Biology subjects

Lo, H.-W.

Publications and source records attributed to Lo, H.-W..

4 recordsLinked to original sources

bioRxiv2025

RET Receptor Tyrosine Kinase Promotes Breast Cancer Metastasis to the Brain and RET Inhibitors Pralsetinib and Selpercatinib Suppress Breast Cancer Brain Metastases

Patients with breast cancer brain metastases (BCBM) exhibit dismal prognosis, largely due to the insufficient biological understanding of BCBM and the scarcity of therapeutics that can penetrate the blood-brain barrier. This study was focused on Rearranged during transfection (RET) receptor tyrosine kinase that has been implicated in tumorigenesis and metastatic progression of several solid tumor types including, non-small cell lung cancer (NSCLC), thyroid carcinomas, and luminal breast cancer subtypes. FDA-approved selective RET inhibitors, pralsetinib and selpercatinib, have demonstrated potent intracranial activity in brain metastases from NSCLC and thyroid cancer; however, their efficacy in BCBM has not been investigated. Here, we report that RET activation is elevated in brain metastases of breast cancer patients compared to matched primary tumors (N=30), and in three brain-tropic breast cancer cell lines compared to the parental lines. High RET pathway activation is associated with shorter overall metastasis-free survival and brain metastasis-free survival in patients with HER2-enriched and triple-negative breast cancer (TNBC). Using isogenic TNBC cells lines RET overexpression, we demonstrated that RET strongly promotes their preferential metastasis to the brain in mice with intracardiac injections to tumors cells. Using intracranial tumor implantation of the isogenic lines, we further found that RET significantly enhances the formation and progression of brain tumors in vivo. Moreover, we report that selective RET inhibition using pralsetinib and selpercatinib significantly reduces cell viability, enhances apoptosis, and attenuates migration of brain-tropic breast cancer cells in vitro. Using two mouse studies that model multi-organ metastases and breast tumor formation in the brain, we observed that RET inhibition significantly prevented the circulating tumor cells from forming brain metastases and suppressed the growth of intracranially implanted tumor cells, but did not significantly inhibit the progression of well-established brain metastases. Together, our findings demonstrated that RET is highly activated in BCBM and functioning as a novel mediator of BCBM, and that RET plays a new role as a viable therapeutic target for BCBM.

cancer biology↗

bioRxiv2025

Extracellular vesicle-derived miR-425-5p (miR-425) activates astrocytes in the brain to promote breast cancer brain metastasis via the novel miR-425-ZNF24-CCL8 signaling axis

Mechanisms underlying breast cancer brain metastasis (BCBM) are still not well understood. Here, we identified that BCBM patient serum contained extracellular vesicles (EVs) with high levels of microRNAs (miRNAs)-107 and -425. Levels of miR-107 and miR-425 were elevated in brain metastases, and the elevation was associated with poor patient prognoses. Ectopic expression of miR-107 and miR-425 promoted mammospheres; inhibition of miR-425, but not miR-107, suppressed breast cancer mammosphere formation. EVs from miR-425-overexpressing breast cancer cells strongly activated astrocytes whereas their inhibitors abrogated the effect. Conditioned media from miR-425-activated astrocytes promoted mammospheres. Within astrocytes, miR-425 suppressed expression of transcription factor ZNF24, which downregulated CCL8 cytokine expression/secretion, leading to subsequent activation of astrocytes. We further determined the role of miR-425 in brain metastasis formation and observed that miR-425-overexpressing breast cancer cells exhibited significantly more aggressive growth in mouse brains compared to control cells. Immunohistochemistry and immunofluorescence analysis of mouse brain metastases revealed that miR-425 tumors exhibited significantly increased activation, intratumoral accumulation, and proliferation of astrocytes, and a decrease in ZNF24 expression compared to control tumors. Together, our findings demonstrate that breast cancer EV-derived miR-425 promotes BCBM via activating astrocytes in the brain microenvironment through the novel EV-miR-425-ZNF24-CCL8 signaling axis.

cancer biology↗

bioRxiv2025

Targeting tGLI1, a novel mediator of tumor therapeutic resistance, using Ketoconazole sensitizes glioblastoma to CDK4/6 therapy and Chemoradiation

Glioblastoma (GBM) remains the most aggressive primary brain tumor in adults, with no effective treatments. While cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) show clinical promise in some cancers, they have not significantly improved survival in GBM patients. This lack of response is attributed to the treatment-resistant glioma stem cell (GSC) population. We previously identified truncated glioma-associated oncogene homolog 1 (tGLI1) as a novel transcription factor promoting GSCs; however, its role in CDK4/6i resistance has never been investigated in any cancer type. Here, we found positive correlations between tGLI1 and CDK4/6 therapeutic resistance in patient datasets and in vitro studies. Pharmacological inhibition of tGLI1 using FDA-approved ketoconazole (KCZ), a tGLI1-specific inhibitor, sensitized GBM and GSCs to CDK4/6is. KCZ+CDK4/6i combination therapy demonstrated synergistic anti-proliferative effects, significantly inhibiting GBM stemness and cell cycle progression while increasing apoptosis. The combination was more efficacious than monotherapies in two orthotopic GBM mouse models. tGLI1 promoted GBM resistance to radiation therapy and temozolomide, while KCZ potentiated effects of these treatments. Collectively, we report for the first time that tGLI1 is a novel mediator of GBM resistance to CDK4/6is, and KCZ sensitizes GBM to CDK4/6is, thereby supporting future clinical utility of novel KCZ+CDK4/6i combinatorial therapy for GBM patients.

cancer biology↗

bioRxiv2023

Anti-CD47 immunotherapy as a therapeutic strategy for the treatment of breast cancer brain metastasis

The presence of cell surface protein CD47 allows cancer cells to evade innate and adaptive immune surveillance resulting in metastatic spread. CD47 binds to and activates SIRP on the surface of myeloid cells, inhibiting their phagocytic activity. On the other hand, CD47 binds the matricellular protein Thrombospondin-1, limiting T-cell activation. Thus, blocking CD47 is a potential therapeutic strategy for preventing brain metastasis. To test this hypothesis, breast cancer patient biopsies were stained with antibodies against CD47 to determine differences in protein expression. An anti-CD47 antibody was used in a syngeneic orthotopic triple-negative breast cancer model, and CD47 null mice were used in a breast cancer brain metastasis model by intracardiac injection of the E0771-Br-Luc cell line. Immunohistochemical staining of patient biopsies revealed an 89% increase in CD47 expression in metastatic brain tumors compared to normal adjacent tissue (p [≤] 0.05). Anti-CD47 treatment in mice bearing brain metastatic 4T1br3 orthotopic tumors reduced tumor volume and tumor weight by over 50% compared to control mice (p [≤] 0.05) and increased IBA1 macrophage/microglia marker 5-fold in tumors compared to control (p [≤] 0.05). Additionally, CD47 blockade increased the M1/M2 macrophage ratio in tumors 2.5-fold (p [≤] 0.05). CD47 null mice had an 89% decrease in metastatic brain burden (p [≤] 0.05) compared to control mice in a brain metastasis model. Additionally, RNA sequencing revealed several uniquely expressed genes and significantly enriched genes related to tissue development, cell death, and cell migration tumors treated with anti-CD47 antibodies. Thus, demonstrating that CD47 blockade affects cancer cell and tumor microenvironment signaling to limit metastatic spread and may be an effective therapeutic for triple-negative breast cancer brain metastasis.

cancer biology↗