Cancer drug resistance induced by EMT: novel therapeutic strategies

AbstractOver the last decade, important clinical benefits have been achieved in cancer patients by using drug-targeting strategies. Nevertheless, drug resistance is still a major problem in most cancer therapies. Epithelial-mesenchymal plasticity (EMP) and tumour microenvironment have been described as limiting factors for effective treatment in many cancer types. Moreover, epithelial-to-mesenchymal transition (EMT) has also been associated with therapy resistance in many different preclinical models, although limited evidence has been obtained from clinical studies and clinical samples. In this review, we particularly deepen into the mechanisms of which intermediate epithelial/mesenchymal (E/M) states and its interconnection to microenvironment influence therapy resistance. We also describe how the use of bioinformatics and pharmacogenomics will help to figure out the biological impact of the EMT on drug resistance and to develop novel pharmacological approaches in the future.

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Cancer drug pan-resistance: pumps, cancer stem cells, quiescence, epithelial to mesenchymal transition, blocked cell death pathways, persisters or what?

Open Biology ◽

10.1098/rsob.120066 ◽

2012 ◽

Vol 2 (5) ◽

pp. 120066 ◽

Cited By ~ 105

Author(s):

Piet Borst

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Epithelial To Mesenchymal Transition ◽

Residual Disease ◽

Cancer Drug ◽

Multi Drug Resistance ◽

Mesenchymal Transition ◽

Cell Death Pathways ◽

P Glycoprotein ◽

Mouse Tumour

Although chemotherapy of tumours has scored successes, drug resistance remains the major cause of death of cancer patients. Initial treatment often leaves residual disease, from which the tumour regrows. Eventually, most tumours become resistant to all available chemotherapy. I call this pan-resistance to distinguish it from multi-drug resistance, usually describing resistance caused by upregulation of drug transporters, such as P-glycoprotein. In this review, I discuss mechanisms proposed to explain both residual disease and pan-resistance. Although plausible explanations are at hand for residual disease, pan-resistance is still a mystery. My conclusion is that it is time for a major effort to solve this mystery using the new genetically modified mouse tumour models that produce real tumours resembling cancer in human patients.

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Non-coding RNAs as Novel Biomarkers in Cancer Drug Resistance

Current Medicinal Chemistry ◽

10.2174/0929867328666210804090644 ◽

2021 ◽

Vol 28 ◽

Author(s):

Haixiu Yang ◽

Changlu Qi ◽

Boyan Li ◽

Liang Cheng

Keyword(s):

Drug Resistance ◽

Computational Methods ◽

Cell Cycle Progression ◽

Epithelial To Mesenchymal Transition ◽

Cancer Drug ◽

Mesenchymal Transition ◽

Treatment Regimens ◽

Anticancer Treatment ◽

Non Coding Rnas ◽

Low Efficiency

: Chemotherapy is often the primary and most effective anticancer treatment; however, drug resistance remains a major obstacle to it being curative. Recent studies have demonstrated that non-coding RNAs (ncRNAs), especially microRNAs and long non-coding RNAs, are involved in drug resistance of tumor cells in many ways, such as modulation of apoptosis, drug efflux and metabolism, epithelial-to-mesenchymal transition, DNA repair, and cell cycle progression. Exploring the relationships between ncRNAs and drug resistance will not only contribute to our understanding of the mechanisms of drug resistance and provide ncRNA biomarkers of chemoresistance, but will also help realize personalized anticancer treatment regimens. Due to the high cost and low efficiency of biological experimentation, many researchers have opted to use computational methods to identify ncRNA biomarkers associated with drug resistance. In this review, we summarize recent discoveries related to ncRNA-mediated drug resistance and highlight the computational methods and resources available for ncRNA biomarkers involved in chemoresistance.

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Contribution of Epithelial Plasticity to Therapy Resistance

Journal of Clinical Medicine ◽

10.3390/jcm8050676 ◽

2019 ◽

Vol 8 (5) ◽

pp. 676 ◽

Cited By ~ 23

Author(s):

Patricia G. Santamaría ◽

Gema Moreno-Bueno ◽

Amparo Cano

Keyword(s):

