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Principal Investigator: Lalita A. Shevde
Organization: UNIVERSITY OF ALABAMA AT BIRMINGHAM
Fiscal Year: 2024
Award: $173,559
Funding agency: National Cancer Institute
ABSTRACT
During tumor progression, loss of cell:cell adhesion and detachment from the extracellular matrix induces
dynamic reorganization of the cytoskeleton, formation of invadopodia by the tumor cells, and activation of
epithelial-to-mesenchymal transition. This is enabled by tuning molecular programs in order to adapt to loss of
attachment. Merlin, encoded by the NF2 gene, is a member of the ezrin-radixin-moesin protein family that links
membrane proteins to the cortical actin cytoskeleton and regulates adhesion, migration, cell-cell contact,
proliferation, and signal transduction. Merlin is critically involved in contact-dependent inhibition of growth.
We found that Merlin protein levels are reduced in the majority of cases of infiltrating ductal carcinoma and
metastatic breast cancer tissues. Decreased Merlin protein expression was also seen with advanced nodal
involvement in breast cancer. In order to ascribe clinical relevance, we re-capitulated the loss of Merlin in breast
cancer cells. Merlin deficiency elicited a markedly invasive phenotype, morphologically and programmatically
evident as epithelial-to-mesenchymal transition. In order to overcome the challenge of embryonic lethality of a
total Nf2-knockout, we generated a unique mammary-specific Nf2-knockout mouse mammary tumor model.
These mice show remarkably accelerated development of tumors.
In this R21 application, our objective is to target potential liabilities in Merlin-deficient mammary tumors to mitigate
their metastasis-conducive tumor portfolio. Using multiple Merlin-deficient mammary tumor systems and tumor-
derived organoids, we will investigate (i) targeting aberrantly activated Hh signaling in Merlin-deficient tumors,
and (ii) the potential to target deregulated tryptophan metabolism in Merlin-deficient tumors. Our approaches are
non-overlapping and complementary. Outcomes from our work will present two unprecedented strategies to
target possible liabilities in Merlin-deficient breast cancer; these findings can be expanded and/or translated to
other tumor types that harbor Merlin deficiency.
Terms: <Acceleration><Actins><Adhesions><Biologic Models><Biological Models><Body Tissues><Breast Cancer><Breast Cancer Cell><Breast Cancer Model><Breast Neoplasms><Breast Tumors><Breast tumor model><Cancers><Cell Body><Cell Communication and Signaling><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cell Survival><Cell Viability><Cell-Cell Adhesion><Cell-Extracellular Matrix><Cells><Cellular Matrix><Cellular Proliferation><Chemoresistance><Clinical Trials><Cytoskeletal Gene><Cytoskeletal Modeling><Cytoskeletal Organization><Cytoskeletal Organization Process><Cytoskeletal Proteins><Cytoskeletal Reorganization><Cytoskeletal System><Cytoskeleton><Development><Diagnosis><ECM><Ectoderm><Embryo><Embryo Development><Embryogenesis><Embryonic><Embryonic Development><Epithelium><Erinaceidae><Exploratory/Developmental Grant><Extracellular Matrix><F-Actin><FDA approved><Failure><Filamentous Actin><Foundations><Gene Family><Generalized Growth><Genetic Alteration><Genetic Change><Genetic defect><Goals><Growth><Hedgehogs><Immune Evasion><Immunotherapeutic agent><Intracellular Communication and Signaling><Investigation><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><L-tryptophanase><Link><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mammary Cancer><Mammary Neoplasms><Membrane><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Merlin><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Metastatic breast cancer><Mice><Mice Mammals><Model System><Modeling><Moesin-Ezrin-Radixin-Like Protein><Molecular><Morphology><Murine><Mus><Mutation><NF2><NF2 Gene Product><NF2 gene><Neoplasm Metastasis><Nervous System><Neurofibromatosis 2 Gene Product><Neurofibromatosis 2 Genes><Neurofibromatosis Type 2 Protein><Neurofibromin 2><Neurologic Body System><Neurologic Organ System><Nodal><Non-metastatic><Nonmetastatic><Null Mouse><Oral><Organoids><Outcome><Patients><Phenotype><Process><Proliferating><Protein Family><Proteins><R21 Mechanism><R21 Program><Receptor Protein><Reporting><Role><Scaffolding Protein><Schwannomerlin><Schwannomin><Schwannomin Protein><Secondary Neoplasm><Secondary Tumor><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Surface Proteins><System><TDO2><TRPO><Testing><Tissue Growth><Tissues><Translating><Tryptamin 2,3-Dioxygenase><Tryptophan 2,3-Dioxygenase><Tryptophan Indole-Lyase><Tryptophan Metabolism><Tryptophan Metabolism Pathway><Tryptophanase><Tumor Cell><Tumor Suppressor Proteins><Tumor Tissue><Tumor-Derived><Work><biological signal transduction><breast tumor cell><cancer cell><cancer metastasis><cancer progression><chemoresistant><chemotherapy resistance><chemotherapy resistant><clinical relevance><clinically relevant><developmental><epithelial to mesenchymal transition><exploratory developmental study><ezrin><genetic approach><genetic strategy><genome mutation><immune drugs><immune evasive><immune-based therapeutics><immunologic therapeutics><immunotherapeutics><immunotherapy agent><infiltrating duct carcinoma><infiltrating ductal adenocarcinoma><infiltrating ductal carcinoma><inhibitor><innovate><innovation><innovative><intracellular skeleton><invasive ductal adenocarcinoma><invasive ductal carcinoma><malignancy><malignant breast tumor><mammary><mammary cancer model><mammary tumor><mammary tumor model><member><membrane structure><membrane-organizing extension spike protein><metabolism measurement><metabolome><metabolomics><metabonome><metabonomics><migration><moesin><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><nf 2 Genes><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><ontogeny><permissiveness><pharmacologic><phosphoprotein p81><pre-clinical study><preclinical study><programs><protein expression><radixin><radixin protein><receptor><receptor-mediated signaling><social role><targeted agent><therapeutic evaluation><therapeutic testing><translatable strategy><tumor><tumor cell metastasis><tumor progression><tumor suppressor><tumorigenic>