{"doi":"10.1038/s41388-021-01906-2","title":"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":"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-Akt high /p-gH2AX low , MCL1 high /p-gH2AX low and GRP78 high /VIM high 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.","journal":"Oncogene","year":2021,"id":167991,"datarank":0.5244761342199721,"base_score":3.4965075614664802,"endowment":3.4965075614664802,"self_citation_contribution":0.5244761342199721,"citation_network_contribution":0.0,"self_endowment_contribution":0.5244761342199721,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":32,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9502,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":697238,"name":"Robert Güth","orcid":null,"position":1,"is_corresponding":false},{"id":697239,"name":"Farhana Runa","orcid":null,"position":2,"is_corresponding":false},{"id":697240,"name":"Francesca Sanchez","orcid":null,"position":3,"is_corresponding":false},{"id":697241,"name":"Eric Vickers","orcid":null,"position":4,"is_corresponding":false},{"id":392096,"name":"Megan J. Agajanian","orcid":"0000-0002-1296-5665","position":5,"is_corresponding":false},{"id":697242,"name":"Justin Molnar","orcid":null,"position":6,"is_corresponding":false},{"id":636682,"name":"Tuan M. Nguyen","orcid":"0000-0003-4879-3962","position":7,"is_corresponding":false},{"id":697243,"name":"Joshua Gamez","orcid":null,"position":8,"is_corresponding":false},{"id":329057,"name":"Jonathan D. Humphries","orcid":"0000-0002-8953-7079","position":9,"is_corresponding":false},{"id":316457,"name":"Anupma Nayak","orcid":"0000-0002-7445-1897","position":10,"is_corresponding":false},{"id":329061,"name":"Martin J. Humphries","orcid":"0000-0002-4331-6967","position":11,"is_corresponding":false},{"id":256200,"name":"Julia Tchou","orcid":"0000-0002-2032-1579","position":12,"is_corresponding":false},{"id":499879,"name":"Ioannis K. Zervantonakis","orcid":"0000-0003-2386-9553","position":13,"is_corresponding":false},{"id":351503,"name":"Jonathan A. 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