Biology subjects

Welsh, E. A.

Publications and source records attributed to Welsh, E. A..

5 recordsLinked to original sources

bioRxiv2025

Dual targeting of RET and SRC synergizes in RET fusion-positive cancer cells

RET fusions drive subsets of non-small cell lung cancer (NSCLC) and papillary thyroid carcinoma (PTC). Despite new selective RET tyrosine kinase inhibitors (TKIs) resistance usually occurs and is often driven by RET-independent bypass mechanisms. Previous studies have implied crosstalk between RET and SRC, but the anti-cancer effects of targeting SRC combined with selective RET TKIs and the underlying molecular mechanisms are not fully understood. Our results showed that the multitargeted SRC TKI dasatinib significantly enhanced efficacy of RET TKIs in RET fusion-positive (RET+) NSCLC and PTC cells. Genetic rescue experiments validated that the combination effects between RET TKIs and dasatinib were indeed SRC-dependent. Phosphoproteomics analysis and validation using selective inhibitors and siRNAs determined that synergy was primarily mediated by suppression of downstream PAK signaling, with contributions from AKT and S6. Importantly, synergy was also observed with eCF506 (NXP900), a next-generation clinical SRC inhibitor. Finally, both SRC TKIs restored sensitivity in selpercatinib-resistant RET+PTC cells. These results elucidate RET and SRC signaling crosstalk in RET+ NSCLC and PTC suggesting that co-inhibiting SRC has clinical potential in TKI-naive and -resistant RET+ cancers.

cancer biology↗

bioRxiv2024

Cancer-associated fibroblasts confer ALK inhibitor resistance in EML4-ALK-driven lung cancer via concurrent integrin and MET signaling

Cancer-associated fibroblasts (CAFs) are associated with tumor progression and modulate drug sensitivity of cancer cells. However, the underlying mechanisms are often incompletely understood and crosstalk between tumor cells and CAFs involves soluble secreted as well as adhesion proteins. Interrogating a panel of non-small cell lung cancer (NSCLC) cell lines driven by EML4-ALK fusions, we observed substantial CAF-mediated drug resistance to clinical ALK tyrosine kinase inhibitors (TKIs). Array-based cytokine profiling of fibroblast-derived conditioned- media identified HGF-MET signaling as a major contributor to CAF-mediated paracrine resistance that can be overcome by MET TKIs. However, Cell Type specific labeling using Amino acid Precursors (CTAP)-based expression and phosphoproteomics in direct coculture also highlighted a critical role for the fibronectin-integrin pathway. Flow cytometry analysis confirmed activation of integrin {beta}1 (ITGB1) in lung cancer cells by CAF coculture. Treatment with pharmacological inhibitors, cancer cell-specific silencing or CRISPR-Cas9-mediated knockout of ITGB1 overcame adhesion protein-mediated resistance. Concurrent targeting of MET and integrin signaling effectively abrogated CAF-mediated resistance of EML4-ALK-driven NSCLC cells to ALK TKIs in vitro. Consistently, combination of the ALK TKI alectinib with the MET TKI capmatinib and/or the integrin inhibitor cilengitide was significantly more efficacious than single agent treatment in suppressing tumor growth using an in vivo EML4-ALK-dependent allograft mouse model of NSCLC. In summary, these findings emphasize the complexity of resistance-associated crosstalk between CAFs and cancer cells, which can involve multiple concurrent signaling pathways, and illustrate how comprehensive elucidation of paracrine and juxtacrine resistance mechanisms can inform on more effective therapeutic approaches.

cancer biology↗

bioRxiv2023

The lipid phosphatase activity of PTEN dampens FRA1 expression via AKT/mTOR signaling to suppress melanoma

PTEN, a phosphatase frequently inactivated in melanoma, opposes PI3K/AKT/mTOR pathway activation. However, AKT- and mTOR-targeted therapies have so far yielded insufficient results in preclinical models and clinical trials of melanoma. We therefore examined whether PTEN suppresses melanoma through lipid phosphatase-independent functions or by opposing lipid phosphatase-dependent, AKT-independent pathways. Restoring different PTEN functions in PTEN-deficient cells or mouse models revealed that PTEN lipid phosphatase activity predominantly suppresses melanoma with minimal contribution from its protein phosphatase and scaffold functions. A drug screen highlighted the dependence of PTEN-deficient melanoma cells on the AKT/mTOR pathway. Moreover, activation of AKT was sufficient to overcome several aspects of PTEN-mediated melanoma suppression. Phosphoproteomics analysis of the PTEN lipid phosphatase activity identified the AP-1 transcription factor FRA1 as a downstream effector. PTEN regulates FRA1 translation via AKT/mTOR and FRA1 overexpression overcomes PTEN-mediated melanoma suppression. Our study affirms AKT as the key mediator of PTEN inactivation in melanoma and identifies an AKT/mTOR/FRA1 axis as a driver of melanomagenesis.

cancer biology↗

bioRxiv2020

Harnessing tumor immune ecosystem dynamics to personalize radiotherapy

Radiotherapy is a pillar of cancer care and augments the response to immunotherapies. However, little is known regarding the relationships between the tumor immune ecosystem (TIES) and intrinsic radiosensitivity, and a pressing question in oncology is how to optimize radiotherapy to improve patient responses to immune therapies. To address this challenge, we profiled over 10,000 primary tumors for their metrics of radiosensitivity and immune cell infiltrate (ICI), and applied a new integrated in silico model that mimics the dynamic relationships between tumor growth, ICI flux and the response to radiation. We then validated this model with a separate cohort of 59 lung cancer patients treated with radiotherapy. These analyses explain radiation response based on its effect on the TIES and quantifies the likelihood that radiation can promote a shift to anti-tumor immunity. Dynamic modeling of the relationship between tumor radiosensitivity and the TIES may provide opportunity to personalize combined radiation and immunotherapy approaches.

cancer biology↗

bioRxiv2017

Escape Excel: a tool for preventing gene symbol and accession conversion errors

BackgroundMicrosoft Excel automatically converts certain gene symbols, database accessions, and other alphanumeric text and numbers into dates, scientific notation, and other numerical representations, which may lead to subsequent, irreversible corruption of the imported text. A recent survey of popular genomic literature estimates that one-fifth of all papers with supplementary data containing gene lists in Excel format suffer from this issue.\n\nResultsHere, we present an open-source tool, Escape Excel, which prevents these erroneous conversions by generating an escaped text file that can be safely imported into Excel. Escape Excel is available in the Galaxy web environment and can be installed through the Galaxy ToolShed. Escape Excel is also available as a stand-alone, command line Perl script on GitHub (http://www.github.com/pstew/escape_excel). A Galaxy test server implementation is accessible at http://apostl.moffitt.org.\n\nConclusionsEscape Excel detects and escapes a wide variety of problematic text strings so that they are not erroneously converted into other representations upon importation into Excel. Examples of problematic strings include date-like strings, time-like strings, leading zeroes in front of numbers, and long numeric and alpha-numeric identifiers that should not be automatically converted into scientific notation. It is hoped that greater awareness of these potential data-corruption issues, together with diligent escaping of text files prior to importation into Excel, will help to reduce the amount of Excel-corrupted data in scientific analyses and publications.

bioinformatics↗