Functionally selective signaling of HER2 isoforms controls early dissemination and immune escape

About This Grant

ABSTRACT Although cancer screening has led to improved detection of early-stage cancers, many cancers can recur and metastasize several years later. In breast cancer, there is a growing and urgent need to develop therapeutics that intercept cancer cells before they invade and disseminate. For instance, although targeted therapies against erb-b2 receptor tyrosine kinase 2 (ERBB2 or HER2) have proven highly successful, metastasis is untreatable. Preliminary data reveal how isoforms of HER2 that are associated with treatment resistance and recurrent metastases – e.g. the exon 16 null isoform (..........and the N-terminally truncated isoform (p95) – elicit distinct tumor phenotypes. Our own observations in a mouse model of HER2 isoform heterogeneity demonstrate that p95 HER2 drives early transitions to motile and invasive behaviors prior to detection. This is in stark contrast to ........or wild-type HER2 (WT)-driven murine mammary cancers that proliferate and are generally detectable prior to invasion. Thus, understanding how HER2 isoforms signal in vivo could provide new opportunities for preventing or treating metastatic breast cancers. The objective here is to determine how isoforms of HER2 can drive distinct tumor cell behaviors. The significance of this application is that it will provide molecular signaling mechanisms explaining how ........ and p95 control ‘go’ and ‘grow’ decisions and immune escape, thereby providing pathways for intercepting or treating metastasis. New molecular insights provide preliminary evidence that these behaviors are receptor-intrinsic, with each isoform signaling through distinct effectors to differentially engage downstream signaling networks associated with either ‘go’ or ‘grow’ phenotypes. Moreover, we show that the ‘go’ phenotype found in p95 expressing cells is associated with upregulation of PDL1 immune checkpoint expression to allow for evasion of adaptive immunity. A strong scientific premise supports testing the central hypothesis that biased signaling of HER2 isoforms promotes functionally selective programs of cancer cell proliferation, invasion, and immune escape. Three specific aims are proposed to test this hypothesis. (Aim 1) Determine how functionally selective HER2 isoform signaling drives ‘grow’ or ‘go’ cell decisions, (Aim 2). Determine how p95 HER2 signaling promotes invasion and early dissemination. (Aim 3) Determine how HER2 isoforms drive intrinsic pathways for avoiding immune recognition. This approach is technically innovative and includes a MPI interdisciplinary team skilled in state-of-the-art live imaging, receptor engineering, and cancer immunology. The innovation of the proposal lies in the identification of isoform-induced signaling bias at HER2 that leads to functionally selective behaviors of tumor cells, including proliferation, motility, and immune escape. The expected long-term impact will be elucidation of signaling targets that could lead to strategies for preventing breast cancer metastasis. The mouse models that we describe in the research plan are utilized to recapitulate the extraordinary complexity of the in vivo environment (such as early dissemination to distant organs and immune escape), which cannot be modelled in vitro.