• NOTCH inhibitors
• cancer stemlike cells
• canonical NOTCH signaling
• drug-tolerant persisters
• epithelial-to-mesenchymal transition
• noncanonical NOTCH signaling
• nongenetic resistance of cancer

• Humans
• Receptors, Notch/metabolism
• Receptors, Notch/genetics
• Signal Transduction
• Drug Resistance, Neoplasm/genetics
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/genetics
• Epithelial-Mesenchymal Transition
• Neoplastic Stem Cells/metabolism

• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Neoplasms/drug therapy
• Tumor Microenvironment
• Drug Tolerance

• MC_UU_00035/13 Medical Research Council

• ChIP-seq
• Copy number variation
• Leukemia
• Melanoma
• Multiomics analysis
• Syngeneic model
• Tumour dormancy
• Whole exome sequencing

• Animals
• Melanoma/genetics
• Melanoma/pathology
• Mice
• Neoplasm, Residual
• Disease Models, Animal
• Leukemia/genetics
• Leukemia/pathology
• DNA Copy Number Variations
• Exome Sequencing
• Mice, Inbred C57BL
• Proteomics
• Transcriptome
• Gene Expression Profiling
• Multiomics

• INCA_18477 INCA
• INCa-DGOS-Inserm 6041 SIRIC

• Anticancer peptides
• Antimicrobial peptides
• Drug resistance
• Lipid metabolism
• Membrane lipids

• Peptides, Cyclic/pharmacology
• Peptides, Cyclic/therapeutic use
• Animals
• Melanoma/drug therapy
• Melanoma/pathology
• Humans
• Drug Resistance, Neoplasm/drug effects
• Cell Line, Tumor
• Imidazoles/pharmacology
• Imidazoles/therapeutic use
• Cell Proliferation/drug effects
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Oximes/pharmacology
• Oximes/therapeutic use
• Antimicrobial Cationic Peptides/pharmacology
• Antimicrobial Cationic Peptides/therapeutic use
• Mice
• Female
• DNA-Binding Proteins

• Animals
• Humans
• Mice
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Exodeoxyribonucleases/antagonists & inhibitors
• Gene Expression Regulation, Neoplastic/drug effects
• Immunity, Innate/drug effects
• Immunity, Innate/genetics
• Lung Neoplasms/genetics
• Lung Neoplasms/drug therapy
• Lung Neoplasms/immunology
• Lung Neoplasms/pathology
• Phosphoproteins/antagonists & inhibitors
• Small Cell Lung Carcinoma/genetics
• Small Cell Lung Carcinoma/drug therapy
• Small Cell Lung Carcinoma/immunology
• Small Cell Lung Carcinoma/pathology
• Xenograft Model Antitumor Assays

• P30 CA196521 NCI NIH HHS

• Acquired resistance
• Antineoplastic agents
• Chemotherapy
• Drug resistance
• Neoplasms

• Humans
• Drug Resistance, Neoplasm
• Neoplasms/drug therapy
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Tumor Microenvironment/drug effects
• Mutation

• cancer therapy
• tumour immunology
• cancer metabolism

• Humans
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/pathology
• Drug Resistance, Neoplasm/genetics
• Drug Resistance, Neoplasm/drug effects
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Cell Plasticity/drug effects
• Cell Plasticity/genetics

• acquired drug resistance
• drug tolerance
• lncRNA
• lung adenocarcinoma
• targeted therapy

• Humans
• RNA, Long Noncoding/genetics
• Lung Neoplasms/genetics
• Lung Neoplasms/drug therapy
• Lung Neoplasms/pathology
• Drug Resistance, Neoplasm/genetics
• Adenocarcinoma of Lung/genetics
• Adenocarcinoma of Lung/drug therapy
• Adenocarcinoma of Lung/pathology
• Gene Expression Regulation, Neoplastic/drug effects
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Drug Tolerance/genetics

• UOO1903 Royal Society Te Apārangi
• CRTNZ 2176 Cancer Research Trust
• AP37609 Otago Medical Research Fund

• ERK
• P2X7
• calcium signaling
• non-genetic drug tolerance

• T32 MH064913 NIMH NIH HHS
• U54 CA217450 NCI NIH HHS
• R50 CA243783 NCI NIH HHS
• R01 DK129340 NIDDK NIH HHS
• R01 DK136768 NIDDK NIH HHS

• T32 MH064913 NIMH NIH HHS
• U54 CA217450 NCI NIH HHS
• S10 OD028719 NIH HHS
• R50 CA243783 NCI NIH HHS
• R01 DK129340 NIDDK NIH HHS
• R01 DK136768 NIDDK NIH HHS
• R50 CA211206 NCI NIH HHS