Epithelial To Mesenchymal Transition ◽

Immune Therapy ◽

Fatal Outcome ◽

Treatment Resistance ◽

Therapy Resistance ◽

Clinical Samples ◽

Tumour Heterogeneity ◽

Mesenchymal Transition ◽

Epithelial Plasticity ◽

Potential Link

Therapy resistance is responsible for tumour recurrence and represents one of the major challenges in present oncology. Significant advances have been made in the understanding of the mechanisms underlying resistance to conventional and targeted therapies improving the clinical management of relapsed patients. Unfortunately, in too many cases, resistance reappears leading to a fatal outcome. The recent introduction of immunotherapy regimes has provided an unprecedented success in the treatment of specific cancer types; however, a good percentage of patients do not respond to immune-based treatments or ultimately become resistant. Cellular plasticity, cancer cell stemness and tumour heterogeneity have emerged as important determinants of treatment resistance. Epithelial-to-mesenchymal transition (EMT) is associated with resistance in many different cellular and preclinical models, although little evidence derives directly from clinical samples. The recognition of the presence in tumours of intermediate hybrid epithelial/mesenchymal states as the most likely manifestation of epithelial plasticity and their potential link to stemness and tumour heterogeneity, provide new clues to understanding resistance and could be exploited in the search for anti-resistance strategies. Here, recent evidence linking EMT/epithelial plasticity to resistance against conventional, targeted and immune therapy are summarized. In addition, future perspectives for related clinical approaches are also discussed.

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Cooperation and Interplay between EGFR Signalling and Extracellular Vesicle Biogenesis in Cancer

Cells ◽

10.3390/cells9122639 ◽

2020 ◽

Vol 9 (12) ◽

pp. 2639

Author(s):

Laura C. Zanetti-Domingues ◽

Scott E. Bonner ◽

R. Sumanth Iyer ◽

Marisa L. Martin-Fernandez ◽

Veronica Huber

Keyword(s):

Epithelial To Mesenchymal Transition ◽

Growth Factor Receptor ◽

Tumour Microenvironment ◽

Extracellular Vesicle ◽

Parental Cancer ◽

Cancer Therapies ◽

Mesenchymal Transition ◽

Vesicle Biogenesis ◽

Functional Consequences ◽

Transfer Of Information

Epidermal growth factor receptor (EGFR) takes centre stage in carcinogenesis throughout its entire cellular trafficking odyssey. When loaded in extracellular vesicles (EVs), EGFR is one of the key proteins involved in the transfer of information between parental cancer and bystander cells in the tumour microenvironment. To hijack EVs, EGFR needs to play multiple signalling roles in the life cycle of EVs. The receptor is involved in the biogenesis of specific EV subpopulations, it signals as an active cargo, and it can influence the uptake of EVs by recipient cells. EGFR regulates its own inclusion in EVs through feedback loops during disease progression and in response to challenges such as hypoxia, epithelial-to-mesenchymal transition and drugs. Here, we highlight how the spatiotemporal rules that regulate EGFR intracellular function intersect with and influence different EV biogenesis pathways and discuss key regulatory features and interactions of this interplay. We also elaborate on outstanding questions relating to EGFR-driven EV biogenesis and available methods to explore them. This mechanistic understanding will be key to unravelling the functional consequences of direct anti-EGFR targeted and indirect EGFR-impacting cancer therapies on the secretion of pro-tumoural EVs and on their effects on drug resistance and microenvironment subversion.

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Active RAC1 Promotes Tumorigenic Phenotypes and Therapy Resistance in Solid Tumors

Cancers ◽

10.3390/cancers12061541 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1541

Author(s):

Pradip De ◽

Brett James Rozeboom ◽

Jennifer Carlson Aske ◽

Nandini Dey

Keyword(s):

Botulinum Toxin ◽

Solid Tumors ◽

Epithelial To Mesenchymal Transition ◽

Critical Role ◽

Copy Number Gain ◽

Therapy Resistance ◽

Cancer Therapies ◽

Mesenchymal Transition ◽

Therapeutic Modalities ◽

Development Of Resistance

Acting as molecular switches, all three members of the Guanosine triphosphate (GTP)-ase-family, Ras-related C3 botulinum toxin substrate (RAC), Rho, and Cdc42 contribute to various processes of oncogenic transformations in several solid tumors. We have reviewed the distribution of patterns regarding the frequency of Ras-related C3 botulinum toxin substrate 1 (RAC1)-alteration(s) and their modes of actions in various cancers. The RAC1 hyperactivation/copy-number gain is one of the frequently observed features in various solid tumors. We argued that RAC1 plays a critical role in the progression of tumors and the development of resistance to various therapeutic modalities applied in the clinic. With this perspective, here we interrogated multiple functions of RAC1 in solid tumors pertaining to the progression of tumors and the development of resistance with a special emphasis on different tumor cell phenotypes, including the inhibition of apoptosis and increase in the proliferation, epithelial-to-mesenchymal transition (EMT), stemness, pro-angiogenic, and metastatic phenotypes. Our review focuses on the role of RAC1 in adult solid-tumors and summarizes the contextual mechanisms of RAC1 involvement in the development of resistance to cancer therapies.

