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1. DRMref: comprehensive reference map of drug resistance mechanisms in human cancer

   https://doi.org/10.1093/nar/gkad1087  

   Liu, Xiaona; Yi, Jiahao; Li, Tina; Wen, Jianguo; Huang, Kexin; Liu, Jiajia; Wang, Grant; Kim, Pora; Song, Qianqian; Zhou, Xiaobo (November 2023, Nucleic Acids Research)

   Abstract Drug resistance poses a significant challenge in cancer treatment. Despite the initial effectiveness of therapies such as chemotherapy, targeted therapy and immunotherapy, many patients eventually develop resistance. To gain deep insights into the underlying mechanisms, single-cell profiling has been performed to interrogate drug resistance at cell level. Herein, we have built the DRMref database (https://ccsm.uth.edu/DRMref/) to provide comprehensive characterization of drug resistance using single-cell data from drug treatment settings. The current version of DRMref includes 42 single-cell datasets from 30 studies, covering 382 samples, 13 major cancer types, 26 cancer subtypes, 35 treatment regimens and 42 drugs. All datasets in DRMref are browsable and searchable, with detailed annotations provided. Meanwhile, DRMref includes analyses of cellular composition, intratumoral heterogeneity, epithelial–mesenchymal transition, cell–cell interaction and differentially expressed genes in resistant cells. Notably, DRMref investigates the drug resistance mechanisms (e.g. Aberration of Drug’s Therapeutic Target, Drug Inactivation by Structure Modification, etc.) in resistant cells. Additional enrichment analysis of hallmark/KEGG (Kyoto Encyclopedia of Genes and Genomes)/GO (Gene Ontology) pathways, as well as the identification of microRNA, motif and transcription factors involved in resistant cells, is provided in DRMref for user’s exploration. Overall, DRMref serves as a unique single-cell-based resource for studying drug resistance, drug combination therapy and discovering novel drug targets. 

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2. Targeting the Interplay between Epithelial-to-Mesenchymal-Transition and the Immune System for Effective Immunotherapy

   https://doi.org/10.3390/cancers11050714  

   Soundararajan, Rama; Fradette, Jared; Konen, Jessica; Moulder, Stacy; Zhang, Xiang; Gibbons, Don; Varadarajan, Navin; Wistuba, Ignacio; Tripathy, Debasish; Bernatchez, Chantale; et al (May 2019, Cancers)

   Over the last decade, both early diagnosis and targeted therapy have improved the survival rates of many cancer patients. Most recently, immunotherapy has revolutionized the treatment options for cancers such as melanoma. Unfortunately, a significant portion of cancers (including lung and breast cancers) do not respond to immunotherapy, and many of them develop resistance to chemotherapy. Molecular characterization of non-responsive cancers suggest that an embryonic program known as epithelial-mesenchymal transition (EMT), which is mostly latent in adults, can be activated under selective pressures, rendering these cancers resistant to chemo- and immunotherapies. EMT can also drive tumor metastases, which in turn also suppress the cancer-fighting activity of cytotoxic T cells that traffic into the tumor, causing immunotherapy to fail. In this review, we compare and contrast immunotherapy treatment options of non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We discuss why, despite breakthrough progress in immunotherapy, attaining predictable outcomes in the clinic is mostly an unsolved problem for these tumors. Although these two cancer types appear different based upon their tissues of origin and molecular classification, gene expression indicate that they possess many similarities. Patient tumors exhibit activation of EMT, and resulting stem cell properties in both these cancer types associate with metastasis and resistance to existing cancer therapies. In addition, the EMT transition in both these cancers plays a crucial role in immunosuppression, which exacerbates treatment resistance. To improve cancer-related survival we need to understand and circumvent, the mechanisms through which these tumors become therapy resistant. In this review, we discuss new information and complementary perspectives to inform combination treatment strategies to expand and improve the anti-tumor responses of currently available clinical immune checkpoint inhibitors. 

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3. Three‐dimensional culture models to study drug resistance in breast cancer

   https://doi.org/10.1002/bit.27356  

   Fisher, Madeline F.; Rao, Shreyas S. (April 2020, Biotechnology and Bioengineering)

   Abstract Despite recent advances in breast cancer treatment, drug resistance frequently presents as a challenge, contributing to a higher risk of relapse and decreased overall survival rate. It is now generally recognized that the extracellular matrix and cellular heterogeneity of the tumor microenvironment influences the cancer cells' ultimate fate. Therefore, strategies employed to examine mechanisms of drug resistance must take microenvironmental influences, as well as genetic mutations, into account. This review discusses three‐dimensional (3D) in vitro model systems which incorporate microenvironmental influences to study mechanisms of drug resistance in breast cancer. These bioengineered models include spheroid‐based models, biomaterial‐based models such as polymeric scaffolds and hydrogels, and microfluidic chip‐based models. The advantages of these model systems over traditionally studied two‐dimensional tissue culture polystyrene are examined. Additionally, the applicability of such 3D models for studying the impact of tumor microenvironment signals on drug response and/or resistance is discussed. Finally, the potential of such models for use in the development of strategies to combat drug resistance and determine the most promising treatment regimen is explored. 

