Glioblastoma mutiforme (GBM), the most aggressive primary malignant brain tumor, has infiltrative character-istics and highly heterogeneous cell populations in the tumor microenvironments. Due to the greatly diffusive behaviors, definitive surgical resection is precluded, and diverse cell components cause radio- and chemo-resistance. Therefore, recurrence occurs frequently, and overall survival is quite short. In this study, I aimed to investigate GBM cell behaviors, specifically focusing on the invasive characteristics. To investigate GBM cell migration and invasion induced by interaction with the tumor microenvironment, I constructed in vitro and in vivo validation models to discover new biomarkers for anti-invasion drugs at the clinical level.
GBM cells migrate along preexisting thin microstructures and invade surrounding normal tissues. I established the biomimetic cell culture platform to mimic these structural and mechanical cues in tumor micro-environments of GBM as well as to mimic striated muscle structures for VSMC phenotypic modulation in Part 2. The biomimetic system induced cytomorphological changes and migration along the pattern.
GSCs, a subpopulation of tumor stromal cells with self-renewal properties and pluripotency, exhibit unique behaviors near microvessels, otherwise known as the “perivascular niche”. However, it has not been identified whether GSCs migrate along microvessels like tumor cells. To monitor the GSC behaviors near the vessels, I constructed two intravital animal models for a GSC invasion study in Part 3. With these animal mod-els, I observed migration of the GSCs along the microvasculature and different adaptations in distinguished microenvironments.
In Part 4, I tried to discover new anti-cancer drug targets by using multi-step computational analysis of GBM patient data obtained from public databases, and then, verify the involvement of the candidate genes in cell migration ability in vitro.
Collectively, these three independent studies could be integrated into a systemic investigation of GBM invasion, from target discovery to in vitro and in vivo validation.
악성교종은 주변 조직으로의 침윤이 잘 일어나 경계가 불분명하여 수술로의 제거가 어렵고, 복잡한 종양주변세포구성으로 인하여 보조치료방법 역시 효율이 낮아 예후가 좋지 않은 것으로 알려져 있다. 본 연구에서는 악성교종의 침투성에 대한 조사를 위하여 뇌조직의 신경해부학적인 구조를 모사한 생체모방 세포배양시스템을 구축하여 교종세포 모양 변화와 이동 성질을 쉽게 관찰 및 분석할 수 있도록 하였다. 또한 종양주변세포 중에서 줄기세포의 성질을 가지는 교종유래줄기세포의 연구를 위하여 생체 영상이 가능한 동물 모델을 구축하였고, 이를 통해 종양 줄기세포의 이동 양상과 미세환경에의 적응성을 직접 관찰하였다. 뿐만 아니라, 교종의 침윤성을 표적으로 하는 새로운 신약 후보를 발굴하기 위하여, 교종 환자 정보를 여러 단계를 통해 계산하였고, 후보유전자를 간추려내어 세포 수준에서 후보유전자의 운동성을 검증하였다. 이와 같은 연구는 앞으로 악성교종의 침윤성을 확인하는 통합연구로써 활용이 가능할 것이다.
