title: The invadopodia scaffold protein Tks5 is required for the growth of human breast cancer cells in vitro and in vivo.
abstract: The ability of cancer cells to invade underlies metastatic progression. One mechanism by which cancer cells can become invasive is through the formation of structures called invadopodia, which are dynamic, actin-rich membrane protrusions that are sites of focal extracellular matrix degradation. While there is a growing consensus that invadopodia are instrumental in tumor metastasis, less is known about whether they are involved in tumor growth, particularly in vivo. The adaptor protein Tks5 is an obligate component of invadopodia, and is linked molecularly to both actin-remodeling proteins and pericellular proteases. Tks5 appears to localize exclusively to invadopodia in cancer cells, and in vitro studies have demonstrated its critical requirement for the invasive nature of these cells, making it an ideal surrogate to investigate the role of invadopodia in vivo. In this study, we examined how Tks5 contributes to human breast cancer progression. We used immunohistochemistry and RNA sequencing data to evaluate Tks5 expression in clinical samples, and we characterized the role of Tks5 in breast cancer progression using RNA interference and orthotopic implantation in SCID-Beige mice. We found that Tks5 is expressed to high levels in approximately 50% of primary invasive breast cancers. Furthermore, high expression was correlated with poor outcome, particularly in those patients with late relapse of stage I/II disease. Knockdown of Tks5 expression in breast cancer cells resulted in decreased growth, both in 3D in vitro cultures and in vivo. Moreover, our data also suggest that Tks5 is important for the integrity and permeability of the tumor vasculature. Together, this work establishes an important role for Tks5 in tumor growth in vivo, and suggests that invadopodia may play broad roles in tumor progression.
authors.affiliation: Tumor Microenvironment and Metastasis Program, NCI Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Barbara
authors.initials: B
authors.lastname: Blouw
authors.affiliation: Tumor Microenvironment and Metastasis Program, NCI Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Manishha
authors.initials: M
authors.lastname: Patel
authors.affiliation: Tumor Microenvironment and Metastasis Program, NCI Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Shinji
authors.initials: S
authors.lastname: Iizuka
authors.affiliation: Tumor Microenvironment and Metastasis Program, NCI Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Abdullah
authors.affiliation: Tumor Microenvironment and Metastasis Program, NCI Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Weon Kyoo
authors.initials: WK
authors.lastname: You
authors.affiliation: Tumor Microenvironment and Metastasis Program, NCI Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Xiayu
authors.initials: X
authors.lastname: Huang
authors.affiliation: Tumor Microenvironment and Metastasis Program, NCI Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Jian-Liang
authors.initials: JL
authors.lastname: Li
authors.affiliation: Tumor Microenvironment and Metastasis Program, NCI Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Begoña
authors.initials: B
authors.lastname: Diaz
authors.affiliation: Tumor Microenvironment and Metastasis Program, NCI Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: William B
authors.initials: WB
authors.lastname: Stallcup
authors.affiliation: Tumor Microenvironment and Metastasis Program, NCI Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Courtneidge
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D016513:Mice, SCID
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C478582:SH3PXD2A protein, human
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