via cell-cell cooperation.
    Keywords:  TFAP2; circulating tumor cell cluster; cluster; cooperation; melanoma; metastasis; zebrafish
  4. Mol Ther. 2021 Sep 14. pii: S1525-0016(21)00464-0. [Epub ahead of print]
      Chemoresistance is the major cause of gastric adenocarcinoma (GA) treatment failure. The mechanisms underlying chemoresistance remain incompletely understood. Here, we sought to identify genes differentially expressed between chemoresistant and chemosensitive GA and to validate the function of the top hit. High-throughput RNA sequencing was performed to detect chemoresistance-related genes. The function of the only gene overexpressed in both chemoresistant tumors and tumor tissue relative to normal gastric epithelia, FOXC1, was examined in GA cells, mouse xenograft models, and patient-derived organoid (PDO) systems, focusing on cancer stem-like cell (CSC) phenotypes, metastasis, and chemoresistance. FOXC1 was expressed at significantly higher levels in GA patient tumors that were resistant to chemotherapy, and high FOXC1 tumor expression was significantly correlated with poor survival among patients undergoing resection (p=0.011). FOXC1 activity was significantly higher in spheroid-forming or CD44+ GA CSCs than in unselected cells. Inhibition of FOXC1 decreased the expression of CD44 and Sox2, decreased spheroid size by 78-82%, and decreased spheroid number (>100 μm) by 75-86%. GA CSC chemotherapy resistance was reversed with FOXC1 inhibition in vitro, in vivo, and in patient-derived organoids (PDOs). Mechanistic studies indicated that FOXC1 acts via the Hedgehog and epithelial-to-mesenchymal transition (EMT) pathways. Our results imply that FOXC1 mediates the CSC phenotypes, metastasis, and chemotherapy resistance of GA through Hedgehog and EMT signaling. FOXC1 inhibitors may thus represent a novel strategy to overcome chemoresistance.
    Keywords:  Forkhead box C1; chemotherapy resistance; gastric cancer; lymphangiogenesis; stemness
  5. EMBO J. 2021 Sep 17. e107680
      Cell plasticity is a crucial hallmark leading to cancer metastasis. Upregulation of Rho/ROCK pathway drives actomyosin contractility, protrusive forces, and contributes to the occurrence of highly invasive amoeboid cells in tumors. Cancer stem cells are similarly associated with metastasis, but how these populations arise in tumors is not fully understood. Here, we show that the novel oncogene RASSF1C drives mesenchymal-to-amoeboid transition and stem cell attributes in breast cancer cells. Mechanistically, RASSF1C activates Rho/ROCK via SRC-mediated RhoGDI inhibition, resulting in generation of actomyosin contractility. Moreover, we demonstrate that RASSF1C-induced amoeboid cells display increased expression of cancer stem-like markers such as CD133, ALDH1, and Nanog, and are accompanied by higher invasive potential in vitro and in vivo. Further, RASSF1C-induced amoeboid cells employ extracellular vesicles to transfer the invasive phenotype to target cells and tissue. Importantly, the underlying RASSF1C-driven biological processes concur to explain clinical data: namely, methylation of the RASSF1C promoter correlates with better survival in early-stage breast cancer patients. Therefore, we propose the use of RASSF1 gene promoter methylation status as a biomarker for patient stratification.