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SOX2 in cancer stemness: tumor malignancy and therapeutic potentials

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjy080 ◽

2018 ◽

Vol 12 (2) ◽

pp. 85-98 ◽

Cited By ~ 8

Author(s):

Mahfuz Al Mamun ◽

Kaiissar Mannoor ◽

Jun Cao ◽

Firdausi Qadri ◽

Xiaoyuan Song

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Epithelial To Mesenchymal Transition ◽

Immune Surveillance ◽

Resistance Mechanisms ◽

Clinical Relapse ◽

Cancer Therapies ◽

Cancer Stemness ◽

Mesenchymal Transition ◽

Anti Cancer

Abstract Cancer stem cells (CSCs), a minor subpopulation of tumor bulks with self-renewal and seeding capacity to generate new tumors, posit a significant challenge to develop effective and long-lasting anti-cancer therapies. The emergence of drug resistance appears upon failure of chemo-/radiation therapy to eradicate the CSCs, thereby leading to CSC-mediated clinical relapse. Accumulating evidence suggests that transcription factor SOX2, a master regulator of embryonic and induced pluripotent stem cells, drives cancer stemness, fuels tumor initiation, and contributes to tumor aggressiveness through major drug resistance mechanisms like epithelial-to-mesenchymal transition, ATP-binding cassette drug transporters, anti-apoptotic and/or pro-survival signaling, lineage plasticity, and evasion of immune surveillance. Gaining a better insight and comprehensive interrogation into the mechanistic basis of SOX2-mediated generation of CSCs and treatment failure might therefore lead to new therapeutic targets involving CSC-specific anti-cancer strategies.

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Galectin-3: A factotum in carcinogenesis bestowing an archery for prevention

Tumor Biology ◽

10.3233/tub-200051 ◽

2021 ◽

Vol 43 (1) ◽

pp. 77-96

Author(s):

T. Jeethy Ram ◽

Asha Lekshmi ◽

Thara Somanathan ◽

K. Sujathan

Keyword(s):

Cancer Progression ◽

Molecular Mechanisms ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Therapy Resistance ◽

Cellular Level ◽

Clinical Samples ◽

Innovative Strategy ◽

Mesenchymal Transition ◽

Galectin 3

Cancer metastasis and therapy resistance are the foremost hurdles in oncology at the moment. This review aims to pinpoint the functional aspects of a unique multifaceted glycosylated molecule in both intracellular and extracellular compartments of a cell namely galectin-3 along with its metastatic potential in different types of cancer. All materials reviewed here were collected through the search engines PubMed, Scopus, and Google scholar. Among the 15 galectins identified, the chimeric gal-3 plays an indispensable role in the differentiation, transformation, and multi-step process of tumor metastasis. It has been implicated in the molecular mechanisms that allow the cancer cells to survive in the intravascular milieu and promote tumor cell extravasation, ultimately leading to metastasis. Gal-3 has also been found to have a pivotal role in immune surveillance and pro-angiogenesis and several studies have pointed out the importance of gal-3 in establishing a resistant phenotype, particularly through the epithelial-mesenchymal transition process. Additionally, some recent findings suggest the use of gal-3 inhibitors in overcoming therapeutic resistance. All these reports suggest that the deregulation of these specific lectins at the cellular level could inhibit cancer progression and metastasis. A more systematic study of glycosylation in clinical samples along with the development of selective gal-3 antagonists inhibiting the activity of these molecules at the cellular level offers an innovative strategy for primary cancer prevention.

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The Role of Autophagy and lncRNAs in the Maintenance of Cancer Stem Cells

Cancers ◽

10.3390/cancers13061239 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1239

Author(s):

