A SNAI2-PEAK1-INHBA stromal axis drives progression and lapatinib resistance in HER2-positive breast cancer by supporting subpopulations of tumor cells positive for antiapoptotic and stress signaling markers

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.

The value of cuproptosis-related differential genes in guiding prognosis and immune status in patients with skin cutaneous melanoma

“…SNAI2 has been implicated in the diseases of melanocytes development and a variety of cancers ( Cobaleda et al, 2007 ). SNAI2 plays a crucial role in regulating T-cell lineages ( Pioli et al, 2016 ) and cancer cell stemness ( Chen et al, 2021 ; Peng et al, 2022 ), as well as modulating lapatinib resistance in HER2-positive breast cancer ( Hamalian et al, 2021 ) and enhancing 5-fluorouracil sensitivity in colorectal cancer ( Findlay et al, 2014 ). We developed a risk-scoring model for SKCM patients according to seven cuproptosis-related differential genes, using a training set to distinguish between low -risk and high -risk groups.…”

Single-cell landscape reveals active cell subtypes and their interaction in the tumor microenvironment of gastric cancer

“…This subset showed high activity of angiogenesis, hedgehog signaling, epithelial mesenchymal transition, NF-κB pathway, and IL10 signaling, suggesting it had essential roles in the remodeling of cancer immunity and progression. In addition, a published study indicated that INHBA over-expression promotes cell proliferation and may be epigenetically regulated in esophageal adenocarcinoma [42].…”

The Role of Mesenchymal Stem Cells in Modulating the Breast Cancer Microenvironment

“…In addition, they identified that MSCs expressing PEAK1 contribute to the emergence of distinct subpopulations within HER2-positive breast cancer cells characterized by high levels of p-Akt, MCL1, and GRP78, as well as low levels of p-γH2AX and VIM. These subpopulations exhibit resistance to lapatinib and demonstrate enhanced tumorigenic potential both in vitro and in vivo settings 197 .…”