Abstract
Intercellular mechanisms by which the stromal microenvironment contributes to solid tumor progression and targeted therapy resistance remain poorly understood, presenting significant clinical hurdles. PEAK1 (Pseudopodium-Enriched Atypical Kinase One) is an actin cytoskeleton- and focal adhesion-associated pseudokinase that promotes cell state plasticity and cancer metastasis by mediating growth factor-integrin signaling crosstalk. Here, we determined that stromal PEAK1 expression predicts poor outcomes in HER2-positive breast cancers high in SNAI2 expression and enriched for MSC content. Specifically, we identified that the fibroblastic stroma in HER2-positive breast cancer patient tissue stains positive for both nuclear SNAI2 and cytoplasmic PEAK1. Furthermore, mesenchymal stem cells (MSCs) and cancer-associated fibroblasts (CAFs) express high PEAK1 protein levels and potentiate tumorigenesis, lapatinib resistance and metastasis of HER2-positive breast cancer cells in a PEAK1-dependent manner. Analysis of PEAK1-dependent secreted factors from MSCs revealed INHBA/activin-A as a necessary factor in the conditioned media of PEAK1-expressing MSCs that promotes lapatinib resistance. Single-cell CycIF analysis of MSC-breast cancer cell co-cultures identified enrichment of p-Akthigh/p-gH2AXlow, MCL1high/p-gH2AXlow and GRP78high/VIMhigh breast cancer cell subpopulations by the presence of PEAK1-expressing MSCs and lapatinib treatment. Bioinformatic analyses on a PEAK1-centric stroma-tumor cell gene set and follow-up immunostaining of co-cultures predict targeting antiapoptotic and stress pathways as a means to improve targeted therapy responses and patient outcomes in HER2-positive breast cancer and other stroma-rich malignancies. These data provide the first evidence that PEAK1 promotes tumorigenic phenotypes through a previously unrecognized SNAI2-PEAK1-INHBA stromal cell axis.
Highlights
Cell state plasticity enhances intratumoral heterogeneity and has been shown to be a culprit underlying metastasis, therapy resistance and progression in cancer [1,2,3,4]
We report that PEAK1 expression in breast cancer stroma is associated with relapse in HER2-positive breast cancer and that PEAK1 is predominantly expressed in tumor associated SNAI2positive fibroblast-like cells
We mined data [29] on breast cancer stromal gene expression and discovered that PEAK1 expression was significantly higher in malignant breast stroma (Fig. 1c), and that elevated stromal PEAK1 expression positively correlated with disease relapse (Fig. 1d)
Summary
Cell state plasticity enhances intratumoral heterogeneity and has been shown to be a culprit underlying metastasis, therapy resistance and progression in cancer [1,2,3,4]. In the case of HER2-positive breast cancer, where upregulation of the receptor tyrosine kinase HER2 (ErbB2) occurs in ~20% of all tumors [9], both trastuzumab- and lapatinib-based regimens offer significant clinical benefit [10]. A substantial percentage of these tumors display either primary resistance or may be initially sensitive but adapt to develop acquired resistance [11], and clinical work suggests that patients who progress on lapatinib therapy commonly develop metastatic disease [12]. While recent work has reported that stromal fibroblasts limit HER2 kinase therapy responses via antiapoptotic signaling [13], the stromal cell non-autonomous mechanisms underlying HER2-targeted therapy resistance and/or resistance-associated metastasis remain poorly understood.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