    Keywords:  RASSF1C oncogene; Rho/ROCK pathway; amoeboid motility; extracellular vesicles; gene methylation
  6. Theranostics. 2021 ;11(18): 8755-8770
      Rationale: Chemoradiation (CRT) is commonly used as an adjuvant or neoadjuvant treatment for colorectal cancer (CRC) patients. However, resistant cells manage to survive and propagate after CRT, increasing the risk of recurrence. Thus, better understanding the mechanism of resistant cancer cells is required to achieve better clinical outcomes. Methods: Here, we explored gene expression profiling of CRC patient tumors to identify therapy resistance genes and discovered that protein tyrosine phosphatase receptor type C (PTPRC), which encodes CD45, was increased in remnant tumor tissues after CRT and correlated with metastasis. Through multiple validations using patient tumors and CRC cell lines, we found for the first time the increase of CD45 expression in CRC (EpCAM+) epithelial cells surviving after CRT. Thus, we investigated the biological role and downstream events of CD45 were explored in human CRC cells and CRC mouse models. Results: Increased CD45 expression in cancer cells in pretreated primary tumors accounts for poor regression and recurrence-free survival in CRT-treated patients. High CD45 expression promotes CRC cell survival upon 5-fluorouracil or radiation treatment, while CD45 depletion sensitizes CRC cells to CRT. Intriguingly, CD45 is preferentially expressed in cancer stem-like cells (CSCs), as determined by spheroid culture and the expression of CSC markers, and is required for the distinct functions of CSCs, such as cancer initiation, repopulation, and metastasis. Mechanistically, CD45 phosphatase activity promotes Wnt transcriptional activity by stabilizing the β-catenin protein, which collectively enhances stemness and the therapy-resistant phenotype. Conclusions: Our results highlight a novel function of CD45 as a mediator of CRT resistance and provide a potential therapy strategy for CRC therapy.
    Keywords:  CD45; Cancer stem-like cell; Chemoradiation; Colorectal cancer; Therapy resistance; Wnt; β-Catenin
  7. Clin Cancer Res. 2021 Sep 13. pii: clincanres.2040.2021. [Epub ahead of print]
      PURPOSE: Although remarkably effective in some patients, precision medicine typically induces only transient responses despite initial absence of resistance-conferring mutations. Using BRAF-mutated myeloma as a model for resistance to precision medicine we investigated if BRAF-mutated cancer cells have the ability to ensure their survival by rapidly adapting to BRAF inhibitor treatment.EXPERIMENTAL DESIGN: Full-length single cell (sc)RNA-seq was conducted on three patients with BRAF-mutated myeloma and one healthy donor. We sequenced 1495 cells before, after one week and at clinical relapse to BRAF/ MEK inhibitor treatment. We developed an in vitro model of dabrafenib-resistance using genetically homogeneous single-cell clones from two cell lines with established BRAF mutations (U266, DP6). Transcriptional and epigenetic adaptation in resistant cells were defined by RNA-seq and H3K23ac ChIP-seq. Mitochondrial metabolism was characterized by metabolic flux analysis.
    RESULTS: Profiling by scRNA-seq revealed rapid cellular state changes in response to BRAF/MEK inhibition in myeloma patients and cell lines. Transcriptional adaptation preceded detectable outgrowth of genetically discernible drug-resistant clones and was associated with widespread enhancer remodeling. As a dominant vulnerability, dependency on oxidative phosphorylation (OxPhos) was induced. In treated individuals, OxPhos was activated at the time of relapse and showed inverse correlation to MAPK activation. Metabolic flux analysis confirmed OxPhos as a preferential energetic resource of drug-persistent myeloma cells.
    CONCLUSIONS: This study demonstrates that cancer cells have the ability to rapidly adapt to precision treatments through transcriptional state changes, epigenetic adaptation and metabolic rewiring, thus facilitating the development of refractory disease while simultaneously exposing novel vulnerabilities.
  8. Nat Commun. 2021 Sep 13. 12(1): 5402
      Chromosomal instability (CIN) and epigenetic alterations have been implicated in tumor progression and metastasis; yet how these two hallmarks of cancer are related remains poorly understood. By integrating genetic, epigenetic, and functional analyses at the single cell level, we show that progression of uveal melanoma (UM), the most common intraocular primary cancer in adults, is driven by loss of Polycomb Repressive Complex 1 (PRC1) in a subpopulation of tumor cells. This leads to transcriptional de-repression of PRC1-target genes and mitotic chromosome segregation errors. Ensuing CIN leads to the formation of rupture-prone micronuclei, exposing genomic double-stranded DNA (dsDNA) to the cytosol. This provokes tumor cell-intrinsic inflammatory signaling, mediated by aberrant activation of the cGAS-STING pathway. PRC1 inhibition promotes nuclear enlargement, induces a transcriptional response that is associated with significantly worse patient survival and clinical outcomes, and enhances migration that is rescued upon pharmacologic inhibition of CIN or STING. Thus, deregulation of PRC1 can promote tumor progression by inducing CIN and represents an opportunity for early therapeutic intervention.
