Document text
Principal Investigator: Jonathan M Kurie
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2024
Award: $530,294
Funding agency: National Cancer Institute
Cancer cells are embedded in a protective and nourishing “niche”, an
environment that cancer cells create by secreting proteins into their surroundings. Because cancer cells
depend on their niche to survive and spread to other parts of the body, we believe that therapies designed to
inhibit secretion could suppress cancer spread and thereby improve the length and quality of cancer patients'
lives. Developing such therapies will require a better understanding of how secretion is activated in cancer. Our
proposal will address this knowledge gap. Here we show that p53 protein loss, an established driver of cancer
spread, enhances secretion by reprogramming the Golgi apparatus, a master regulator of protein transport in
cells. We show that p53 loss activates the formation of a Golgi protein complex that controls secretion, and we
have identified secreted proteins that are essential for lung cancer growth and spread. Furthermore, we have
identified a drug that can block the formation of the Golgi protein complex, reduce secretion, and inhibit lung
cancer growth and spread. In this application, we seek to elucidate the molecular underpinnings and
therapeutic implications of the heightened secretion driven by p53 loss. In aim 1, we propose studies to
elucidate how the Golgi protein complex enhances secretion and drives lung cancer progression. In aim 2, we
propose studies to determine how the Golgi protein complex increases sensitivity to the drug we have
identified. These studies will provide insight into how secretion is activated in cancer and may lead to new
ways to target secretion in cancer patients.
Terms: <1-Phosphatidylinositol 4-Kinase><Acceleration><Adenocarcinoma Cell><Adhesions><Antioncogene Protein p53><Autophagocytosis><Autophagosome><Binding Proteins><Binding Sites><Biogenesis><Biological><Body Tissues><Body part><Bypass><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancer Genes><Cancer Patient><Cancer-Promoting Gene><Cancers><Cell Body><Cell membrane><Cells><Cellular Tumor Antigen P53><Clinical><Combining Site><Complex><Conditioned Culture Media><Conditioned Medium><Cytoplasmic Membrane><Dedications><Development><Docking><Drugs><EC 2.7.1.67><Ectopic Expression><Endoplasmic Reticulum><Environment><Enzyme Gene><Enzymes><Ergastoplasm><GOLPH3><GOLPH3 gene><GORASP2><GORASP2 gene><GRASP55><Generalized Growth><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Golgi><Golgi Apparatus><Golgi Complex><Golgi Phosphoprotein 3><Golgi Reassembly Stacking Protein 2><Golgi Reassembly Stacking Protein, 55-KD><Growth><Human><Hydrophobicity><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><KRAS(G12D)><KRASG12D><Knowledge><LC/MS><Length><Ligand Binding Protein><Ligand Binding Protein Gene><Lung Adenocarcinoma><Malignant Cell><Malignant Glandular Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Mediating><Medication><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modern Man><Molecular><Murine><Mus><Mutation><N-terminal><NH2-terminal><NPIK><Neoplasm Metastasis><Oncogenes><Oncoprotein p53><Origin of Life><P53><PI 4-Kinase><PI3CGPI4KBeta><PI4K92><PI4KB><PI4KBeta><PIK4CB><PIK4CB gene><PTK Receptors><Pathway interactions><Peptide Signal Sequences><Peptide Transport><Pharmaceutical Preparations><Phosphatidylinositiol Kinase><Phosphatidylinositol 4-Kinase><Phosphatidylinositol 4-Kinase Beta><Phosphatidylinositol 4-Kinase, Catalytic, Beta><Phosphatidylinositol 4-Kinase, Type III, Beta><Phosphatidylinositol Kinase Type II><Phosphoinositide Kinase><Phosphoinositide-4-Kinase Catalytic Beta Polypeptide><Phosphoprotein P53><Phosphoprotein pp53><Plasma Membrane><Play><Primary Neoplasm><Primary Tumor><Process><Property><Protein Binding><Protein Secretion><Protein TP53><Protein Trafficking><Proteins><PtdIns 4-Kinase><Pulmonary Cancer><Pulmonary malignant Neoplasm><Reactive Site><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Regulatory Pathway><Sampling><Secondary Neoplasm><Secondary Tumor><Signal Peptide><Signal Sequences><Stress><Surface><T8 Cells><T8 Lymphocytes><TP53><TP53 gene><TRP53><Testing><Therapeutic><Tissue Growth><Tissues><Transforming Genes><Transmembrane Receptor Protein Tyrosine Kinase><Tumor Burden><Tumor Load><Tumor Protein p53><Tumor Protein p53 Gene><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><Vesicle><Wortmannin-Sensitive Phosphatidylinositol 4-Kinase><angiogenesis><antagonism><antagonist><autophagy><biologic><bound protein><cancer cell><cancer metastasis><cancer microenvironment><cancer progression><cohort><design><designing><developmental><drug/agent><genome mutation><immune suppression><immune suppressive activity><immune suppressive function><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><inhibitor><insight><intervention design><liquid chromatography mass spectrometry><lung cancer><malignancy><metastatic process><mouse model><murine model><mutant><neoplasm progression><neoplasm/cancer><neoplastic progression><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><ontogeny><p53 Antigen><p53 Genes><p53 Tumor Suppressor><pathway><pharmacologic><plasmalemma><programs><protein complex><protein p53><protein signal sequence><protein transport><shRNA><short hairpin RNA><small hairpin RNA><small molecule><therapeutically effective><therapy design><tool><treatment design><tumor><tumor cell metastasis><tumor growth><tumor microenvironment><tumor progression><tumorigenic><vesicle transport><vesicular transport>