Cell Signaling in Cancer Microenvironment

AbdelFattah, HebatAllah Samy; Ibrahim, Mayar Tarek; Nasr, Mostafa; Amin, Shaimaa Nasr Nasr

doi:10.18576/ab/020204

Cited by 2 publications

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“…Specifically, oxygen levels have proven to be key determiners of tumor progression[217]. The composition of these signals in the TME affects critical aspects of a tumor, such as angiogenesis[104,218–220], proliferation[219], differentiation[221], drug response[220], and metastatic capacity[104,220,222]. In a tumor, soluble signal gradients can cause migration of immune cells[222], endothelial cells[219], and mesenchymal cells[223] to the tumor.…”

Section: Soluble Signaling In the ‘Cancer-organ’ Modelsmentioning

confidence: 99%

Integrated cancer tissue engineering models for precision medicine

et al. 2019

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Tumors are not merely cancerous cells that undergo mindless proliferation. Rather, they are highly organized and interconnected organ systems. Tumor cells reside in complex microenvironments in which they are subjected to a variety of physical and chemical stimuli that influence cell behavior and ultimately the progression and maintenance of the tumor. As cancer bioengineers, it is our responsibility to create physiologic models that enable accurate understanding of the multi-dimensional structure, organization, and complex relationships in diverse tumor microenvironments. Such models can greatly expedite clinical discovery and translation by closely replicating the physiological conditions while maintaining high tunability and control of extrinsic factors. In this review, we discuss the current models that target key aspects of the tumor microenvironment and their role in cancer progression. In order to address sources of experimental variation and model limitations, we also make recommendations for methods to improve overall physiologic reproducibility, experimental repeatability, and rigor within the field. Improvements can be made through an enhanced emphasis on mathematical modeling, standardized in vitro model characterization, transparent reporting of methodologies, and designing experiments with physiological metrics. Taken together these considerations will enhance the relevance of in vitro tumor models, biological understanding, and accelerate treatment exploration ultimately leading to improved clinical outcomes. Moreover, the development of robust, user-friendly models that integrate important stimuli will allow for the in-depth study of tumors as they undergo progression from non-transformed primary cells to metastatic disease and facilitate translation to a wide variety of biological and clinical studies.

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Section: Soluble Signaling In the ‘Cancer-organ’ Modelsmentioning

confidence: 99%

Integrated cancer tissue engineering models for precision medicine

et al. 2019

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“…The overexpression of YAP1/TAZ coactivators is common in several solid tumors by not only initiating the tumor growth but also maintaining the continued growth of the tumor [3]. This is attributed to the role that YAP1 activation plays in affecting the tumor microenvironment, inducing resistance to chemotherapy, and performing as an intrinsic oncogenic driver [11][12][13]. Therefore, targeting TAZ1/YAP1-TEAD interaction offers a promising cancer therapeutic approach.…”

Section: Figurementioning

confidence: 99%

Novel Allosteric Effectors Targeting Human Transcription Factor TEAD

Ibrahim

Verkhivker

Misra

et al. 2023

IJMS

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The Hippo pathway is an evolutionary conserved signaling network involved in several cellular regulatory processes. Dephosphorylation and overexpression of Yes-associated proteins (YAPs) in the Hippo-off state are common in several types of solid tumors. YAP overexpression results in its nuclear translocation and interaction with transcriptional enhanced associate domain 1-4 (TEAD1-4) transcription factors. Covalent and non-covalent inhibitors have been developed to target several interaction sites between TEAD and YAP. The most targeted and effective site for these developed inhibitors is the palmitate-binding pocket in the TEAD1-4 proteins. Screening of a DNA-encoded library against the TEAD central pocket was performed experimentally to identify six new allosteric inhibitors. Inspired by the structure of the TED-347 inhibitor, chemical modification was performed on the original inhibitors by replacing secondary methyl amide with a chloromethyl ketone moiety. Various computational tools, including molecular dynamics, free energy perturbation, and Markov state model analysis, were employed to study the effect of ligand binding on the protein conformational space. Four of the six modified ligands were associated with enhanced allosteric communication between the TEAD4 and YAP1 domains indicated by the relative free energy perturbation to original molecules. Phe229, Thr332, Ile374, and Ile395 residues were revealed to be essential for the effective binding of the inhibitors.

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Cell Signaling in Cancer Microenvironment

Cited by 2 publications

References 0 publications

Integrated cancer tissue engineering models for precision medicine

Integrated cancer tissue engineering models for precision medicine

Novel Allosteric Effectors Targeting Human Transcription Factor TEAD

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