[CCoE Notice] Dissertation Announcement: Megan Mendieta, "Modulating 3D Tumor Microenvironments to Investigate the Impact of Experimental Therapeutics on Glioblastoma Signaling Pathways and Drug Resistance"

[Greenwell, Stephen J]

[Dissertation Defense Announcement at the Cullen College of Engineering]
Modulating 3D Tumor Microenvironments to Investigate the Impact of Experimental Therapeutics on Glioblastoma Signaling Pathways and Drug Resistance
Megan Mendieta
April 29, 2025; 10:30 AM - 12:30 PM (CST)
Location: SERC Floor 2 Rm 2013
Teams Meeting link<https://urldefense.com/v3/__https://teams.microsoft.com/l/meetup-join/19*3ameeting_ZTUyZjE3MjgtZjNhOS00OGViLTg4MDQtMWE1ZTY5ZThjY2Fh*40thread.v2/0?context=*7b*22Tid*22*3a*22170bbabd-a2f0-4c90-ad4b-0e8f0f0c4259*22*2c*22Oid*22*3a*22b8186c7b-13e6-48f4-b9b7-c4268a9d94a5*22*7d__;JSUlJSUlJSUlJSUlJSUl!!LkSTlj0I!DOkZS9nyxCjcQPn2UGSrCp5J4kw_sMVBc4FKD5aQhDxTP5qhBUCjvQL1mGjhDagRqKHpTugZg8tmIYUo6RO5dp9LQVo$ >
Committee Co-Chairs:
Metin Akay, Ph.D. and Yasemin Akay, Ph.D.
Committee Members:
Bulent Ozpolat, M.D., Ph.D. | Yuncheng Du, Ph.D. | Tianfu Wu, Ph.D.
Abstract
Glioblastoma multiforme (GBM) is the most aggressive and treatment-resistant primary brain tumor, characterized by high recurrence rates and poor patient outcomes. Standard of care involves surgical resection followed by radiation and chemotherapy, with Temozolomide (TMZ) as the gold standard. However, GBM often evades therapy through dysregulation of key signaling pathways, including downregulation of apoptosis (Bax) and upregulation of survival mechanisms (NF-κB). To confront these challenges, we explored novel therapeutic strategies using three complementary approaches: improving therapeutic efficacy by targeting drug resistance pathways, biomechanical analysis of cell-cell interactions, and increasing tumor microenvironment complexity.
In our first study, we investigated the efficacy of apoptosis pathway activation and suppression of survival mechanisms using AAAPT, a targeted approach using therapeutics activated in the presence of tumor-related substrates to enhance chemotherapy efficacy at lower doses. GBM spheroids treated within 3D PEGDA microwells demonstrated increased cell death, upregulation of apoptosis pathway expression, and downregulation of NF-κB expression compared to TMZ alone, suggesting a promising strategy to reduce off-target toxicity. Second, we assessed the biomechanical response of GBM spheroids to TMZ using nanobomb optical coherence elastography (nb-OCE) and Brillouin microscopy. TMZ-treated monocultured GBM spheroids showed significant reductions in stiffness, indicating increased treatment sensitivity. However, co-culturing GBM with human astrocytes (HA) conferred resistance, where treated co-culture spheroids exhibited minimal changes in stiffness, highlighting the stabilizing role of the tumor microenvironment. Lastly, we explored the therapeutic potential of miRNA, to suppress GBM spheroid formation and migration. When combined with TMZ, both miRs enhanced tumor suppression through inhibition of NF-κB and SRC/FAK signaling pathways, suggesting that miR-based therapy could synergize with and enhance TMZ treatment.
Together, these findings emphasize the importance of integrating targeted sensitization and molecular therapy, biomechanical assessment, and in vitro microenvironment complexity to develop more effective GBM treatments. By leveraging 3D tumor models and advanced biomechanical tools, we provide new insights into GBM treatment resistance and potential strategies to improve therapeutic outcomes.
[Engineered For What's Next]


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