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Principal Investigator: Roberta Faccio
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $393,846
Funding agency: National Cancer Institute
ABSTRACT
In order to survive, grow and metastasize, tumors need the support of a favorable host environment. Local
changes in normal cells in close proximity to a developing tumor can create a favorable tumor micro-environment
(TME) that is necessary for tumor growth. Mesenchymal populations, including cancer-associated fibroblasts
(CAFs), secrete pro- tumorigenic and immune suppressive factors, and produce extracellular matrix to create a
stiffer, tumor-conducive soil. Several CAF subsets with specific functions have been identified, however, whether
distinct CAF subsets derive from the same progenitor that acquire functional specificity during tumor progression
or from different progenitors committed to give rise to a specific CAF population, is under investigation.
We recently made the unexpected observation that cells expressing bone osteolineage marker Osterix (Osx) are
present in the TME of tumors outside the bone and support tumor growth. In adult animals, Osx is expressed by
committed osteoblasts (OB) and drives their differentiation. Surprisingly, we detected Osx in stromal cells,
isolated from various breast cancer tumors, expressing CAF and OB makers, and in the tumor-associated stroma
of patients with breast carcinomas. Co-injection of Osx+ cells with tumor cells enhance tumor growth.
Importantly, Osx expression correlates with poor prognosis in breast cancer. Based on these rather unexpected
findings, we hypothesize that bone-derived osteolineage Osx+ cells represent a novel subset of tumor infiltrating
stromal populations contributing to tumor progression and CAF diversity. Aim 1 will determine the functional
relevance of Osx+ cells in the TME and pre-metastatic sites; Aim 2 will determine the origin of Osx+ cells in the
TME and pre-metastatic sites. This information will broaden the concept of cellular heterogeneity within the TME
and offer a new platform for targeting the stroma with the purpose of inhibiting tumor growth.
Terms: <21+ years old><4T1><Adoptive Transfer><Adult><Adult Human><Affect><Antigen Presentation><Assay><Basal Transcription Factor><Basal transcription factor genes><Bioassay><Biological Assay><Bone Marrow><Bone Marrow Grafting><Bone Marrow Reticuloendothelial System><Bone Marrow Transplant><Bone Marrow Transplantation><Breast Cancer><Breast Carcinoma><Breast Neoplasms><Breast Tumors><Cancer Treatment><Cancers><Cell Body><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cell-Extracellular Matrix><Cells><ChIP Sequencing><ChIP-seq><ChIPseq><Circulation><Deposit><Deposition><Development><Disease><Disorder><Distant><ECM><Ectopic Expression><Embryo><Embryonic><Environment><Extracellular Matrix><Fibroblasts><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Generations><Genes><Genetic><Growth><Growth Agents><Growth Factor><Growth Substances><Heterogeneity><Immune><Immunes><Immunomodulation><Infiltration><Injections><Interruption><Investigation><Lung><Lung Respiratory System><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mammary Cancer><Mammary Carcinoma><Mammary Neoplasms><Marrow Transplantation><Mesenchymal><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Metastatic breast cancer><Mice><Mice Mammals><Murine><Mus><Neoplasm Metastasis><Normal Cell><Osteoblasts><Patients><Population><Production><Prognosis><Proteins Growth Factors><PyMT><Reporter Genes><Role><Secondary Neoplasm><Secondary Tumor><Site><Skeleton><Soil><Source><Specificity><Stromal Cells><Surface><TM-MKR><Tissue Growth><Transcription Factor Proto-Oncogene><Transcription factor genes><Transplantation><Tumor Cell><Tumor Markers><adult animal><adulthood><anti-cancer therapy><bone><breast cancer progression><cancer cell><cancer metastasis><cancer microenvironment><cancer progression><cancer therapy><cancer-directed therapy><cell sorting><chromatin immunoprecipitation-sequencing><cytokine><design><designing><developmental><fighting><immune modulation><immune regulation><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><malignancy><malignant breast tumor><mammary><mammary tumor><mature animal><mesenchymal stromal cell><mouse model><murine model><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><new marker><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel biomarker><novel marker><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><ontogeny><osteogenic><polyoma middle tumor antigen><postnatal><precancer><precancerous><premalignant><progenitor><promoter><promotor><pulmonary><recruit><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><skeletal progenitor><skeletal progenitor cell><skeletal stem cell><skeletons><social role><transcription factor><transplant><tumor><tumor biomarker><tumor cell metastasis><tumor growth><tumor microenvironment><tumor progression><tumor specific biomarker><tumorigenic>