[F31] Regulation of Early Breast Cancer Invasion by Cancer-Associated Fibroblasts
Ente: National Cancer Institute
Scadenza: 2029-06-30
Importo max: 50.114 EUR
Paese: US
Descrizione
Project Summary / Abstract
Ductal carcinoma in situ (DCIS) is a non-deadly, pre-invasive lesion, which, if left untreated, can progress to
invasive breast cancer (IBC), a disease with a significantly worse prognosis. While genetic alterations fail to
explain this transition, structural changes in the tumor microenvironment (TME) may play a critical role in enabling
disease progression. TME alterations, including activation of cancer-associated fibroblasts (CAFs) and
increased extracellular matrix (ECM) stiffness have been correlated to disease progression, yet the precise
mechanisms by which these factors initiate the transition from DCIS to IBC remain unclear. In this proposal, we
utilize ex vivo analyses to identify transcriptomic, proteomic, and mechanical features associated with CAF
populations and determine how these features correlate with invasive progression. With these findings, we will
develop an in vitro stromal model and, by employing advanced perturbation techniques, we will determine if
these features of the stromal matrix are causal drivers of disease progression. The overall hypothesis of this
proposal is that CAF-driven matrix remodeling, through fibronectin secretion or contractility-driven collagen
bundling, generates a mechanical niche that drives carcinoma invasion. Preliminary single-cell sequencing work
of patient samples reveals collagen and fibronectin signaling as the dominant cell-cell signaling pathways
between CAF populations and invasive carcinoma cells within invasive breast cancer. Additionally, preliminary
work from our 3D in vitro stromal model reveals CAFs to be mechanoresponsive to matrix properties and are
necessary to facilitate carcinoma invasion. In Aim 1, we will determine the correlative relationships between CAF
phenotype, transcriptomic profiles, and matrix mechanics within ex vivo DCIS and IBC patient samples. In Aim
2, we will identify how matrix mechanics shape CAF phenotype and whether CAF-driven ECM deposition and
remodeling drive mechanical changes in ECM within a 3D stromal model. In aim 3, we will establish whether
CAF-mediated matrix alterations are sufficient to enable carcinoma invasion within a 3D co-culture stromal
model. Using cutting edge analysis techniques, the proposed work will establish a comprehensive understanding
of the biophysical, molecular, and cellular landscape distinguishing the location, phenotype, and context of CAFs
in DCIS versus IBC. Additionally, this proposal features an innovative in vitro experimental design that seeks to
uncover how CAFs respond to and remodel 3D viscoelastic matrices, and to establish the mechanical
interactions between CAFs and carcinoma cells that drive invasion. Completion of this proposed work will
improve our understanding of the mechanisms underlying breast cancer invasion and inform therapeutic
strategies.
Istituzione: STANFORD UNIVERSITY
PI: Cole James Allan
Progetto: 1F31CA310602-01
Settori: National Cancer Institute
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