The laminin binding integrins (LB integrins) play critical roles during carcinoma initiation, progression, metastasis, and survival. Among the different integrins, only the LB integrins (a6?1, a6?4, a3?1, a7?1) undergo palmitoylation, and associate closely with tetraspanin CD151, which enables their recruitment into tetraspanin-enriched microdomains. In this context, CD151 and other associated partner proteins regulate LB integrin-dependent cell spreading, motility, signaling, adhesion strengthening, EGFR collaboration, and lateral diffusion, on epithelial, endothelial and other cell types. CD151 itself also associates positively with tumor cell malignancy, in multiple carcinoma types. In this regard, our CD151 knockout mice are deficient in hosting primary and/or secondary tumor growth in ectopic tumor injection models, and in a spontaneous mouse mammary tumor model. This host defect in CD151-null mice is due, at least in part, to a deficit in pathological angiogenesis. Tumor cell CD151 also notably supports tumor progression, as seen in both orthotopic and ectopic xenograft models. Consequently, we hypothesize that tetraspanin CD151 uses extracellular, intracellular, and lateral association sites to link LB integrins to tetraspanin-enriched microdomains, which contributes to the specialized functional properties of laminin-binding integrins, and promotes tumor cell malignancy. To test this model, we will carry out a comprehensive analysis of LB integrin and CD151-associated molecules, cytoskeletal interactions, and dominant negative mutations, both in vitro, and in vivo during primary and secondary tumor growth.
In Aim 1 we will use a differential mass spectrometry approach to identify additional membrane and cytoskeletal partner proteins for LB integrins, as well as possible compensating proteins, which preferentially associate with LB integrins when CD151 is absent.
In Aim 2, we will sort out positive and negative effects, exerted by the cytoskeleton on LB integrin functions, and on the EGFR.
Aim 3 will be used to amplify disruption of LB integrin functions, using a) dominant negative mutant forms of CD151, b) knockdown of proteins that may compensate for CD151 absence, and c) knockdown of supporting proteins.
In Aim 4, we will learn the extent to which LB integrin complexes contribute to primary tumor growth in vivo, using transgenic mouse models of spontaneous mammary cancer.
Aim 5 will study, in both tumor and host, the effects of LB integrin complex disruption on metastasis.
LB integrins and CD151 have been implicated in tumor progression at many levels, including tumor initiation, primary growth, and metastasis, through tumor effects and host animal effects. Our preliminary results suggest that disruption of LB integrin complexes, largely by deleting or modifying CD151, profoundly affects tumor progression, while minimally affecting normal physiology. Our proposed studies of this alternative method for modulating LB integrins should lead to novel strategies for therapeutic intervention in breast cancer and other cancers.
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