Prajakta Ambegaokar has joined the lab!
Prajakta is a third year graduate student at UMass Chan Mecical School.
We are excited to have you on the team! Welcome!
Mercurio Lab News
Prajakta Ambegaokar has joined the lab!
Prajakta is a third year graduate student at UMass Chan Mecical School.
We are excited to have you on the team! Welcome!
Out of 1,330 entrants, Ayush Kumar has been selected as the winner of the 2024 AMA Research Challenge for his work on Enhancing the radiosensitivity of triple-negative breast cancer by targeting VEGF/Neuropilin-2.
You can read more about Ayush’s journey to winning the contest, as well as watch the video of the impressive work presented by all 5 finalists in the competition!
ABSTRACT
Although programmed cell death ligand 1 (PD-L1) is best known for its role in immune suppression, tumor-intrinsic functions are emerging. Here, we report that tumor cells that express PD-L1 are sensitive to ferroptosis inducers such as imidazole ketone erastin (IKE). PD-L1 promotes ferroptosis sensitivity because it suppresses SLC7A11 expression and diminishes glutathione levels. Although the use of anti-PD-L1 antibody drug conjugates (ADCs) could be effective for the delivery of ferroptosis inducers to specific tumor populations, the chemistry of most ferroptosis inducers precludes their incorporation in ADCs. To overcome this challenge, we synthesized an antibody nanogel conjugate (ANC) comprised of an anti-PD-L1 antibody conjugated to a nanogel encapsulated with IKE. This ANC targets PD-L1-expressing cells in vitro and in vivo and induces ferroptosis, resulting in tumor suppression. Importantly, this approach is superior to systemic administration of IKE because it enables enhanced delivery of IKE specifically to tumor cells and it requires lower drug doses for efficacy.
Wang M, Prachyathipsakul T, Wisniewski CA, Xiong C, Goel S, Goel HL, Karner ER, Mukhopadhyay D, Gupta P, Majee A, Thayumanavan S, Mercurio AM. Therapeutic induction of ferroptosis in tumors using PD-L1 targeting antibody nanogel conjugates. Cell Chem Biol. 2024 Nov 26.
Abstract
The high rate of recurrence after radiation therapy in triple-negative breast cancer (TNBC) indicates that novel approaches and targets are needed to enhance radiosensitivity. Here, we report that neuropilin-2 (NRP2), a receptor for vascular endothelial growth factor (VEGF) that is enriched on sub-populations of TNBC cells with stem cell properties, is an effective therapeutic target for sensitizing TNBC to radiotherapy. Specifically, VEGF/NRP2 signaling induces nitric oxide synthase 2 (NOS2) transcription by a mechanism dependent on Gli1. NRP2-expressing tumor cells serve as a hub to produce nitric oxide (NO), an autocrine and paracrine signaling metabolite, which promotes cysteine-nitrosylation of Kelch-like ECH-asssociated protein 1 (KEAP1) and, consequently, nuclear factor erythroid 2-related factor 2 (NFE2L2)-mediated transcription of antioxidant response genes. Inhibiting VEGF binding to NRP2, using a humanized monoclonal antibody (mAb), results in NFE2L2 degradation via KEAP1 rendering cell lines and organoids vulnerable to irradiation. Importantly, treatment of patient-derived xenografts with the NRP2 mAb and radiation resulted in significant tumor necrosis and regression compared to radiation alone. Together, these findings reveal a targetable mechanism of radioresistance and they support the use of NRP2 mAb as an effective radiosensitizer in TNBC.
Kumar A, Goel HL, Wisniewski CA, Wang T, Geng Y, Wang M, Goel S, Hu K, Li R, Zhu LJ, Clark JL, Ferreira LM, Brehm M, Fitzgerald TJ, Mercurio AM. Neuropilin-2 expressing cells in breast cancer are S-nitrosylation hubs that mitigate radiation-induced oxidative stress. J Clin Invest. 2024 Oct 1. PMID: 39352757
The Mercurio lab is grateful for the opportunity to continue advancing our research in therapy resistant breast cancer!
You can read more from UMass Chan News and also the Worcester Business Journal.