Unveiling how the molecular landscape of TNBC sculps intratumoral macrophage origin and function

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Charlotte Helena Rivas
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $51,974
Funding agency: National Cancer Institute

ABSTRACT/PROJECT SUMMARY. Triple-negative breast cancer (TNBC) is a heterogenous set of diseases
and is considered one of the most aggressive breast cancer subtypes. TNBC lack of well-defined endocrine
markers limits the therapeutic options for these patients. This has spurred significant efforts towards developing
therapies directed towards the tumor microenvironment, but these have demonstrated only modest success.
This is attributed to the high functional heterogeneity of macrophages, which is in part determined by their origin,
and the distinct molecular landscape of different TNBC subtypes. Our overarching objective is to elucidate a
link between the molecular profile of TNBC and macrophage origin and function in order to establish the
groundwork for the finetuning of the next generation of macrophage-targeted therapies to consider the tumor's
molecular signature as a proxy for macrophage function. The overall objective of this proposal is to examine a
potential enrichment of macrophages from different origins and functional profiles in TNBC subtypes with
divergent molecular landscapes. The central hypothesis is that luminal TNBC subtypes are enriched for tumor
antagonistic TRMs and their ablation gives way to pro-tumor MDMs colonization. The rationale is that
intratumoral macrophages can stem from different origins (i.e., embryonically derived tissue-resident (TRMs) or
monocyte-derived (MDMs)), which strongly influence their functional profile. MDMs are associated with tumor
promoting properties, while TRMs have been reported to play tumor antagonistic roles. Our preliminary data
supports that TNBC with divergent molecular profiles are enriched for macrophages of divergent origins. This
proposal consists of proof-of-principle studies to demonstrate macrophages TNBC molecular subtypes that
preserve epithelial properties are enriched for tumor antagonistic TRMs, while TNBC molecular subtypes that
have acquired mesenchymal features are enriched for tumor-promoting MDMs. Along this trajectory, the central
hypothesis will be tested by pursuing two specific aims. Aim 1 will determine the origin and function of
intratumoral macrophages in claudin-low and luminal-like TNBC tumor subtypes and the need for epithelial
features to main a TRM pool. Aim 2 will determine a skewing of the macrophage compartment towards pro-
tumor MDMs in luminal-like TNBC after cessation of macrophage-ablation therapy. The proposed studies are
innovative because they will establish a correlation between TNBC molecular profile and macrophage origin and
function. The project is significant because establishing the molecular landscape of TNBC as a proxy for
macrophage function will serve to tailor macrophage-targeted therapies to account for macrophage
heterogeneity.

Terms: <Ablation><Adoptive Transfer><Assay><B220><Bioassay><Biological Assay><Blood monocyte><Body Tissues><Bone Marrow><Bone Marrow Grafting><Bone Marrow Reticuloendothelial System><Bone Marrow Transplant><Bone Marrow Transplantation><Breast Cancer><CD45><Cell Body><Cells><Characteristics><Color><Data><Disease><Disorder><ES cell><Embryo><Embryonic><Endocrine><Epithelium><Exhibits><Expression Signature><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Fluorescence Activated Cell Sorting Fractionation><Fluorescence-Activated Cell Sorting><Fluorescence-Activated Cell Sortings><GP180><Gene Expression Profile><Gene variant><Generations><Hematopoietic><Heterogeneity><Home><Human><Immune infiltrates><Incidence><Induction of Apoptosis><LY5><Link><Macrophage><Maintenance><Malignant Breast Neoplasm><Marrow Transplantation><Marrow monocyte><Mesenchymal><Mice><Mice Mammals><Modality><Modern Man><Molecular><Molecular Fingerprinting><Molecular Profiling><Murine><Mus><Myelogenous><Myeloid><Mφ><PTPRC><PTPRC gene><Patients><Persons><Play><Population><Position><Positioning Attribute><Prevalence><Property><Proxy><Receptor Protein><Recurrence><Recurrent><Reporting><Research Proposals><Role><Shapes><Survival Rate><T200><TNBC><Testing><Therapeutic><Tissues><Tumor Promotion><Tumor Subtype><aggressive breast cancer><allele variant><allelic variant><cancer microenvironment><cancer progression><cancer sub-types><cancer subtypes><clinical relevance><clinically relevant><develop therapy><embryonic progenitor><embryonic stem cell><experience><experiment><experimental research><experimental study><experiments><expression subtypes><flow cytophotometry><gene expression pattern><gene expression signature><genetic variant><genomic variant><hemopoietic><homes><immune cell infiltrate><innovate><innovation><innovative><intervention development><malignant breast tumor><mammary><molecular profile><molecular signature><molecular sub-types><molecular subsets><molecular subtypes><monocyte><neoplasm progression><neoplastic progression><next generation><preservation><prevent><preventing><progenitor><receptor><resistance to therapy><resistant to therapy><social role><standard care><standard treatment><stem><stem cell of embryonic origin><success><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapy development><therapy resistant><transcriptional profile><transcriptional signature><transplant model><treatment development><treatment resistance><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor microenvironment><tumor progression>