• barcoding
• cancer systems biology
• clonal tracing
• drug resistance
• scRNA-seq

• Humans
• Neoplasms/genetics
• Neoplasms/pathology
• Clone Cells/pathology
• Single-Cell Analysis/methods
• Exome Sequencing

• DP5 OD028144 NIH HHS
• P50 CA174523 NCI NIH HHS
• P50 CA261608 NCI NIH HHS
• R01 GM149671 NIGMS NIH HHS

• Cancer cell plasticity
• Cancer stem cells
• Drug resistance
• Epithelial-mesenchymal transition
• Targeted therapies
• Tumor heterogeneity

• Humans
• Cell Plasticity/genetics
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/pathology
• Drug Resistance, Neoplasm/genetics
• Epithelial-Mesenchymal Transition/genetics
• Signal Transduction

• SDR400175 Sidra Medicine
• SDR400105 Sidra Medicine
• Sidra Medical and Research Center

• 3D spheroid
• Cancer drug resistance
• Fluorescent ubiquitination-based cell cycle indicator (FUCCI)
• Invasion
• Mathematical modeling
• Migration
• Real-time imaging
• Tumor heterogeneity
• Tumor microenvironment

• Humans
• Melanoma/pathology
• Cell Cycle
• Cell Division
• Diagnostic Imaging
• Cell Culture Techniques, Three Dimensional
• Spheroids, Cellular/metabolism

• Acquired drug resistance
• Adaptive cancer drug resistance
• Cancer persisters
• Cellular reprogramming
• Epigenetics
• H3K4me3
• Metabolism
• OGT
• TET1

• Humans
• Histones/genetics
• AMP-Activated Protein Kinases
• Down-Regulation
• Mixed Function Oxygenases
• Proto-Oncogene Proteins

• I01 BX001228 BLRD VA
• P01 CA114046 NCI NIH HHS
• P30 CA010815 NCI NIH HHS
• R01 CA197919 NCI NIH HHS

• Bulk RNA sequencing
• Drug tolerant persister
• Epidermal growth factor receptor
• Non-small cell lung cancer
• Single-cell RNA sequencing
• Tyrosine kinase inhibitor

• SOCS1
• chemotherapy resistance
• cisplatin
• drug-tolerant persister cells
• intrinsic resistance
• lung adenocarcinoma
• lung cancer
• non-small cell lung carcinoma

• acquired drug resistance
• drug‐tolerant cells
• phenotype plasticity
• translational remodeling

• West China Hospital, Sichuan University
• Sichuan Province Science and Technology Support Program
• National Natural Science Foundation of China

• Humans
• Neoplasm Recurrence, Local
• Melanoma/drug therapy
• Melanoma/genetics
• Melanoma/pathology
• Immunotherapy
• Macrophages/metabolism
• Proto-Oncogene Proteins B-raf
• Drug Resistance, Neoplasm/genetics
• Protein Kinase Inhibitors/pharmacology
• Cell Line, Tumor
• Tumor Microenvironment

• R01 AR075755 NIAMS NIH HHS
• T32 OD011000 NIH HHS

• cancer
• characteristics
• drug tolerance
• molecular mechanisms
• therapeutic strategies

• Natural Science Foundation of Hainan Province
• Hainan Provincial Department of Science and Technology

• Regulated Cell Death
• Cell Death/genetics
• Neoplasms/genetics

• R35 CA231620 NCI NIH HHS
• T32 CA272387 NCI NIH HHS

Cutaneous melanoma is a lethal form of skin cancer with morbidity and mortality rates highest amongst European, North American and Australasian populations. The developments of targeted therapies (TTs) directed at the oncogene BRAF and its downstream mediator MEK, and immune checkpoint inhibitors (ICI), have revolutionized the treatment of metastatic melanoma, improving patient outcomes. However, both TT and ICI have their limitations. Although TTs are associated with high initial response rates, these are typically short‐lived due to resistance. Conversely, although ICIs provide more durable responses, they have lower initial response rates. Due to these distinct yet complementary response profiles, it has been proposed that sequencing ICI with TT could lead to a high frequency of durable responses whilst circumventing the toxicity associated with combined ICI + TT treatment. However, several questions remain unanswered, including the mechanisms underpinning this synergy and the optimal sequencing strategy. The key to determining this is to uncover the biology of each phase of the therapeutic response.