  9. Clin Cancer Res. 2021 Sep 15. pii: clincanres.4796.2020. [Epub ahead of print]
      PURPOSE: Bladder cancer (BC) treatment remains a major clinical challenge due to therapy resistance and a high recurrence rate. Profiling intratumor heterogeneity can reveal the molecular mechanism of BC recurrence.EXPERIMENTAL DESIGN: Here, we performed single-cell RNA-seq and ATAC-seq on tumors from 13 patients with low recurrence risk, high recurrence risk and recurrent BC.
    RESULTS: Our study generated a comprehensive cancer cell atlas consisting of 54,971 single cells and identified distinct cell subpopulations. We found that the cancer stem cell subpopulation is enriched during BC recurrence with elevated expression of EZH2. We further defined a subpopulation-specific molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of the NCAM1 gene, thereby inactivating the cell invasive and stemness transcriptional program. Furthermore, taking advantage of this large single-cell dataset, we elucidated the spectrum of epithelial-mesenchymal transition (EMT) in clinical samples and revealed distinct EMT features associated with BC subtypes. We identified that TCF7 promotes EMT in corroboration with scATAC-seq analysis. Additionally, we constructed regulatory networks specific to recurrent BC.
    CONCLUSIONS: Our study and analytical approaches herein provide a rich resource for the further study of cancer stem cells and EMT in the BC research field.
  10. Genes Dev. 2021 Sep 16.
      Activating mutations in KRAS (KRAS*) are present in nearly all pancreatic ductal adenocarcinoma (PDAC) cases and critical for tumor maintenance. By using an inducible KRAS* PDAC mouse model, we identified a deubiquitinase USP21-driven resistance mechanism to anti-KRAS* therapy. USP21 promotes KRAS*-independent tumor growth via its regulation of MARK3-induced macropinocytosis, which serves to maintain intracellular amino acid levels for anabolic growth. The USP21-mediated KRAS* bypass, coupled with the frequent amplification of USP21 in human PDAC tumors, encourages the assessment of USP21 as a novel drug target as well as a potential parameter that may affect responsiveness to emergent anti-KRAS* therapy.
    Keywords:  KRAS; MARK3; USP21; macropinocytosis; targeted therapy resistance
  11. Cancer Res. 2021 Sep 17. pii: canres.1180.2021. [Epub ahead of print]
      High blood glucose has long been established as a risk factor for tumor metastasis, yet the molecular mechanisms underlying this association have not been elucidated. Here we describe that hyperglycemia promotes tumor metastasis via increased platelet activity. Administration of glucose, but not fructose, reprogrammed the metabolism of megakaryocytes to indirectly prime platelets into a pro-metastatic phenotype with increased adherence to tumor cells. In megakaryocytes, a glucose metabolism-related gene array identified the mitochondrial molecular chaperone glucose-regulated protein 75 (GRP75) as a trigger for platelet activation and aggregation by stimulating the Ca2+-PKCα pathway. Genetic depletion of Glut1 in megakaryocytes blocked MYC-induced GRP75 expression. Pharmacological blockade of platelet GRP75 compromised tumor-induced platelet activation and reduced metastasis. Moreover, in a pilot clinical study, drinking a 5% glucose solution elevated platelet GRP75 expression and activated platelets in healthy volunteers. Platelets from these volunteers promoted tumor metastasis in a platelet-adoptive transfer mouse model. Together, under hyperglycemic conditions, MYC-induced upregulation of GRP75 in megakaryocytes increases platelet activation via the Ca2+-PKCα pathway to promote cancer metastasis, providing a potential new therapeutic target for preventing metastasis.
  12. Cancer Cell. 2021 Sep 13. pii: S1535-6108(21)00401-3. [Epub ahead of print]39(9): 1175-1177
      Fibroblasts are a major non-neoplastic component of solid tumors, yet it is unclear whether they promote or oppose cancer. In this issue of Cancer Cell, Hutton et al. report two distinct fibroblast subpopulations that are defined by a single marker, one subpopulation that is tumor permissive and the other that is tumor suppressive and supports anti-tumor immunity.