Leila Jahangiri ◽

Tala Ishola ◽

Perla Pucci ◽

Ricky M. Trigg ◽

Joao Pereira ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Progression ◽

Regulatory Networks ◽

Epithelial To Mesenchymal Transition ◽

Tumour Microenvironment ◽

Repair Capacity ◽

Mesenchymal Transition ◽

Cellular Processes

Cancer stem cells (CSCs) possess properties such as self-renewal, resistance to apoptotic cues, quiescence, and DNA-damage repair capacity. Moreover, CSCs strongly influence the tumour microenvironment (TME) and may account for cancer progression, recurrence, and relapse. CSCs represent a distinct subpopulation in tumours and the detection, characterisation, and understanding of the regulatory landscape and cellular processes that govern their maintenance may pave the way to improving prognosis, selective targeted therapy, and therapy outcomes. In this review, we have discussed the characteristics of CSCs identified in various cancer types and the role of autophagy and long noncoding RNAs (lncRNAs) in maintaining the homeostasis of CSCs. Further, we have discussed methods to detect CSCs and strategies for treatment and relapse, taking into account the requirement to inhibit CSC growth and survival within the complex backdrop of cellular processes, microenvironmental interactions, and regulatory networks associated with cancer. Finally, we critique the computationally reinforced triangle of factors inclusive of CSC properties, the process of autophagy, and lncRNA and their associated networks with respect to hypoxia, epithelial-to-mesenchymal transition (EMT), and signalling pathways.

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Deeper Insight in Metastatic Cancer progression;Epithelial-to-Mesenchymal Transition and Genomic Instability: implications on treatment resistance

Current Molecular Medicine ◽

10.2174/1566524021666210202114844 ◽

2021 ◽

Vol 21 ◽

Author(s):

Kenneth Omabe ◽

Sandra Uduituma ◽

David Igwe ◽

Maxwell Omabe

Keyword(s):

Dna Damage ◽

Cancer Treatment ◽

Epithelial To Mesenchymal Transition ◽

Dna Damage Repair ◽

Treatment Resistance ◽

Therapy Resistance ◽

Cellular Reprogramming ◽

Repair System ◽

Mesenchymal Transition ◽

Damage Repair

: Therapy resistance remains the major obstacle to successful cancer treatment. Epithelial-to- mesenchymal transition [EMT], a cellular reprogramming process involved in embryogenesis and organ development and regulated by a number of transcriptional factors [EMT-TFs] such as ZEB1/2, is recognized for its role in tumor progression and metastasis. Recently, a growing body of evidence has implicated EMT in cancer therapy resistance but the actual mechanism that underlie this finding has remained elusive. For example, whether it is, the EMT states in itself or the EMT-TFs that modulates chemo or radio-resistance in cancer is still contentious. Here, we summarise the molecular mechanisms of EMT program and chemotherapeutic resistance in cancer with specific reference to DNA damage response [DDR]. We provide an insight into the molecular interplay that exist between EMT program and DNA repair machinery in cancer and how this interaction influences therapeutic response. We review conflicting studies linking EMT and drug resistance via the DNA damage repair axis. We draw scientific evidence demonstrating how several molecular signalling, including EMT-TFs work in operational harmony to induce EMT and confer stemness properties on the EMT-susceptible cells. We highlight the role of enhanced DNA damage repair system associated with EMT-derived stem cell-like states in promoting therapy resistance and suggest a multi-targeting modality in combating cancer treatment resistance.

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Stromal-derived interleukin 6 drives epithelial-to-mesenchymal transition and therapy resistance in esophageal adenocarcinoma

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1820459116 ◽

2019 ◽

Vol 116 (6) ◽

pp. 2237-2242 ◽

Cited By ~ 24

Author(s):

Eva A. Ebbing ◽

Amber P. van der Zalm ◽

Anne Steins ◽

Aafke Creemers ◽

Simone Hermsen ◽

...

Keyword(s):

Esophageal Adenocarcinoma ◽

Epithelial To Mesenchymal Transition ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Treatment Resistance ◽

Serum Levels ◽

Therapy Resistance ◽

Mesenchymal Transition ◽

Dismal Prognosis ◽

Organoid Cultures

Esophageal adenocarcinoma (EAC) has a dismal prognosis, and survival benefits of recent multimodality treatments remain small. Cancer-associated fibroblasts (CAFs) are known to contribute to poor outcome by conferring therapy resistance to various cancer types, but this has not been explored in EAC. Importantly, a targeted strategy to circumvent CAF-induced resistance has yet to be identified. By using EAC patient-derived CAFs, organoid cultures, and xenograft models we identified IL-6 as the stromal driver of therapy resistance in EAC. IL-6 activated epithelial-to-mesenchymal transition in cancer cells, which was accompanied by enhanced treatment resistance, migratory capacity, and clonogenicity. Inhibition of IL-6 restored drug sensitivity in patient-derived organoid cultures and cell lines. Analysis of patient gene expression profiles identified ADAM12 as a noninflammation-related serum-borne marker for IL-6–producing CAFs, and serum levels of this marker predicted unfavorable responses to neoadjuvant chemoradiation in EAC patients. These results demonstrate a stromal contribution to therapy resistance in EAC. This signaling can be targeted to resensitize EAC to therapy, and its activity can be measured using serum-borne markers.

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