In this review, we show that melanoma responds to TT and ICI in three phases: early response, minimal residual disease (MRD) and disease progression. We explore the effects of ICI and TT on melanoma cells and the tumour immune microenvironment, with a particular focus on MRD which is predicted to underpin the development of acquired resistance in the third phase of response.

In doing so, we provide a new framework which may inform novel therapeutic approaches for melanoma, including optimal sequencing strategies and agents that target MRD, thereby ultimately improving clinical outcomes for patients.

• acquired resistance
• braf/mek inhibitors
• combination treatment
• cross‐resistance
• immune checkpoint inhibitors
• intrinsic resistance
• melanoma
• minimal residual disease

• cancer therapy
• tumour heterogeneity

• Humans
• Antineoplastic Agents/therapeutic use
• Neoplasms/drug therapy
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use

• Wellcome Trust
• 14867 Cancer Research UK
• Biotechnology and Biological Sciences Research Council

Melanoma, one of the most aggressive malignancies, its high mortality and low survival rates are associated with effective metastatic colonization. Melanoma metastasis hinges on the bidirectional cell-cell communication within the complex metastatic microenvironments (MME). Extracellular vesicles (EVs) are recognized as a new class of molecular mediator in MME programing. Published studies show that melanoma EVs can educate MME stromal cells to acquire the pro-metastatic phenotype to enhance metastatic colonization. Whether EVs can mediate the interactions between heterogenous cancer cells within the MME that alter the course of metastasis has not been investigated at the mechanistic level. In this study, melanoma parental cells (MPCs) and paired derivative cancer stem cell line melanoma stem cells (MSCs) that were derived from melanoma cell line M14 were used. We demonstrate that the EVs-mediated crosstalk between the MSCs and the MPCs is a novel mechanism for melanoma metastasis. We characterized miR-592, a relatively novel microRNA of prognostic potential, in mediation of such intercellular crosstalk. EVs can encapsulate and deliver miR-592 to target MPCs. Upon entering, miR-592 inhibits the expression of its gene target protein tyrosine phosphatase non-receptor type7 (PTPN7), a phosphatase targeting MAPKs. This leads to the relief of the inhibitory effect of PTPN7 on MAPK/ERK signaling and consequently the augmentation of metastatic colonization of MPCs. Thus, via the extracellular vesicle miR-592/PTPN7/MAPK axis, melanoma-CSCs can transfer their metastatic ability to the low-metastatic non-CSC melanoma cells.

• acetaldehyde
• alcohol
• alcohol dehydrogenase
• aldehyde dehydrogenase
• ethanol
• ethanol metabolism
• melanoma
• ultraviolet radiation

• I01 BX001228 BLRD VA
• R01 AI156534 NIAID NIH HHS
• R01 CA197919 NCI NIH HHS
• R21 AA028904 NIAAA NIH HHS

• Drug resistance
• Epigenetics
• Immunotherapy
• Melanoma

Metastatic melanoma has a high mortality rate and poor survival. This is associated with efficient metastatic colonization, but the underlying mechanisms remain elusive. Communication between cancer stem cells (CSCs) and cancer cells plays an important role in metastatic dissemination. Whether cancer stem cells can alter the metastatic properties of non-CSC cells; and whether exosomal crosstalk can mediate such interaction, have not been demonstrated in melanoma prior to this report.

The results revealed that exosomes secreted by highly metastatic melanoma CSCs (OL-SCs) promoted the invasiveness of the low metastatic melanoma cells (OL) and accelerated metastatic progression. miR-1268a was up-regulated in cells and exosomes of OL-SCs. Moreover, OL-SCs-derived exosomal miR-1268a, upon taking up by OL cells, promoted the metastatic colonization ability of OL cells in vitro and in vivo. In addition, the pro-metastatic activity of exosomal miR-1268a is achieved through inhibition of autophagy.

Our study demonstrates that OL cells can acquire the “metastatic ability” from OL-SCs cells. OL-SCs cells achieves this goal by utilizing its exosomes to deliver functional miRNAs, such as miR-1268a, to the targeted OL cells which in turn augments metastatic colonization by inactivating the autophagy pathway in OL cells.

The online version contains supplementary material available at 10.1186/s40659-022-00397-z.

