Tinagl1 Gene Therapy Suppresses Growth and Remodels the Microenvironment of Triple Negative Breast Cancer

Abstract

Triple negative breast cancer (TNBC) remains one of the most challenging subtypes of breast cancer to treat and is responsible for approximately 12% of breast cancer cases in the US per year. In 2019, the protein Tinagl1 was identified as a key factor for improved prognoses in certain TNBC patients. While the intracellular mechanism of action has been thoroughly studied, little is known about the role of Tinagl1 in the tumor microenvironment. In this study, we developed a lipid nanoparticle-based gene therapy to directly target the expression of Tinagl1 in tumor cells for localized expression. Additionally, we sought to characterize the changes to the tumor microenvironment induced by Tinagl1 treatment, with the goal of informing future choices for combination therapies including Tinagl1. We found that Tinagl1 gene therapy was able to slow tumor growth from the first dose and that the effects held steady for nearly a week following the final dose. No toxicity was found with this treatment. Additionally, the use of Tinagl1 increases the tumor vasculature by 3-fold but does not increase the tumor permeability or risk of metastasis. However, the increase in vasculature arising from Tinagl1 therapy reduced the expression of Hif1a significantly (p < 0.01), which may decrease the risk of drug resistance.

Down‐regulated TINAGL1 in fibroblasts impairs wound healing in diabetes

“…Currently, multiple biological functions of matricellular proteins have been found (including activation cellular signaling, and regulation of cell adhesion, differentiation, proliferation and migration), and studies have shown that matricellular proteins play an important role in multiple diseases 24 . At present, except for tumors, little is still known about the function of TINAGL1 in other diseases 22,25‐28 . Here, we found that the expression of TINAGL1 is decreased in diabetic wound tissues, and topical application of TINAGL1 promotes wound healing in diabetic mice by promoting granulation tissue formation.…”

Low TINAGL1 expression is a marker for poor prognosis in breast cancer

“…Recent studies identi ed TINAGL1 expression as a prognostic factor in hepatocellular carcinoma (Sun et al 2019), gastric cancer (Shan et al 2021), and breast cancer (Shen et al 2019). TINAGL1 was suggested to inhibit tumor growth and metastasis in breast cancer (Shen et al 2019;Musetti et al 2021; Korpal et al 2011), and TINAGL1 expression was dependent on Sec23 homolog A (SEC23A), an essential component of coat protein complex II vesicles that is indispensable for ECM protein secretion (Korpal et al 2011). SEC23A was also reported to regulate the translocation of secretory and ECM proteins (Korpal et al 2011; Zeng et al 2021).…”