Hauer Caroline, Blomberg Rachel, Sompel Kayla, Magin Chelsea M, Tennis Meredith A
bioRxiv. 2024 May 2:2024.04.29.591698. doi: 10.1101/2024.04.29.591698.
Lung cancer is the leading cause of global cancer death and prevention strategies are key to reducing mortality. Medical prevention may have a larger impact than treatment on mortality by targeting high-risk populations and reducing their lung cancer risk. Premalignant lesions (PMLs) that can be intercepted by prevention agents are difficult to study in humans but easily accessible in murine preclinical carcinogenesis studies. Precision-cut lung slices (PCLS) are underutilized as an model for lung cancer studies due to limited culture time. Embedding PCLS within bioengineered hydrogels extends PCLS viability and functionality for up to six weeks. Here, we embedded PCLS generated from urethane-induced murine PMLs in cell-degradable and non-degradable hydrogels to study viability and activity of the tissues over six weeks. PMLs in hydrogel-embedded PCLS maintained viability, gene expression, and proliferation. Treatment of hydrogel-embedded PCLS containing urethane-induced PMLs with iloprost, a known lung cancer prevention agent, recapitulated gene expression and activity. These studies also showed that iloprost reduced proliferation and PML size in hydrogel-embedded PCLS, with some differences based on hydrogel formulation and suggested that hydrogel-embedded PCLS models may support long-term culture of generated PMLs to improve preclinical studies of lung cancer and prevention agents.
肺癌是全球癌症死亡的主要原因，预防策略是降低死亡率的关键。通过针对高危人群并降低其肺癌风险，医学预防对死亡率的影响可能比治疗更大。可被预防药物拦截的癌前病变（PMLs）在人体中难以研究，但在小鼠临床前致癌研究中很容易获得。由于培养时间有限，精密切割肺切片（PCLS）作为肺癌研究模型未得到充分利用。将PCLS嵌入生物工程水凝胶中可将其活力和功能延长至六周。在这里，我们将由聚氨酯诱导的小鼠PMLs产生的PCLS嵌入可细胞降解和不可降解的水凝胶中，以研究组织在六周内的活力和活性。水凝胶包埋的PCLS中的PMLs保持了活力、基因表达和增殖。用已知的肺癌预防药物伊洛前列素处理含有聚氨酯诱导的PMLs的水凝胶包埋的PCLS，重现了基因表达和活性。这些研究还表明，伊洛前列素减少了水凝胶包埋的PCLS中的增殖和PML大小，根据水凝胶配方存在一些差异，并表明水凝胶包埋的PCLS模型可能支持所产生的PMLs的长期培养，以改善肺癌和预防药物的临床前研究。
