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Principal Investigator: Colin Goding
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $393,894
Funding agency: National Cancer Institute
SUMMARY
Despite the emergence novel therapeutic modalities, including BRAF inhibitors and immunotherapies, over
7,100 people are expected to die each year from malignant melanoma, primarily from metastatic dissemination
and therapy resistance. The proposed studies leverage the expertise of the two co-PIs in tumor
microenvironment, the Integrated Stress Response (ISR) and melanoma progression to test the overall
hypothesis that as part of the adaptive response to tumor microenvironmental (TME) stress, bi-directional
interactions between melanoma cells and fibroblasts, endothelial cells and adipocytes promote survival,
metastatic dissemination, and therapy resistance. Preliminary results and published reports from the two PIs
indicate that the ISR is activated in human melanomas and that genetic or pharmacological disruption of the
ISR severely impairs primary tumor growth and metastasis in multiple experimental tumors, including
melanomas. The studies will delineate the salient roles of the transcription factor ATF4, a major transcriptional
effector of the Integrated Stress Response, in a pro-survival and pro-metastatic program mediated by the non-
canonical tumor suppressor BRN2, a transcription factor effector of multiple melanoma-associated signaling
pathways. To test the central hypothesis, we will pursue three specific aims: In Aim 1 we will use a novel,
conditional global ATF4 knockout mouse model, as well as Fibroblast (FB)-specific and Endothelial (EC)-
specific ATF4 knockout mice and cells to determine the role of ATF4 expression in each TME component on
melanoma progression and metastasis. Preliminary results with global or FB-specific deletion of ATF4 results
in a severe deficiency in tumor growth of flank melanoma tumors. In Aim 2 we will study how SRC promotes
melanoma progression via ATF4-BRN2 cooperativity. Both BRN2 and ATF4 can repress anoikis/apoptosis,
and in preliminary studies we reveal that BRN2 interacts with ATF4. Therefore, we will test the hypothesis that
Extracellular Matrix (ECM)-driven integrin signaling, and monounsaturated fatty acid (MUFA) uptake from
adipocytes and lymph converge on SRC to impose a cooperative BRN2-ATF4 anti-apoptotic and pro-
metastasis gene expression program, driven in part by hippo signaling. Finally, under Aim 3, we will determine
how MUFAs dictate melanoma phenotype. Here we will dissect a novel mechanism underpinning MUFA-
mediated nuclear localization of -catenin and test the hypothesis that the resulting SRC-driven nuclear CAV1-
-catenin complex promotes a pro-metastasis gene expression program via BRN2-ATF4, and the contribution
of ATF4 and BRN2 to melanoma phenotypic heterogeneity and tumor immune infiltration. By delineating how
the ISR uses ATF4 to coordinate the output of the TME to shape melanoma progression, we will identify
therapeutically exploitable pathways for anti-melanoma approaches.
Terms: <22-kD Gene Caveolae Protein><22kD Gene Caveolin 1 Caveolae Protein><3-D><3-Dimensional><3D><Ablation><Adipocytes><Adipose Cell><Allografting><Alpha Isoform Gene Caveolin 1><Anoikis><Antioxidants><Apoptosis><Apoptosis Pathway><Apoptotic><Autophagocytosis><B-raf-1><BRAF><BRAF gene><Basal Transcription Factor><Basal transcription factor genes><Beta Isoform Gene Caveolin 1><Binding><Blood Vessels><CAV Gene><CAV1><CAV1 gene><Cancer Genes><Cancer-Promoting Gene><Caveolin-1 Gene><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell-Extracellular Matrix><Cells><Co-culture><Cocultivation><Coculture><Coculture Techniques><Collagen><Complex><DNA Alteration><DNA Sequence Alteration><DNA mutation><ECM><ER stress><Endothelial Cells><Endothelium><Equilibrium><Experimental Neoplasms><Experimental Tumor><Exposure to><Extracellular Matrix><Fat Cells><Fatty Acid Desaturases><Fatty Acid Desaturating Enzymes><Fatty Acids><Fibroblasts><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genes><Genetic><Genetic Transcription><Genetic mutation><Growth><Heterogeneity><Heterograft><Heterologous Transplantation><Human><Immune infiltrates><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><Impairment><Inflammation><Integrins><Integrins Extracellular Matrix><Intracellular Communication and Signaling><Invaded><KO mice><Knock-out Mice><Knockout Mice><Link><Lipocytes><Lymph><MITF protein><Malignant Melanoma><Mature Lipocyte><Mature fat cell><Mediating><Mediator><Melanoma><Melanoma Cell><Melanoma Tumor><Metastasis><Metastasis to the Lung><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to the Lung><Metastatic Tumor><Metastatic Tumor to the Lung><Mice><Mice Mammals><Microphthalmic-associated transcription factor><Modality><Modeling><Modern Man><Molecular Interaction><Monounsaturated Fatty Acids><Murine><Mus><Neoplasm Metastasis><Non-Malignant><Nuclear><Null Mouse><O element><O2 element><Oncogenes><Oncogenic><Output><Oxygen><Pathway interactions><Patients><Persons><Phenotype><Primary Neoplasm><Primary Tumor><Programmed Cell Death><Proliferating><Publishing><RAFB1><RNA Expression><Recovery><Refractory><Reporting><Repression><Resistance><Role><Secondary Neoplasm><Secondary Tumor><Sequence Alteration><Shapes><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stress><Testing><Therapeutic><Therapeutic Intervention><Tissue Growth><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transforming Genes><Translational Inhibition><Translational Repression><Tumor Cell><Tumor Suppressor Proteins><Tumor growth in melanoma><Tumor-infiltrating immune cells><VIP21 Gene><Xenograft><Xenograft procedure><Xenotransplantation><angiogenesis><autophagy><balance><balance function><biological adaptation to stress><biological signal transduction><cancer metastasis><cancer microenvironment><check point blockade><checkpoint blockade><endoplasmic reticulum stress><gain of function><genomic alteration><immune cell infiltrate><immune cell infiltration of tumors><immune cells infiltrating the tumor><immune cells that infiltrate the tumor><immune check point blockade><immune checkpoint blockade><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved><infiltration of tumors by immune cells><inhibitor><intervention therapy><intratumoral immune cell><intratumoral immune infiltrate><lung metastasis><lymphatic fluid><metastasize to the lung><microphthalmia-associated transcription factor><mouse model><murine model><neoplastic cell><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><nonmalignant><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><nutrient deprivation><nutritional deprivation><ontogeny><pathway><pharmacologic><programs><pulmonary metastasis><reaction; crisis><resistant><response><social role><stress response><stress; reaction><targeted agent><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><three dimensional><transcription factor><transcription factor Microphthalmia><tumor><tumor cell metastasis><tumor growth><tumor immune cell><tumor immune infiltrate><tumor infiltration of immune cells><tumor microenvironment><tumor suppressor><tumorigenic><uptake><v-raf Murine Sarcoma Viral Oncogene Homolog B1><vascular><xeno-transplant><xeno-transplantation>