A SNAI2-PEAK1 stromal axis drives progression and lapatinib resistance in HER2-positive breast cancer by supporting a cytokine expression profile that converges on PI3K/Akt signaling

Abstract

38Intercellular mechanisms by which the stromal microenvironment contributes to solid tumor 39 progression and targeted therapy resistance remain poorly understood, presenting significant 40 clinical hurdles. PEAK1 (Pseudopodium-Enriched Atypical Kinase One) is an actin cytoskeleton-41 and focal adhesion-associated pseudokinase that promotes cell state plasticity and cancer 42 metastasis by mediating growth factor-integrin signaling crosstalk. Here, we determined that 43 stromal PEAK1 expression predicts poor outcomes in HER2-positive breast cancers high in 44SNAI2 expression and enriched for MSC content. Notably, we identified that mesenchymal stem 45 cells (MSCs) and cancer-associated fibroblasts (CAFs) express high PEAK1 protein levels and 46MSCs require PEAK1 to potentiate tumorigenesis, lapatinib resistance and metastasis of HER2-47 65Cell state plasticity enhances intratumoral heterogeneity and has been shown to be a culprit 66 underlying metastasis, therapy resistance and progression in cancer [1][2][3]. Previous studies have 67 demonstrated a causative relationship between increased stromal tissue content (i.e., 68 desmoplasia), including cancer associated fibroblasts (CAFs) or mesenchymal stem cells 69 (MSCs), in breast cancers and lapatinib resistance or metastasis [4][5][6][7]. In the case of HER2-70 positive breast cancer, where upregulation of the receptor tyrosine kinase HER2 (ErbB2) occurs 71in approximately 20% of all breast malignancies [8], both trastuzumab-and lapatinib-based 72 regimens offer significant clinical benefit [9]. However, a substantial percentage of these tumors 73 display either primary resistance or may be initially sensitive but then adapt to develop acquired 74 resistance [10], and clinical work suggests that patients who progress on lapatinib therapy 75 commonly develop metastatic disease [11]. Importantly, stromal cell non-autonomous 76 mechanisms by which the tumor microenvironment drives lapatinib resistance and/or resistance-77 associated metastasis remain poorly understood. 78Pseudopodium-Enriched Atypical Kinase One (PEAK1 or SGK269) is a cytoskeleton-79 associated pseudokinase [12] and member of the new NFK3 kinase family that has been 80 demonstrated to play key roles in cancer initiation and progression across multiple cancer types 81 including breast [13][14][15], pancreatic [12, 16], lung [17] and colon [12, 18, 19]. Importantly, two 82 other NFK3 kinase family members (SGK223 or Pragmin and PEAK3) have been recently 83 demonstrated to also regulate cancer progression [20, 21]. We previously characterized breast 84 cancer cell autonomous functions of PEAK1 and upstream eIF5A1/2-dependent translation in 85 mediating epithelial-mesenchymal transition (EMT), metastasis and transforming growth factor 86 beta (TGFβ)/fibronectin signaling [13][14][15] 22]. In this regard, PEAK1 has been previously identified 87 as part of the meta-adhesome [23] and a regulator of focal adhesion dynamics [24]. Notably, 88PEAK1 was recently determined to be a core constituent of the fibr...

Polarimetric coherent diffraction imaging on cancer-associated fibroblasts and SARS-CoV-2 viruses

“…The TB129 cancer-associated fibroblasts were provided by Dr. Julia Tchou's laboratory of the Perleman Center for Advanced Medicine at the University of Pennsylvania. Isolation and maintenance protocols of these CAFs have been described [17,18]. The TB129 cancer-associated fibroblasts were plated on collagen, fibronectin, or laminin extracellular matrix proteins (5µg/mL).…”