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Principal Investigator: Bisrat G Debeb
Organization: UNIVERSITY OF TEXAS AT AUSTIN
Fiscal Year: 2024
Award: $669,122
Funding agency: National Cancer Institute
Highly aggressive cancers are frequently characterized by tumor cell emboli within the lymphatic and blood
vasculature. Termed lymphovascular space invasion (LVSI), this phenomenon has been of high interest to
cancer researchers as it may represent one of the necessary events during progression from a localized to
metastatic cancer. Despite these biological implications, relatively little is known about the mechanisms that
directly enable and promote LVSI formation. Existing in vitro systems lack the multi-tissue and vascular
complexity to model these events. In vivo models, while available, are not amenable to mechanistic studies or
pharmacological screening because of the sheer number of animals required for such experiments. Therefore,
a critical need in the field is to develop models that can faithfully recreate specific phenomena related to
metastatic spread, such as LVSI. Using our novel, multi-cellular, vascularized 3D in vitro platform, we were able
to model intravasation of epithelial emboli and LVSI formation of inflammatory breast cancer (IBC) ex vivo for
the first time. IBC is an aggressive breast cancer variant characterized by extensive LVSI. Gene expression data
from IBC patients identified stromal infiltration and activation as a critical component of LVSI. Using our new in
vitro platform and animal models, we were able to confirm this finding when we discovered that macrophages in
the microenvironment directly promote LVSI formation. Leveraging our new in vitro platform, we propose to
answer three major questions relating to LVSI: What mechanisms promote 1) formation, 2) migration, and 3)
intra-vessel survival of tumor emboli? We hypothesize that LVSI formation is a two-step process where matrix
properties and epithelial marker, E-cadherin which is strongly expressed in IBC, regulate tumor emboli formation
and survival, while the cytokine axis, CCR7/CCL21, homes epithelial emboli to lymphatics. To test this
hypothesis, we propose to use our new in vitro platform in three aims: 1) Determine the role of matrix mechanics
and lymphatic pumping in the temporal kinetics of LVSI, 2) Determine the role of E-cadherin in emboli formation
and survival, and 3) Identify the mechanisms that promote emboli homing to vasculature. Despite the strong
clinical evidence that LVSI is a critical, pre-metastatic phenomenon, our inability to fully recreate LVSI in vitro
has severely limited our mechanistic understanding of responsible pathways. For the first time, our team was
able to recreate LVSI ex vivo using a novel microfluidic platform. Here, we propose to use our in vitro platform
to define the signaling steps that promote LVSI formation and survival in vasculature to better define critical
targets related to cancer progression. To execute the proposal, we have assembled a team composed of experts
in tissue bioengineering, clinical research, and preclinical models of breast cancer. If successful, our work will
offer novel and customizable platforms for studying LVSI and new biological discoveries that hold therapeutic
potential for patients with advanced breast cancer.
Terms: <3-D><3-Dimensional><3D><92-kDa Gelatinase><92-kDa Type IV Collagenase><API3><Affect><Animal Model><Animal Models and Related Studies><Animals><Anoikis><Apoptotic><BIRC4><BIRC4 gene><Binding><Biological><Biomedical Engineering><Blood><Blood Reticuloendothelial System><Blood Vessels><Body Tissues><Breast><Breast Cancer><Breast Cancer Model><Breast Cancer Patient><Breast Neoplasms><Breast Tumor Patient><Breast Tumors><Breast tumor model><CCL19><CCL19 gene><CCL21><CCL21 gene><CKb11><CKb9><Cadherin-1><Cancers><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Locomotion><Cell Migration><Cell Movement><Cell Signaling><Cell Survival><Cell Viability><Cell-Extracellular Matrix><Cell-to-Cell Interaction><Cells><Cellular Migration><Cellular Motility><Characteristics><Chemotactic Cytokines><Clinical><Clinical Research><Clinical Study><Collagen><Data><Dendritic Cells><Disseminated Malignant Neoplasm><Distant><E-Cadherin><ECM><Embolism><Embolus><Epithelial Calcium-Dependent Adhesion Protein><Epithelial Cells><Epithelial-Cadherin><Epithelium><Event><Extracellular Matrix><Fiber><Gelatinase B><Gene Expression><Home><Homing><Homologous Chemotactic Cytokines><Immune><Immunes><In Vitro><Infiltration><Intercrines><Intracellular Communication and Signaling><Invaded><Investigators><Kinetics><Ligands><Lymphatic><Lymphatic function><Lymphovascular><MGC34433><MGC34555><MIP-3b><MIP3B><MMP-9><MMP-9 Protein><Macrophage><Macrophage Gelatinase><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mammary Cancer><Mammary Neoplasms><Mammary gland><Matrix Metalloproteinase-9><Mechanics><Mediating><Mesenchymal><Metastasis><Metastasize><Metastatic Cancer><Metastatic Lesion><Metastatic Malignant Neoplasm><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Microfluidics><Modeling><Molecular Interaction><Mφ><Neoplasm Metastasis><Oncogenic><Organ><Pathway interactions><Patients><Permeability><Physiologic pulse><Porosity><Pre-Clinical Model><Preclinical Models><Primary Neoplasm><Primary Tumor><Process><Property><Proteins><Pulse><Research Personnel><Researchers><Resistance><Role><SCYA19><SCYA21><SIS cytokines><SLC><Sampling><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><System><TCA4><Testing><Therapeutic><Time><Tissue Engineering><Tissues><Tumor Cell><Tumor Cell Migration><Tumor Promotion><Tumor Suppressor Proteins><Type V Collagenase><Uvomorulin><Variant><Variation><Vascularization><Veiled Cells><Work><XIAP><advanced breast cancer><advanced stage breast cancer><aggressive breast cancer><bio-engineered><bio-engineers><bioengineered tissue><bioengineering><biologic><biological engineering><biological signal transduction><cancer cell><cancer metastasis><cancer microenvironment><cancer progression><cell motility><chemoattractant cytokine><chemokine><cytokine><engineered tissue><experiment><experimental research><experimental study><experiments><homes><in vivo><in vivo Model><inflammatory breast cancer><interest><lymph flow><lymph pump><lymphatic contraction><lymphatic flow><lymphatic propulsion><lymphatic pump><lymphatic vasculature><malignancy><malignant breast tumor><mammary cancer model><mammary tumor><mammary tumor model><mechanic><mechanical><migration><model of animal><multiplexed imaging><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><novel><pathway><pharmacologic><pre-clinical><preclinical><resistant><screening><screenings><social role><therapeutic target><three dimensional><trafficking><tumor><tumor cell metastasis><tumor growth><tumor microenvironment><tumor progression><tumor suppressor><vascular><µfluidic>