• Autophagy
• Exosomes
• Melanoma stem cells
• Metastasis
• miR-1268a

• drug tolerant persister cells
• drug resistance
• cancers
• abcb5
• cd133
• cd271
• jarid1b
• aldh

• Aldehyde Dehydrogenase
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Humans
• Neoplasms/drug therapy
• Neoplastic Stem Cells
• Tumor Microenvironment

• R01 CA241148 NCI NIH HHS

• intertumoural heterogeneity
• intratumoural heterogeneity
• melanoma
• resistance
• tumour heterogeneity

• APP1158283 National Health and Medical Research Council

Deregulation of cellular metabolism through metabolic rewiring and translational reprogramming are considered hallmark traits of tumor development and malignant progression. The transcription factor YY1 is a master regulator of metabolism that we have previously shown to orchestrate a metabolic program required for melanoma formation. In this study, we demonstrate that YY1, while being essential for primary melanoma formation, suppresses metastatic spreading. Its downregulation or loss resulted in the induction of an invasiveness gene program and sensitized melanoma cells for pro-invasive signaling molecules, such as TGF-β. In addition, NGFR, a key effector in melanoma invasion and phenotype switching, was among the most upregulated genes after YY1 knockdown. High levels of NGFR were also associated with other metabolic stress inducers, further indicating that YY1 knockdown mimics a metabolic stress program associated with an increased invasion potential in melanoma. Accordingly, while counteracting tumor growth, loss of YY1 strongly promoted melanoma cell invasiveness in vitro and metastasis formation in melanoma mouse models in vivo. Thus, our findings show that the metabolic regulator YY1 controls phenotype switching in melanoma.

Patients with lung cancer benefit from more effective treatments, such as targeted therapies, and the overall survival has increased in the past decade. However, the efficacy of targeted therapies is limited due to the emergence of resistance. Growing evidence suggests that resistances may arise from a small population of drug-tolerant persister (DTP) cells. Understanding the mechanisms underlying DTP survival is therefore crucial to develop therapeutic strategies to prevent the development of resistance. Herein, we propose an overview of the current scientific knowledge about the characterisation of DTP, and summarise the new therapeutic strategies that are tested to target these cells.

Lung cancer is the leading cause of cancer-related deaths among men and women worldwide. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective therapies for advanced non-small-cell lung cancer (NSCLC) patients harbouring EGFR-activating mutations, but are not curative due to the inevitable emergence of resistances. Recent in vitro studies suggest that resistance to EGFR-TKI may arise from a small population of drug-tolerant persister cells (DTP) through non-genetic reprogramming, by entering a reversible slow-to-non-proliferative state, before developing genetically derived resistances. Deciphering the molecular mechanisms governing the dynamics of the drug-tolerant state is therefore a priority to provide sustainable therapeutic solutions for patients. An increasing number of molecular mechanisms underlying DTP survival are being described, such as chromatin and epigenetic remodelling, the reactivation of anti-apoptotic/survival pathways, metabolic reprogramming, and interactions with their micro-environment. Here, we review and discuss the existing proposed mechanisms involved in the DTP state. We describe their biological features, molecular mechanisms of tolerance, and the therapeutic strategies that are tested to target the DTP.

• EGFR-TKI
• drug-tolerant persisters
• lung cancer
• targeted therapies

Around 5–10% of advanced melanoma patients progress early on anti-BRAF targeted therapy and 20–30% respond only with the stabilization of the disease. Presumably, these patients could benefit more from first-line immunotherapy. Resistance to BRAF/MEK inhibitors is generated by genetic and non-genetic factors inherent to a tumor or acquired during therapy. Some of them are well documented as a cause of treatment failure. They are potential predictive markers that could improve patients’ selection for both standard and also alternative therapy as some of them have therapeutic potential. Here, a summary of the most promising predictive and therapeutic targets is presented. This up-to-date knowledge may be useful for further study on implementing more accurate genetic/molecular tests in melanoma treatment.

Melanoma is the most aggressive skin cancer, the number of which is increasing worldwide every year. It is completely curable in its early stage and fatal when spread to distant organs. In addition to new therapeutic strategies, biomarkers are an important element in the successful fight against this cancer. At present, biomarkers are mainly used in diagnostics. Some biological indicators also allow the estimation of the patient’s prognosis. Still, predictive markers are underrepresented in clinics. Currently, the only such indicator is the presence of the V600E mutation in the BRAF gene in cancer cells, which qualifies the patient for therapy with inhibitors of the MAPK pathway. The identification of response markers is particularly important given primary and acquired resistance to targeted therapies. Reliable predictive tests would enable the selection of patients who would have the best chance of benefiting from treatment. Here, up-to-date knowledge about the most promising genetic and non-genetic resistance-related factors is described. These are alterations in MAPK, PI3K/AKT, and RB signaling pathways, e.g., due to mutations in NRAS, RAC1, MAP2K1, MAP2K2, and NF1, but also other changes activating these pathways, such as the overexpression of HGF or EGFR. Most of them are also potential therapeutic targets and this issue is also addressed here.