  13. Nat Commun. 2021 Sep 13. 12(1): 5404
      Inactivating mutations in SMARCA4 and concurrent epigenetic silencing of SMARCA2 characterize subsets of ovarian and lung cancers. Concomitant loss of these key subunits of SWI/SNF chromatin remodeling complexes in both cancers is associated with chemotherapy resistance and poor prognosis. Here, we discover that SMARCA4/2 loss inhibits chemotherapy-induced apoptosis through disrupting intracellular organelle calcium ion (Ca2+) release in these cancers. By restricting chromatin accessibility to ITPR3, encoding Ca2+ channel IP3R3, SMARCA4/2 deficiency causes reduced IP3R3 expression leading to impaired Ca2+ transfer from the endoplasmic reticulum to mitochondria required for apoptosis induction. Reactivation of SMARCA2 by a histone deacetylase inhibitor rescues IP3R3 expression and enhances cisplatin response in SMARCA4/2-deficient cancer cells both in vitro and in vivo. Our findings elucidate the contribution of SMARCA4/2 to Ca2+-dependent apoptosis induction, which may be exploited to enhance chemotherapy response in SMARCA4/2-deficient cancers.
  14. Dev Cell. 2021 Sep 13. pii: S1534-5807(21)00676-6. [Epub ahead of print]56(17): 2399-2400
      In this issue of Developmental Cell, papers from Ippolito et al. and from Lukow et al. show that increasing the range of aneuploidy states in cells increases their chance of developing resistance when they are subjected to chemotherapy.
  15. Cancer Res. 2021 Sep 13. pii: canres.3242.2020. [Epub ahead of print]
      Oxidative phosphorylation (OXPHOS) is an active metabolic pathway in many cancers. RNA from pre-treatment biopsies from patients with triple negative breast cancer (TNBC) who received neoadjuvant chemotherapy demonstrated that the top canonical pathway associated with worse outcome was higher expression of an OXPHOS signature. In multiple TNBC patient-derived xenografts (PDXs), treatment with IACS-10759, a novel inhibitor of OXPHOS, stabilized tumor growth. Gene expression profiling revealed that all sensitive models displayed a basal-like 1 TNBC subtype, and expression of mitochondrial genes was significantly higher in sensitive PDXs. An in vivo functional genomics screen in tumors treated with IACS-10759 found several potential synthetic lethal targets, including CDK4. A combination of palbociclib, a CDK4/6 inhibitor, and IACS-10759 exhibited significant anti-tumor efficacy in vitro and in vivo. In addition, the combination of IACS-10759 and multi-kinase inhibitor cabozantinib had improved antitumor efficacy compared to either single agent. Taken together, these data suggest that OXPHOS is a metabolic vulnerability in TNBC that may be leveraged with novel therapeutics in combination regimens.
  16. Blood. 2021 Sep 15. pii: blood.2021013201. [Epub ahead of print]
      AML is characterized by the presence of leukemia stem cells (LSCs), and failure to fully eradicate this population contributes to disease persistence/relapse. Prior studies have characterized metabolic vulnerabilities of LSCs, which demonstrate preferential reliance on oxidative phosphorylation (OXPHOS) for energy metabolism and survival. In the present study, using both genetic and pharmacologic strategies in primary human AML specimens, we show that signal transducer and activator of transcription 3 (STAT3) mediates OXPHOS in LSCs. STAT3 regulates AML-specific expression of MYC, which in turn controls transcription of the neutral amino acid transporter SLC1A5. We show that genetic inhibition of MYC or SLC1A5 acts to phenocopy the impairment of OXPHOS observed with STAT3 inhibition, thereby establishing this axis as a regulatory mechanism linking STAT3 to energy metabolism. Inhibition of SLC1A5 reduces intracellular levels of glutamine, glutathione and multiple TCA metabolites, leading to reduced TCA cycle activity and inhibition of OXPHOS. Based on these findings, we used a novel small molecule STAT3 inhibitor, that binds STAT3 and disrupts STAT3-DNA, to evaluate the biological role of STAT3. We show that STAT3 inhibition selectively leads to cell death in AML stem and progenitor cells derived from newly diagnosed and relapsed patients, while sparing normal hematopoietic cells. Together, these findings establish a STAT3-mediated mechanism that controls energy metabolism and survival in primitive AML cells.
