Biology subjects

McGinn, R. A.

Publications and source records attributed to McGinn, R. A..

4 recordsLinked to original sources

bioRxiv2026

Targeting fibroblast activation suppresses chemotherapy-induced pro-invasive remodeling of the extracellular matrix

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that accounts for nearly 20% of breast cancer diagnoses. Despite recent approvals of novel therapeutic agents for TNBC, neoadjuvant chemotherapy remains part of standard of care treatment for TNBC patients. However, approximately 60% of TNBC patients who received neoadjuvant chemotherapy fail to achieve pathological complete response and face significantly elevated risks of recurrence and distant metastasis. We have shown that chemotherapy can induce significant changes in TNBC tumor extracellular matrix (ECM) that drive tumor cell invasion and may contribute to recurrence. Here, we investigate how chemotherapy drugs can impact resident fibroblasts, the major generators of ECM in the breast tissue. We find that chemotherapy activates fibroblasts and that doxorubicin specifically induces the production of pro-invasive ECM by fibroblasts via TGF-{beta}/Smad3 signaling. An FDA-approved tyrosine kinase inhibitor nintedanib suppressed doxorubicin-induced fibroblast activation and pro-invasive ECM production by fibroblasts in vitro. Additionally, in a TNBC mouse model, nintedanib reduced fibroblast activation markers in tumors, suppressed tumor cell motility in the tumor ECM, and reduced lung metastasis. These findings demonstrate a novel mechanism by which chemotherapy can induce fibroblast activation and imply that targeting fibroblast activation reduces chemotherapy-induced metastasis in TNBC.

cancer biology↗

bioRxiv2025

Systems-level characterization of EGFR kinase inhibitors reveals heterogeneous effects on Mtb-macrophage interactions

Mycobacterium tuberculosis (Mtb) causes deadly, antibiotic-recalcitrant disease. Host-directed therapy (HDT) is a proposed, antibiotic-complementary approach that enhances host antimicrobial function, thereby restricting intracellular Mtb. Drug repurposing screens suggest that inhibiting epidermal growth factor receptor (EGFR) may improve macrophage restriction of Mtb. However, the role of EGFR in restriction is not well understood. We show EGFR kinase inhibitors are not generally Mtb-restrictive in human monocyte-derived macrophages. Few EGFR inhibitors restrict intracellular Mtb and do so via heterogeneous mechanisms, including direct antibiotic effects and host-dependent, likely EGFR-independent mechanisms. During host-dependent therapy, intracellular Mtb induce defined, stress-responsive gene modules, with each drug inducing a unique combination of restriction-associated stresses. We decompose intracellular Mtb responses into host-dependent contributions and host-independent contributions suggestive of direct drug-Mtb interaction. Together, our data nuances the host-directed model of EGFR inhibitors for tuberculosis and provides a roadmap for systematically characterizing repurposed drugs from multiple angles of the drug-host-pathogen interaction.

systems biology↗

bioRxiv2023

Cell morphology best predicts tumorigenicity and metastasis in vivo across multiple TNBC cell lines of different metastatic potential

BackgroundMetastasis is the leading cause of death in breast cancer patients. For metastasis to occur, tumor cells must invade locally, intravasate, and colonize distant tissues and organs, all steps that require tumor cell migration. The majority of studies on invasion and metastasis rely on human breast cancer cell lines. While it is known that these cells have different properties and abilities for growth and metastasis, the in vitro morphological, proliferative, migratory, and invasive behavior of these cell lines and their correlation to in vivo behavior is poorly understood. Thus, we sought to classify each cell line as poorly or highly metastatic by characterizing tumor growth and metastasis in a murine model of six commonly used human triple-negative breast cancer xenografts, as well as determine which in vitro assays commonly used to study cell motility best predict in vivo metastasis. MethodsWe evaluated the liver and lung metastasis of human TNBC cell lines MDA-MB-231, MDA-MB-468, BT549, Hs578T, BT20, and SUM159 in immunocompromised mice. We characterized each cell lines cell morphology, proliferation, and motility in 2D and 3D to determine the variation in these parameters between cell lines. ResultsWe identified MDA-MB-231, MDA-MB-468, and BT549 cells as highly tumorigenic and metastatic, Hs578T as poorly tumorigenic and metastatic, BT20 as intermediate tumorigenic with poor metastasis to the lungs but highly metastatic to the livers, and SUM159 as intermediate tumorigenic but poorly metastatic to the lungs and livers. We showed that metrics that characterize cell morphology are the most predictive of tumor growth and metastatic potential to the lungs and liver. Further, we found that no single in vitro motility assay in 2D or 3D significantly correlated with metastasis in vivo. ConclusionsOur results provide an important resource for the TNBC research community, identifying the metastatic potential of 6 commonly used cell lines. Our findings also support the use of cell morphological analysis to investigate the metastatic potential and emphasize the need for multiple in vitro motility metrics using multiple cell lines to represent the heterogeneity of metastasis in vivo.

cancer biology↗

bioRxiv2021

Chemotherapy-induced collagen IV drives cancer cell invasion through activation of Src/FAK signaling

Triple-negative breast cancer (TNBC) is the most aggressive and deadly subtype of breast cancer, accounting for 30,000 cases annually in the US. While there are several clinical trials ongoing to identify new agents to treat TNBC, the majority of TNBC patients are treated with anthracycline- or taxane-based chemotherapies in the neoadjuvant setting, followed by surgical resection and adjuvant chemotherapy. While many patients respond well to this approach, as many as 25% will suffer local or metastatic recurrence within five years. Understanding the mechanisms that drive recurrence after chemotherapy treatment is critical to improving survival for patients with TNBC. It is well-established that the extracellular matrix, which provides structure and support to tissues, is a major driver of tumor growth, local invasion and dissemination of cancer cells to distant metastatic sites. In the present study, we show that decellularized extracellular matrix (dECM) obtained from chemotherapy-treated mice increases invasion of treatment-naive breast cancer cells compared to vehicle-treated dECM. Using tandem-mass-tag proteomics, we further demonstrate that anthracycline- and taxane-based chemotherapies induce drug-specific changes in tumor ECM composition. We identify the basement membrane protein collagen IV as significantly upregulated in the ECM of chemotherapy-treated mice and patients treated with neoadjuvant chemotherapy. We show that collagen IV drives invasion via Src/FAK signaling and that inhibiting collagen IV-driven signaling decreases invasion in chemotherapy-treated dECM. These studies provide a novel mechanism by which chemotherapy may induce metastasis via effects on ECM composition. One Sentence SummaryChemotherapy alters the extracellular matrix of breast tumors leading to increased invasion of residual cancer cells.

cancer biology↗