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4. Advances in Natural-Product-Based Fluorescent Agents and Synthetic Analogues for Analytical and Biomedical Applications

   https://doi.org/10.3390/bioengineering11121292  

   Joshi, Soniya; Moody, Alexis; Budthapa, Padamlal; Gurung, Anita; Gautam, Rachana; Sanjel, Prabha; Gupta, Aakash; Aryal, Surya P; Parajuli, Niranjan; Bhattarai, Narayan (December 2024, Bioengineering)

   Fluorescence is a remarkable property exhibited by many chemical compounds and biomolecules. Fluorescence has revolutionized analytical and biomedical sciences due to its wide-ranging applications in analytical and diagnostic tools of biological and environmental importance. Fluorescent molecules are frequently employed in drug delivery, optical sensing, cellular imaging, and biomarker discovery. Cancer is a global challenge and fluorescence agents can function as diagnostic as well as monitoring tools, both during early tumor progression and treatment monitoring. Many fluorescent compounds can be found in their natural form, but recent developments in synthetic chemistry and molecular biology have allowed us to synthesize and tune fluorescent molecules that would not otherwise exist in nature. Naturally derived fluorescent compounds are generally more biocompatible and environmentally friendly. They can also be modified in cost-effective and target-specific ways with the help of synthetic tools. Understanding their unique chemical structures and photophysical properties is key to harnessing their full potential in biomedical and analytical research. As drug discovery efforts require the rigorous characterization of pharmacokinetics and pharmacodynamics, fluorescence-based detection accelerates the understanding of drug interactions via in vitro and in vivo assays. Herein, we provide a review of natural products and synthetic analogs that exhibit fluorescence properties and can be used as probes, detailing their photophysical properties. We have also provided some insights into the relationships between chemical structures and fluorescent properties. Finally, we have discussed the applications of fluorescent compounds in biomedical science, mainly in the study of tumor and cancer cells and analytical research, highlighting their pivotal role in advancing drug delivery, biomarkers, cell imaging, biosensing technologies, and as targeting ligands in the diagnosis of tumors. 

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5. Three-dimensional models of breast cancer–fibroblasts interactions

   https://doi.org/10.1177/1535370220917366  

   Singh, Sunil; Tran, Sydnie; Putman, Justin; Tavana, Hossein (May 2020, Experimental Biology and Medicine)

   Tumor microenvironment is a complex niche consisting of cancer cells and stromal cells in a network of extracellular matrix proteins and various soluble factors. Dynamic interactions among cellular and non-cellular components of the tumor microenvironment regulate tumor initiation and progression. Fibroblasts are the most abundant stromal cell type and dynamically interact with cancer cells both in primary tumors and in metastases. Cancer cells activate resident fibroblasts to produce and secrete soluble signaling molecules that support proliferation, migration, matrix invasion, and drug resistance of cancer cell and tumor angiogenesis. In recent years, various forms of three-dimensional tumor models have been developed to study tumor–stromal interactions and to identify anti-cancer drugs that block these interactions. There is currently a technological gap in development of tumor models that are physiologically relevant, scalable, and allow convenient, on-demand addition of desired components of the tumor microenvironment. In this review, we discuss three studies from our group that focus on developing bioengineered models to study tumor-stromal signaling. We will present these studies chronologically and based on their increasing complexity. We will discuss the validation of the models using a CXCL12-CXCR4 chemokine-receptor signaling present among activated fibroblasts and breast cancer cells in solid tumors, highlight the advantages and shortcomings of the models, and conclude with our perspectives on their applications. Impact statement Tumor stroma plays an important role in progression of cancers to a fatal metastatic disease. Modern treatment strategies are considering targeting tumor stroma to improve outcomes for cancer patients. A current challenge to develop stroma-targeting therapeutics is the lack of preclinical physiologic tumor models. Animal models widely used in cancer research lack human stroma and are not amenable to screening of chemical compounds for cancer drug discovery. In this review, we outline in vitro three-dimensional tumor models that we have developed to study the interactions among cancer cells and stromal cells. We describe development of the tumor models in a modular fashion, from a spheroid model to a sophisticated organotypic model, and discuss the importance of using correct physiologic models to recapitulate tumor-stromal signaling. These biomimetic tumor models will facilitate understanding of tumor-stromal signaling biology and provide a scalable approach for testing and discovery of cancer drugs. 

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