Biology subjects

Griffen, A.

Publications and source records attributed to Griffen, A..

3 recordsLinked to original sources

bioRxiv2026

PRMT5 inhibitors actively promote metastatic progression of lung adenocarcinoma

Epigenetic changes are a major driver of cancer progression, placing considerable focus on epigenetic regulators as therapeutic targets. Protein arginine methyltransferase 5 (PRMT5) is one such regulator, and numerous PRMT5 inhibitors (PRMT5i) in clinical trials. Despite this, the mechanisms and consequences of PRMT5i-resistance are unknown. Here, we demonstrate that aggressive cancer progression is an inbuilt feature of PRMT5i-resistance acquisition in lung adenocarcinoma (LUAD). Independently-generated resistant cell lines gain dedifferentiation signatures that typify late-stage disease and show increased metastatic potential in vivo. We establish that these state shifts are a direct consequence of PRMT5i action; treatment induces rapid and widespread chromatin rewiring, enabling derepression of late-stage disease states that are stably established in resistant cells. Notably, treatment of lung tumor-bearing mice drives rapid disease advancement without decreasing tumor burden, showing that drug-induced disease progression supersedes any benefits from PRMT5 inhibition in vivo. Furthermore, analyses of human cell lines and patient cohorts supports the notion of PRMT5 inhibition-mediated dedifferentiation. Collectively our data show that PRMT5i can actively promote self-resistance and disease progression in different tumor types. This raises serious concerns for the use of PRMT5i in patients, arguing that clinical studies should consider the possibility of drug-induced plasticity, resistance, and disease advancement.

cancer biology↗

bioRxiv2024

Intratumoral CXCL12 Gradients Contextualize Tumor Cell Invasion, Migration and Immune Suppression in Breast Cancer

Although the CXCL12/CXCR4 pathway has been prior investigated for its prometastatic and immuno- suppressive roles in the tumor microenvironment, evidence on the spatiotemporal regulation of these hallmarks has been lacking. Here, we demonstrate that CXCL12 forms a gradient specifically around cancer cell intravasation doorways, also known as Tumor Microenvironment of Metastasis (TMEM) doorways, thus facilitating the chemotactic translocation of prometastatic tumor cells expressing CXCR4 toward the perivascular TMEM doorways for subsequent entry into peripheral circulation. Fur- thermore, we demonstrate that the CXCL12-rich micro-environment around TMEM doorways may cre- ate immunosuppressive niches, whereby CD8+ T cells, despite being attracted to these regions, often exhibit reduced effector functions, limiting their efficacy. While the CXCL12/CXCR4 pathway can mini- mally influence the overall composition of immune cell populations, it biases the distribution of CD8+ T cells away from TMEM doorways, justifying its prior-established role as immunosuppressive factor for CD8+ T cells. Our research suggests that the complex interactions between CXCL12 and the various tumor and immune cell types contributes not only to the completion of the initial steps of the metastatic cascade, but also offers an immunological "sanctuary" to prometastatic tumor cells homed around TMEM doorways. Overall, our study enhances our current understanding on the mechanisms, via which CXCL12 orchestrates tumor cell behavior and immune dynamics, potentially guiding future thera- peutic strategies to combat breast cancer metastasis and improve anti-tumor immunity.

cancer biology↗

bioRxiv2023

Identification and Pharmacological Targeting of Treatment-Resistant, Stem-like Breast Cancer Cells for Combination Therapy

Tumors frequently harbor isogenic yet epigenetically distinct subpopulations of multi-potent cells with high tumor-initiating potential--often called Cancer Stem-Like Cells (CSLCs). These can display preferential resistance to standard-of-care chemotherapy. Single-cell analyses can help elucidate Master Regulator (MR) proteins responsible for governing the transcriptional state of these cells, thus revealing complementary dependencies that may be leveraged via combination therapy. Interrogation of single-cell RNA sequencing profiles from seven metastatic breast cancer patients, using perturbational profiles of clinically relevant drugs, identified drugs predicted to invert the activity of MR proteins governing the transcriptional state of chemoresistant CSLCs, which were then validated by CROP-seq assays. The top drug, the anthelmintic albendazole, depleted this subpopulation in vivo without noticeable cytotoxicity. Moreover, sequential cycles of albendazole and paclitaxel--a commonly used chemotherapeutic --displayed significant synergy in a patient-derived xenograft (PDX) from a TNBC patient, suggesting that network-based approaches can help develop mechanism-based combinatorial therapies targeting complementary subpopulations. Statement of significanceNetwork-based approaches, as shown in a study on metastatic breast cancer, can develop effective combinatorial therapies targeting complementary subpopulations. By analyzing scRNA-seq data and using clinically relevant drugs, researchers identified and depleted chemoresistant Cancer Stem-Like Cells, enhancing the efficacy of standard chemotherapies.

systems biology↗