Wnt-driven adhesion and extracellular matrix dynamics in breast cancer metastasis - Project Summary Triple-negative breast cancer (TNBC), an aggressive breast cancer subtype that constitutes 10%–15% of all breast cancer cases in the United States, disproportionately affects Hispanic and African-American women. TNBC is associated with relatively poorer outcomes than other breast cancer subtypes due to the inherently invasive clinical behavior of TNBC and the lack of expression of molecules targeted by therapeutic agents that are effective for other breast cancer subtypes. TNBC displays molecular and transcriptomic heterogeneity, and both canonical (β-catenin–dependent) and noncanonical (β-catenin–independent) Wnt signaling dysfunction can mediate TNBC progression. Our group identified an inverse correlation between canonical and noncanonical Wnt signaling pathways, in which the noncanonical receptor, tyrosine kinase-like orphan receptor (Ror2), spatiotemporally regulates Wnt signaling in basal-like breast cancer. More recently, our lab identified that Wnt– Ror2 signaling can regulate tumor cell–driven extracellular matrix (ECM) modifications to support basal-like breast cancer invasion. However, the integration of Wnt signaling cues that drive ECM remodeling and promote colonization competence at distant sites remains unresolved. We hypothesize that Wnt signaling plasticity, influenced by the presence or absence of Ror2, fosters adhesion and matrix alterations in the lung metastatic niche to mediate micro-to-macrometastasis progression in TNBC. In Specific Aim 1, we will investigate how fluctuations in Wnt signaling modulate the ECM to bolster the ability of basal-like TNBC to colonize the lungs. Specifically, Aim 1.1 will map the dynamics of Wnt signaling transitions and monitor associated changes in ECM composition through various metastatic stages using models of lung metastasis. Aim 1.2 will focus on discerning alterations in the integrin–fibronectin relationship in response to genetic shifts in Wnt signaling. In Specific Aim 2, we will determine how Wnt signaling alterations influence tumor cell interactions with the lung endothelium, focusing on adhesion, extravasation, and macrometastatic progression post-colonization. Aim 2.1 will assess how perturbations in Wnt–Ror2 signaling impact interactions with the perivascular lung niche, potentially dictating patterns of basal-like TNBC tumor cell growth and arrest. Aim 2.2 will explore the role of Wnt signaling in regulating tumor dormancy cycles. Our overarching goal is to decode how Wnt signaling variations drive the metastatic journey of TNBC within the lungs. Utilizing both in vitro and in vivo methodologies, including genetically engineered mouse models of TNBC, we aim to unravel how Wnt–Ror2 signaling modifications affect metastatic aptitude in TNBC.
