P95-HER2 promotes metastatic progression by biasing MRTFA dependent signaling

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Proto-oncogene Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2, HER2) exists in naturally occurring isoforms.
• These isoforms, including the N-terminally truncated p95, influence breast cancer progression and metastasis.
• Isoform-specific signaling pathways contribute to distinct tumor behaviors.

Purpose of the Study:

• To investigate how different HER2 isoforms differentially promote "go-or-grow" phenotypes.
• To elucidate the role of tyrosine autophosphorylation sites in the HER2 intracellular tail.
• To understand the molecular mechanisms driving isoform-specific tumor cell behaviors and metastasis.

Main Methods:

• Generation of humanized full-length HER2 (WT), exon-16 splice HER2 (d16), and p95 HER2 expressing tumor cell lines from HER2 Crainbow mice.
• Functional assays including proliferation, tumor growth rate, cell motility, collective cell migration, cellular morphology, and invasive potential.
• Quantitative analysis, single-cell analysis, and gene knockdown experiments (MRTFA, TGFB1I1) were performed.

Main Results:

• WT, d16, and p95 HER2 expressing cells exhibited distinct behaviors: WT cells favored proliferation and collective migration, d16 cells favored proliferation and individual motility, and p95 cells favored individual motility and invasion.
• p95 cells showed a myogenic-like state transition with increased nuclear translocation of Myocardin Related Transcription Factor A (MRTFA).
• Knockdown of MRTFA or TGFB1I1 inhibited the p95 invasive phenotype; mutation of tyrosine 1139 (Y1139F) in p95 cells abolished invasion and motility.

Conclusions:

• HER2 isoforms differentially utilize tyrosine autophosphorylation sites to promote distinct "go-or-grow" phenotypes.
• The p95 HER2 isoform's invasive phenotype is dependent on MRTFA nuclear translocation, mediated by Y1139.
• Targeting HER2-biased signaling pathways is crucial for developing therapeutics to intercept metastasis.