bims-pimaco 2022-02-20 papers

Front Cell Dev Biol. 2021 ;9 806258

Role of ARHGEF3 as a GEF and mTORC2 Regulator.

Sana Abdul Khaliq, Zobia Umair, Mee-Sup Yoon.

Guanine nucleotide exchange factors (GEFs) activate GTPases by stimulating the release of guanosine diphosphate to permit the binding of guanosine triphosphate. ARHGEF3 or XPLN (exchange factor found in platelets, leukemic, and neuronal tissues) is a selective guanine nucleotide exchange factor for Rho GTPases (RhoGEFs) that activates RhoA and RhoB but not RhoC, RhoG, Rac1, or Cdc42. ARHGEF3 contains the diffuse B-cell lymphoma homology and pleckstrin homology domains but lacks similarity with other known functional domains. ARHGEF3 also binds the mammalian target of rapamycin complex 2 (mTORC2) and subsequently inhibits mTORC2 and Akt. In vivo investigation has also indicated the communication between ARHGEF3 and autophagy-related muscle pathologies. Moreover, studies on genetic variation in ARHGEF3 and genome-wide association studies have predicted exciting novel roles of ARHGEF3 in controlling bone mineral density, platelet formation and differentiation, and Hirschsprung disease. In conclusion, we hypothesized that additional biochemical and functional studies are required to elucidate the detailed mechanism of ARHGEF3-related pathologies and therapeutics.

Keywords: ARHGEF3; Akt; XPLN; mTORC2; rho guanine nucleotide exchange factors

DOI: https://doi.org/10.3389/fcell.2021.806258

Clin Exp Med. 2022 Feb 16.

Selumetinib: a selective MEK1 inhibitor for solid tumor treatment.

Mohaddeseh Hedayat, Reza Jafari, Naime Majidi Zolbanin.

Cancer incidence is rapidly growing. Solid tumors are responsible for a majority of cancers. Recently, molecular-targeted agents have played a significant role in cancer treatment. Ras-Raf-MEK-ERK signaling pathway, is a substantial element in the survival, propagation, and drug resistance of human cancers. MEK is a specific part of the so-called cascade, and ERK proteins are its sole target. Furthermore, their downstream position in the Ras-ERK cascade, is noteworthy to direct their function in patients with upstream mutated genes. MEK1 mutations are responsible for initiating several solid tumors. Selumetinib (AZD6244) is a second-generation, selective, potent, and non-ATP competitive allosteric MEK1 inhibitor. The efficacy of selumetinib in various solid tumors such as colorectal cancer, lung cancer, neurofibroma, and melanoma is investigated. The present paper provides an overview of the MAPK cascade, the role of selumetinib as a MEK1/2 inhibitor, and the related findings of clinical trials for solid tumor treatment.

Keywords: Cancer; MAPK; MEKIs; Selumetinib; Solid tumors

DOI: https://doi.org/10.1007/s10238-021-00783-z

Trends Cancer. 2022 Feb 10. pii: S2405-8033(22)00018-8. [Epub ahead of print]

Intestinal stem cell dynamics in homeostasis and cancer.

Rana Ramadan, Milou S van Driel, Louis Vermeulen, Sanne M van Neerven.

The relationship between intestinal stem cells (ISCs) and colorectal cancer (CRC) has been a topic of intense study. Uncovering stem cell dynamics in homeostasis and following acquisition of oncogenic mutations has provided unprecedented insights into CRC initiation, and it is increasingly evident that the microenvironment plays a key role in regulating stem cell fate and functionality. Consequently, imbalances in the signaling between the niche and ISCs perturb homeostasis and promote cancer development. Furthermore, stem cell-like cells drive growth and progression of established CRCs and these cells also critically rely on microenvironmental input. Here, we highlight the importance of stem cell/niche interactions in developing and established CRC and discuss how these can be modulated to develop novel preventive and therapeutic interventions.

Keywords: cell competition; colorectal cancer; intestinal stem cells; microenvironment; mutations; stem cell niche

DOI: https://doi.org/10.1016/j.trecan.2022.01.011

Cancers (Basel). 2022 Feb 03. pii: 784. [Epub ahead of print]14(3):

Shifting the Focus of Signaling Abnormalities in Colon Cancer.

Markus A Brown, Thomas Ried.

Colon cancer tumorigenesis occurs incrementally. The process involves the acquisition of mutations which typically follow an established pattern: activation of WNT signaling, activation of RAS signaling, and inhibition of TGF-β signaling. This arrangement recapitulates, to some degree, the stem cell niche of the intestinal epithelium, which maintains WNT and EGF activity while suppressing TGF-β. The resemblance between the intestinal stem cell environment and colon cancer suggests that the concerted activity of these pathways generates and maintains a potent growth-inducing stimulus. However, each pathway has a myriad of downstream targets, making it difficult to identify which aspects of these pathways are drivers. To address this, we utilize the cell cycle, the ultimate regulator of cell proliferation, as a foundation for cross-pathway integration. We attempt to generate an overview of colon cancer signaling patterns by integrating the major colon cancer signaling pathways in the context of cell replication, specifically, the entrance from G1 into S-phase.

