Biology subjects

Rugo, H. S.

Publications and source records attributed to Rugo, H. S..

3 recordsLinked to original sources

bioRxiv2026

MYC Overexpression Confers Sensitivity to TACC3 Inhibition for Triple-Negative Breast Cancer

The oncogenic transcription factor MYC is overexpressed across many cancer types, including triple-negative breast cancers (TNBCs), where it drives cell proliferation, chromosomal instability, and immune suppression. As MYC has proven difficult to target directly, identifying vulnerabilities created by MYC-driven mitotic rewiring is of significant therapeutic interest. Using a focused pharmacological screen of mitosis-related targets that are overexpressed in the context of MYC signaling, we identified several previously unrecognized dependencies on mitotic spindle proteins, including KIF18A and TACC3 in MYCHIGH cells. We focused on TACC3 and found the small molecule inhibitor BO-264 induced pronounced micronuclei formation, cell cycle arrest, transcriptional reactivation of inflammatory signaling, and heightened cytotoxicity in MYCHIGH models. TACC3 inhibition activates interferon-stimulated response element (ISRE) mediated inflammatory signaling and can activate the cGAS-STING pathway in a subset of triple-negative breast cancer contexts. Together, these findings identify TACC3 as a MYC-driven mitotic vulnerability. We highlight TACC3 inhibition as a promising strategy to impair tumor cell fitness and activate tumor-intrinsic inflammatory responses in MYC-driven cancers.

cancer biology↗

bioRxiv2022

Dissecting the contributions of tumor heterogeneity on metastasis at single-cell resolution

Metastasis is the leading cause of cancer-related deaths, but metastasis research is challenged by limited access to patient material and a lack of experimental models that appropriately recapitulate tumor heterogeneity. Here, we analyzed single-cell transcriptomes of matched primary tumor and metastasis from patient-derived xenograft models of breast cancer, demonstrating that primary tumor and metastatic cells show profound transcriptional differences across heterogeneous tumors. While primary tumor cells upregulated several metabolic genes, metastatic cells displayed a motility phenotype in micrometastatic lesions and increased stress response signaling during metastatic progression. Additionally, we identified gene signatures that are associated with the metastatic potential and correlated with patient outcomes. Poorly metastatic primary tumors showed increased immune-regulatory control that may prevent metastasis, whereas highly metastatic primary tumors upregulated markers of epithelial-mesenchymal transition (EMT). We found that intra-tumor heterogeneity is dominated by epithelial-mesenchymal plasticity (EMP) which presented as a dynamic continuum with intermediate cell states that were characterized by novel, specific markers. These intermediate EMP markers correlated with worse patient outcomes and could serve as potential new therapeutic targets to block metastatic development.

cancer biology↗

bioRxiv2021

Combinatorial immunotherapies overcome MYC-driven immune evasion

For many human cancers, including triple negative breast cancer (TNBC), a modest number of patients benefit from immune checkpoint inhibitors, and few experience cancer remission1. Expression of programed death-ligand 1 (PD-L1), tumor immune infiltration, or tumor mutation burden have been widely investigated for predicting cancer immunotherapy response1-5. Whether specific oncogenes diminish response to immunotherapy6-10 and whether these effects are reversible remains poorly understood. We predicted that MYC, an oncogene that is frequently overexpressed11,12 and is associated with worse prognosis12, may predict immunotherapy response in patients with TNBC. Here, we report that MYC-elevated TNBCs are resistant to immune checkpoint inhibitors. Using mouse models of TNBC and patient data we report that MYC signaling is associated with low tumor cell PD-L1, low overall immune cell infiltration, and low tumor cell MHC-I expression. Restoring interferon signaling in the tumor reduces MYC expression and increases MHC-I expression. By combining a TLR9 agonist and an agonistic antibody against OX40 with anti-PD-L1, most mice experience complete tumor regression and are protected from new TNBC tumor outgrowth. Our findings demonstrate that MYC-dependent immune evasion is reversible and druggable, and if strategically targeted, may improve outcomes for patients treated with immune checkpoint inhibitors.

cancer biology↗