  17. Gastroenterology. 2021 Sep 14. pii: S0016-5085(21)03496-X. [Epub ahead of print]
      BACKGROUND AND AIMS: A major clinical challenge for pancreatic cancer (PC) patients is metabolic adaptation. Neoplastic cells harboring molecular perturbations suffice for their increased anabolic demand and nucleotide biosynthesis to acquire chemoresistance. The mucin 5AC expressed de novo in malignant pancreas promotes cancer cell stemness and is significantly associated with poor patient survival. Identification of MUC5AC-associated drivers of chemoresistance through metabolic alterations may facilitate sculpting a new combinatorial regimen.METHODS: The contribution of MUC5AC on glutaminolysis and gemcitabine resistance were examined by TCGA data analysis, RNA sequencing, and immunohistochemistry analysis on pancreatic tissues of KrasG12D; Pdx1-Cre (KC) and KrasG12D; Pdx1-Cre; Muc5ac-/- (KCM) mice. These were followed by metabolite flux assays, biochemical and xenograft studies on MUC5AC-depleted human and murine PC cells. Murine and human pancreatic 3D-tumoroids were used to evaluate gemcitabine's efficacy in combination with β-catenin and glutaminolysis inhibitors.
    RESULTS: Transcriptional analysis demonstrated that high MUC5AC-expressing human and autochthonous murine PC tumors exhibit higher resistance to gemcitabine due to enhanced glutamine utilization and nucleotide biosynthesis. Gemcitabine treatment led to MUC5AC overexpression, resulting in disruption of E-Cadherin/β-catenin junctions and the nuclear translocation of β-catenin, which increased c-Myc expression with a concomitant rise in glutamine uptake and glutamate release. MUC5AC-depletion and glutamine deprivation sensitized human PC cells to gemcitabine, which was obviated by glutamine replenishment in MUC5AC-expressing cells. Co-administration of β-catenin and glutaminolysis inhibitors with gemcitabine abrogated the MUC5AC-mediated resistance in murine and human tumoroids.
    CONCLUSIONS: MUC5AC/β-catenin/c-Myc axis increases the uptake and utilization of glutamine in PC cells and co-targeting this axis along with gemcitabine may improve the therapeutic efficacy in PC.
    Keywords:  c-Myc; gemcitabine; glutamine; pancreatic cancer; β-catenin
  18. Cancer Res. 2021 Sep 13. pii: canres.CAN-21-0164-A.2021. [Epub ahead of print]
      Despite impressive advances in melanoma-directed immunotherapies, resistance is common and many patients still succumb to metastatic disease. In this context, harnessing natural killer (NK) cells, which have thus far been sidelined in the development of melanoma immunotherapy, could provide therapeutic benefits for cancer treatment. To identify molecular determinants of NK cell-mediated melanoma killing (NKmK), we quantified NK cell cytotoxicity against a panel of genetically diverse melanoma cell lines and observed highly heterogeneous susceptibility. Melanoma protein microarrays revealed a correlation between NKmK and the abundance and activity of a subset of proteins, including several metabolic factors. Oxidative phoshorylation, measured by oxygen consumption rate, negatively correlated with melanoma cell sensitivity towards NKmK, and proteins involved in mitochondrial metabolism and EMT were confirmed to regulate NKmK. Two- and three-dimensional killing assays and melanoma xenografts established that the PI3K/Akt/mTOR signaling axis controls NKmK via regulation of NK cell-relevant surface proteins. A "protein-killing signature" based on the protein analysis predicted NKmK of additional melanoma cell lines and the response of melanoma patients to anti-PD-1 checkpoint therapy. Collectively, these findings identify novel NK cell-related prognostic biomarkers and may contribute to improved and personalized melanoma-directed immunotherapies.
