Dataset Information

Proteome-wide profiling study unmasked lineage-based and clinical feature-based molecular landscapes of pituitary neuroendocrine tumors

ABSTRACT: Pituitary neuroendocrine tumors (PitNETs) account for the second most common intracranial tumors. Currently, there is still a lack of comprehensive understanding regarding the molecular mechanisms associated with lineage or clinical features of PitNETs, which hinders development of effective treatment strategies. Herein, we performed in-depth proteome profiling of 68 PitNET tumors and 4 pituitary glands. We systematically investigated the common and specific aberrant biological mechanisms in TPIT (ACTH/SCA) and PIT1 (TSH/PRL/GH) lineages. Our findings revealed that Wnt signaling pathway and MAPK signaling pathway played crucial regulatory roles in both lineages, while lipid metabolism abnormalities were more prominent in TPIT lineage, and decreased cell adhesion was more significant in PIT1 lineage. Based on these findings, we delved into the interactions between drugs and proteins to explore reliable drug targets and treatment options. We identified 17 potential drug targets and 51 FDA-approved drugs in TPIT lineage, and 19 potential drug targets and 97 FDA-approved drugs in PIT1 lineage, respectively. Additionally, we reclassified the samples based on 4 important clinical phenotypes: invasiveness, recurrence, high incidence in women of childbearing age, and tumor stiffness. By combining artificial intelligence (AI) and bioinformatics analysis, we further investigated the related mechanistic information. Our results highlighted the close association of abnormal neuronal activity with tumor invasiveness, as well as the intimate correlation between cell adhesion alterations and the other 3 clinical phenotypes. Overall, our study provides valuable insights into both of lineage-based and clinical feature-based pathophysiological mechanisms of PitNETs, and offers novel reference for future targeted therapies.

ORGANISM(S): Homo Sapiens

SUBMITTER: Catherine C.L. Wong

PROVIDER: PXD047883 | iProX | Sun Dec 17 00:00:00 GMT 2023

REPOSITORIES: iProX

ACCESS DATA

Similar Datasets

Project description:Gene Expression Profiling of Breast Cancer Patients with Brain Metastases Brain metastases confer the worst prognosis of breast cancer as no therapy exists that prevents or eliminates the cancer from spreading to the brain. We developed a new computational modeling method to derive specific downstream signaling pathways that reveal unknown target-disease connections and new mechanisms for specific cancer subtypes. The model enables us to reposition drugs based on available gene expression data of patients. We applied this model to repurpose known or shelved drugs for brain, lung, and bone metastases of breast cancer with the hypothesis that cancer subtypes have their own specific signaling mechanisms. To test the hypothesis, we addressed the specific CSBs for each metastasis that satisfy that (1) CSB proteins are activated by the maximal number of enriched signaling pathways specific to this metastasis, and (2) CSB proteins involve in the most differential expressed coding-genes specific to the specific breast cancer metastasis. The identified signaling networks for the three types of metastases contain 31, 15, and 18 proteins, respectively, and are used to reposition 15, 9, and 2 drug candidates for the brain, lung, and bone metastases of breast cancer. We performed in vitro and in vivo preclinical experiments as well as analysis on patient tumor specimens to evaluate the targets and repositioned drugs. Two known drugs, Sunitinib (FDA approved for renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor) and Dasatinib (FDA approved for chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia), were shown to prohibit the metastatic colonization in brain. The TMH-52 cohort includes 11 patients who were examined with brain metastasis at the time of breast cancer diagnosis. The other 41 patients were examined with other organ metastasis at the time of breast cancer diagnosis.

Project description:The outcome for patients afflicted with glioblastoma (GBM), the most common and malignant of primary brain tumors in adults, has changed little despite decades of clinical, translational, and basic research. Any effective, systemically administered GBM therapy needs to target cellular components that are indispensable for the malignant phenotype with drugs that cross the blood brain barrier (BBB) and have manageable toxicities. However, while a number of signaling pathways have been shown to drive the malignant phenotype in GBM, and while relatively non-toxic, CNS permeant inhibitors of several of these have been identified, their efficacy in GBM has been disappointing. In this study, we examine the mechanism of resistance to the Kif11 inhibitor ispinesib in murine and human GBM. We find that development of resistance in these tumors occurs by a mechanism not previously described for Kif11 inhibitors, is associated with broad scale transcriptomic and phenotypic changes, and can be reversed with drugs that are FDA approved or in clinical investigation. Our findings also point to ways of enhancing the efficacy of Kif11 inhibitors that are directly translatable into a clinical setting.The outcome for patients afflicted with glioblastoma (GBM), the most common and malignant of primary brain tumors in adults, has changed little despite decades of clinical, translational, and basic research. Any effective, systemically administered GBM therapy needs to target cellular components that are indispensable for the malignant phenotype with drugs that cross the blood brain barrier (BBB) and have manageable toxicities. However, while a number of signaling pathways have been shown to drive the malignant phenotype in GBM, and while relatively non-toxic, CNS permeant inhibitors of several of these have been identified, their efficacy in GBM has been disappointing. In this study, we examine the mechanism of resistance to the Kif11 inhibitor ispinesib in murine and human GBM. We find that development of resistance in these tumors occurs by a mechanism not previously described for Kif11 inhibitors, is associated with broad scale transcriptomic and phenotypic changes, and can be reversed with drugs that are FDA approved or in clinical investigation. Our findings also point to ways of enhancing the efficacy of Kif11 inhibitors that are directly translatable into a clinical setting.

Dataset Information

Proteome-wide profiling study unmasked lineage-based and clinical feature-based molecular landscapes of pituitary neuroendocrine tumors

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure