Mutant p53–associated myosin-X upregulation promotes breast cancer invasion and metastasis

Abstract

Mutations of the tumor suppressor TP53 are present in many forms of human cancer and are associated with increased tumor cell invasion and metastasis. Several mechanisms have been identified for promoting dissemination of cancer cells with TP53 mutations, including increased targeting of integrins to the plasma membrane. Here, we demonstrate a role for the filopodia-inducing motor protein Myosin-X (Myo10) in mutant p53-driven cancer invasion. Analysis of gene expression profiles from 2 breast cancer data sets revealed that MYO10 was highly expressed in aggressive cancer subtypes. Myo10 was required for breast cancer cell invasion and dissemination in multiple cancer cell lines and murine models of cancer metastasis. Evaluation of a Myo10 mutant without the integrin-binding domain revealed that the ability of Myo10 to transport β 1 integrins to the filopodia tip is required for invasion. Introduction of mutant p53 promoted Myo10 expression in cancer cells and pancreatic ductal adenocarcinoma in mice, whereas suppression of endogenous mutant p53 attenuated Myo10 levels and cell invasion. In clinical breast carcinomas, Myo10 was predominantly expressed at the invasive edges and correlated with the presence of TP53 mutations and poor prognosis. These data indicate that Myo10 upregulation in mutant p53-driven cancers is necessary for invasion and that plasma-membrane protrusions, such as filopodia, may serve as specialized metastatic engines.

Lgr4 and Lgr5 drive the formation of long actin-rich cytoneme-like membrane protrusions

“…Two recent reports suggest that MyoX is an important marker of cancer invadopodia and cancer cell invasiveness. MyoX-dependent transport of integrins to the filopodium tip is essential for tumor cell invasion (Arjonen et al, 2014) and metastasis . These reports also demonstrate that MyoX expression is an important marker of aggressive and highly malignant breast cancers.…”

Pancreatic Cancer Progression Relies upon Mutant p53-Induced Oncogenic Signaling Mediated by NOP14

“…These data indicated that NOP14 enhanced the stability of mutp53 mRNA in PDAC cells. Interestingly, several of the abovementioned genes have been reported to be direct or indirect effectors of p53 in diverse cancers (2,3,(12)(13)(14). To determine whether these genes are regulated by mutp53 in PDAC cells, qRT-PCR, and immunoblotting analyses were performed and we found that mutp53 inhibition led to increased expression of P21 and decreased expression of PDGFRb, TGFB1, ZEB1, EGFR, and SMAD2 in PANC-1 and MIA PaCa-2 cells ( Fig.…”

Regulated lysosomal exocytosis mediates cancer progression

“…Among these changes is gaining the ability to alter cellular metabolic/catabolic machinery to create the most permissive conditions for invasion, dissemination, and survival (41). Many determinants of migration/invasion are cytoskeletal and vesicular trafficking components and biosynthetic/processing enzymes (42)(43)(44).…”

“…Altered expression of motor myosins has been linked to cancer cell survival, invasion, and metastasis, indicating that cytoskeletal components mediating cell contractility and organelle trafficking function in cancer cell behavior (44,49). Recent examples are Myosin-X upregulation in mutant p53-driven breast cancer models and Myosin-Va in colorectal cancer (42,50). In addition, up-regulation of other proteins involved in regulated exocytosis (that is, BAIAP3 and Rab27b) has been linked to tumorigenesis in desmoplastic small round cell tumor and breast cancer (51,52).…”