  19. Mol Ther Nucleic Acids. 2021 Dec 03. 26 269-279
      Cisplatin-based chemotherapy remains the standard care for non-small cell lung cancer (NSCLC) patients. Relapse after chemotherapy-induced dormancy affects the overall survival of patients. The evolution of cancer cells under chemotherapy stress is regulated by transcription factors (TFs) with binding sites initially buried deep within inaccessible chromatin. The transcription machinery and dynamic epigenetic alterations during the process of dormancy-reactivation of lung cancer cells after chemotherapy need to be investigated. Here, we investigated the chromatin accessibility of lung cancer cells after cisplatin treatment, using an assay for transposase-accessible chromatin sequencing (ATAC-seq). We observed that global chromatin accessibility was extensively improved. Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining (TRRUST) v.2 was used to elucidate TF-target interaction during the process of dormancy and reactivation. Enhancer regions and motifs specific to key TFs including JUN, MYC, SMAD3, E2F1, SP1, CTCF, SMAD4, STAT3, NFKB1, and KLF4 were enriched in differential loci ATAC-seq peaks of dormant and reactivated cancer cells induced by chemotherapy. The findings suggest that these key TFs regulated gene expressions during the process of dormancy and reactivation of cancer cells through altering promoter accessibility of target genes. Our study helps advance understanding of how cancer cells adapt to the stress induced by chemotherapy through TF binding motif accessibility.
    Keywords:  NSCLC; chemotherapy; chromatin accessibility; dormancy and reactivation; transcription factors
  20. Cancer Discov. 2021 Sep 17.
      A novel, cost-effective method quantifies immune infiltration using whole-exome sequencing data.
  21. Mol Cancer. 2021 09 13. 20(1): 117
      As an important medium of intercellular communication, exosomes play an important role in information transmission between tumor cells and their microenvironment. Tumor metastasis is a serious influencing factor for poor treatment effect and shortened survival. Lung cancer is a major malignant tumor that seriously threatens human health. The study of the underlying mechanisms of exosomes in tumor genesis and development may provide new ideas for early and effective diagnosis and treatment of lung cancer metastasis. Many studies have shown that tumor-derived exosomes promote lung cancer development through a number of processes. By promoting epithelial-mesenchymal transition of tumor cells, they induce angiogenesis, establishment of the pretransfer microenvironment, and immune escape. This understanding enables researchers to better understand the mechanism of lung cancer metastasis and explore new treatments for clinical application. In this article, we systematically review current research progress of tumor-derived exosomes in metastasis of lung cancer. Although positive progress has been made toward understanding the mechanism of exosomes in lung cancer metastasis, systematic basic research and clinical translational research remains lacking and are needed to translate our scientific understanding toward applications in the clinical diagnosis and treatment of lung cancer metastasis in the near future.
    Keywords:  Diagnosis; Exosomes; Lung cancer; Metastases; Therapeutic targets
  22. Nat Biotechnol. 2021 Sep 16.
      Genetic and non-genetic heterogeneity within cancer cell populations represent major challenges to anticancer therapies. We currently lack robust methods to determine how preexisting and adaptive features affect cellular responses to therapies. Here, by conducting clonal fitness mapping and transcriptional characterization using expressed barcodes and single-cell RNA sequencing (scRNA-seq), we have developed tracking differential clonal response by scRNA-seq (TraCe-seq). TraCe-seq is a method that captures at clonal resolution the origin, fate and differential early adaptive transcriptional programs of cells in a complex population in response to distinct treatments. We used TraCe-seq to benchmark how next-generation dual epidermal growth factor receptor (EGFR) inhibitor-degraders compare to standard EGFR kinase inhibitors in EGFR-mutant lung cancer cells. We identified a loss of antigrowth activity associated with targeted degradation of EGFR protein and an essential role of the endoplasmic reticulum (ER) protein processing pathway in anti-EGFR therapeutic efficacy. Our results suggest that targeted degradation is not always superior to enzymatic inhibition and establish TraCe-seq as an approach to study how preexisting transcriptional programs affect treatment responses.