• DNA barcoding
• cellular plasticity
• clonal dynamics
• clonal evolution
• drug resistance
• functionalized lineage tracing
• homogenization
• tumor heterogeneity

• Antineoplastic Agents/therapeutic use
• Clone Cells
• Humans
• Neoplasms/pathology

The mean survival of metastatic melanoma is less than 1 year. While the high mortality rate is associated with the efficient metastatic colonization of the involved organs, the underlying mechanisms remain elusive. The role of exosomes in facilitating the interactions between cancer cells and the metastatic microenvironment has received increasing attention. Previous studies on the role of exosomes in metastasis have been heavily focused on cancer cell-derived exosomes in modulating the functions of stromal cells. Whether the extravasated neighboring cancer cells at the distant organ can alter the metastatic properties of one another, a new mechanism of metastatic colonization, has not been demonstrated prior to this report. In this study, a paired M4 melanoma derivative cell lines, i.e., M14-OL and POL, that we established and characterized were employed. They exhibit high (POL cells) and low (OL cells) metastatic colonization efficiency in vivo, respectively. We show that exosomal crosstalk between metastatic cancer cells is a new mechanism that underlies cancer metastasis and heterogeneity. Low metastatic melanoma cells (OL) can acquire the “metastatic power” from highly metastatic melanoma cells (POL). POL achieves this goal by utilizing its exosomes to deliver functional miRNAs, such as miR-199a-1-5p, to the targeted OL cell which in turn inactivates cell cycle inhibitor CDKN1B and augments metastatic colonization.

• DNA methylation
• breast cancer
• drug resistance
• epigenetics

• DNA Methylation
• Doxorubicin/pharmacology
• Epigenesis, Genetic
• Fluorescence

• P30 CA023168 NCI NIH HHS

Malignant melanoma has shown an increasing incidence during the last two decades, exhibiting a large spectrum of locations and clinicopathological characteristics. Although current histopathological, biochemical, immunohistochemical, and molecular methods provide a deep insight into its biological behaviour and outcome, melanoma is still an unpredictable disease, with poor outcome. This review of the literature is aimed at updating the knowledge regarding melanoma’s clinicopathological and molecular hallmarks, including its heterogeneity and plasticity, involving cancer stem cells population. A special focus is given on the interplay between different cellular components and their secretion products in melanoma, considering its contribution to tumour progression, invasion, metastasis, recurrences, and resistance to classical therapy. Furthermore, the influences of the specific tumour microenvironment or “inflammasome”, its association with adipose tissue products, including the release of “extracellular vesicles”, and distinct microbiota are currently studied, considering their influences on diagnosis and prognosis. An insight into melanoma’s particular features may reveal new molecular pathways which may be exploited in order to develop innovative therapeutic approaches or tailored therapy.

• Humans
• Melanoma
• Microbiota
• Prognosis
• Skin Neoplasms/pathology
• Tumor Microenvironment

• acetylation
• adjuvant
• combination therapy
• epigenetics
• immunotherapy
• melanoma
• methylation
• resistance
• targeted therapy

Liver cancer is the sixth most commonly occurring cancer and costs millions of lives per year. The diagnosis of hepatocellular carcinoma (HCC) has relied on scanning techniques and serum-based markers such as α-fetoprotein. These measures have limitations due to their detection limits and asymptomatic conditions during the early stages, resulting in late-stage cancer diagnosis where targeted chemotherapy or systemic treatment with sorafenib is offered. However, the aid of conventional therapy for patients in the advanced stage of HCC has limited outcomes. Thus, it is essential to seek a new treatment strategy and improve the diagnostic techniques to manage the disease. Researchers have used the omics profile of HCC patients for sub-classification of tissues into different groups, which has helped us with prognosis. Despite these efforts, a promising target for treatment has not been identified. The hurdle in this situation is genetic and epigenetic variations in the tumor, leading to disparities in response to treatment. Understanding reversible epigenetic changes along with clinical traits help to define new markers for patient categorization and design personalized therapy. Many clinical trials of inhibitors of epigenetic modifiers (also known as epi-drugs) are in progress. Epi-drugs like azacytidine or belinostat are already approved for other cancer treatments. Furthermore, epigenetic changes have also been observed in drug-resistant HCC tumors. In such cases, combinatorial treatment of epi-drugs with systemic therapy or trans-arterial chemoembolization might re-sensitize resistant cells.

• Hepatocellular carcinoma
• Diagnosis
• Treatment
• Epigenetics
• Epi-drugs
• Drug resistance