Keywords: K-RAS; MYC; RAS signaling; SMAD4; TGF-β signaling; WNT signaling; β-catenin

DOI: https://doi.org/10.3390/cancers14030784

Cancers (Basel). 2022 Jan 28. pii: 673. [Epub ahead of print]14(3):

Dual Inhibition of Myc Transcription and PI3K Activity Effectively Targets Colorectal Cancer Stem Cells.

Miriam Gaggianesi, Laura Rosa Mangiapane, Chiara Modica, Vincenzo Davide Pantina, Gaetana Porcelli, Simone Di Franco, Melania Lo Iacono, Caterina D'Accardo, Francesco Verona, Irene Pillitteri, Alice Turdo, Veronica Veschi, Ornella Roberta Brancato, Giampaolo Muratore, Giuseppe Pistone, Maria Rita Bongiorno, Matilde Todaro, Ruggero De Maria, Giorgio Stassi.

Despite advances in the curative approach, the survival rate of advanced colorectal cancer (CRC) patients is still poor, which is likely due to the emergence of cancer cell clones resistant to the available therapeutic options. We have already shown that CD44v6-positive CRC stem cells (CR-CSCs) are refractory toward standard anti-tumor therapeutic agents due to the activation of the PI3K pathway together with high HER2 expression levels. Tumor microenvironmental cytokines confer resistance to CR-CSCs against HER2/PI3K targeting by enhancing activation of the MAPK pathway. Here, we show that the CSC compartment, spared by BRAF inhibitor-based targeted therapy, is associated with increased expression levels of CD44v6 and Myc and retains boosted clonogenic activity along with residual tumorigenic potential. Inhibition of Myc transcription, downstream of the MAPK cascade components, and PI3K pathway activity was able to overcome the protective effects of microenvironmental cytokines, affecting the survival and the clonogenic activity of CR-CSCs, regardless of their mutational background. Likewise, the double targeting induced stabilization of mouse tumor avatars. Altogether, these data outline the rationale for dual kinase targeting of CR-CSCs to prevent their adaptive response, which would lead to disease progression.

Keywords: anti-tumor drug resistance; cancer stem cells; colorectal cancer; combination therapies

DOI: https://doi.org/10.3390/cancers14030673

Cell Mol Gastroenterol Hepatol. 2022 Feb 14. pii: S2352-345X(22)00034-0. [Epub ahead of print]

A proximal-to-distal survey of healthy adult human small intestine and colon epithelium by single-cell transcriptomics.

Joseph Burclaff, R Jarrett Bliton, Keith A Breau, Meryem T Ok, Ismael Gomez-Martinez, Jolene S Ranek, Aadra P Bhatt, Jeremy E Purvis, John T Woosley, Scott T Magness.

BACKGROUND AND AIMS: Single-cell transcriptomics offer unprecedented resolution of tissue function at the cellular level, yet studies analyzing healthy adult human small intestine and colon are sparse. Here, we present single-cell transcriptomics covering the duodenum, jejunum, ileum, and ascending, transverse, and descending colon from 3 humans.
METHODS: 12,590 single epithelial cells from three independently processed organ donors were evaluated for organ-specific lineage biomarkers, differentially regulated genes, receptors, and drug targets. Analyses focused on intrinsic cell properties and capacity for response to extrinsic signals along the gut axis across different humans.
RESULTS: Cells were assigned to 25 epithelial lineage clusters. Multiple accepted intestinal stem cell (ISC) markers do not specifically mark all human ISCs. Lysozyme expression is not unique to human Paneth cells, and Paneth cells lack expression of expected niche-factors. BEST4+ cells express NPY and show maturational differences between small intestine and colon. Tuft cells possess a broad ability to interact with the innate and adaptive immune systems through previously unreported receptors. Some classes of mucins, hormones, cell-junction, and nutrient absorption genes show unappreciated regional expression differences across lineages. Differential expression of receptors and drug targets across lineages reveals biological variation and potential for variegated responses.
CONCLUSIONS: Our study identifies novel lineage marker genes; covers regional differences; shows important differences between mouse and human gut epithelium; and reveals insight into how the epithelium responds to the environment and drugs. This comprehensive cell atlas of the healthy adult human intestinal epithelium resolves likely functional differences across anatomical regions along the gastrointestinal tract and advances our understanding of human intestinal physiology.

Keywords: BEST4; Cell Atlas; Intestinal Stem Cell; Paneth cell; scRNAseq

DOI: https://doi.org/10.1016/j.jcmgh.2022.02.007