This proposal will examine the unanticipated hypothesis that the ?6?4 integrin (referred to as `?4') contributes to the initiation and metastasis of breast tumors by a non-cell autonomous mechanism. This hypothesis derives from the observations that the expression of ?4 is low or absent in breast cancer stem cells (CSCs) but that it contributes to the formation and metastasis of breast cancers. A major goal of this proposal is to reconcile these discrepant observations and understand how ?4 contributes to tumor formation and metastasis. Interestingly, triple-negative breast cancers (TNBCs) contain a distinct sub-population of cells characterized by high expression of the ?4 integrin (?4high) that is distinct from CSCs (?4-/low/CD24low/CD44high), exhibits basal epithelial differentiation and lacks stem cell properties. These observations indicate that repression of ?4 is necessary for CSC function. In fact, we observed unexpectedly that ?4 expression in CSCs promotes their differentiation and inhibits their self-renewal. The first specific aim will investigate the mechanism that underlies this phenomenon and it will focus on the exciting possibility that it involves the ability of ?4 to modulate focal adhesions and cytoskeletal tension resulting in diminished stem cell properties.
This aim will also test the possibility that alterations in cytoskeletal tension have a causal role in promoting the differentiation of CSCs. The second specific aim will evaluate the hypothesis that the ?4high sub-population exerts non-cell autonomous regulation of CSCs. In other terms, a key function of the ?4high subpopulation is to expand the CSC population. More specifically, it is proposed that this distinct sub-population engages in paracrine signaling with CSCs mediated by parathyroid hormone-related protein (PTHrP) and that this signaling contributes to the expansion of CSCs. This hypothesis is based on the observations that ?4 regulates PTHrP expression and that the ?4high sub-population and CSCs are in proximity in breast tumors. Also, our preliminary data indicate that the ?4high sub-population helps to maintain self-renewal and survival. These observations provide an explanation for how the ?4 integrin contributes to tumor initiation and metastasis without being expressed in CSCs. The final specific aim will study the relationship between CSCs and ?4high cells in vivo and evaluate their relative contribution to tumor initiation and metastasis. The first set of experiments will examine whether both CSCs and ?4high cells are required for efficient tumor formation and metastasis using a transgenic model of TNBC. The second sub-aim probe more deeply into the relationship between CSCs and ?4high cells by evaluating the extent to which CSCs differentiate in vivo and assessing their association with ?4high cells in niches. These goals will be facilitated by the use of reporter constructs to tag these distinct populations. This approach will allow us to address several key issues including the frequency that CSCs (GFP+) differentiate in vivo, the association of ?4high and CSCs in `niches' and the relative frequency of CSCs and ?4high cells in metastases.

Public Health Relevance

This proposal seeks to understand mechanisms that contribute to the formation and growth of breast cancers with an emphasis on tumor heterogeneity and the inter-relationship among different sub-populations of tumor cells. We propose to investigate how a specific sub-population contributes to tumor formation and metastasis by regulating the expansion and function of cancer stem cells. The results to be obtained from these studies will have a major impact on our understanding of the biology of breast cancer and reveal new mechanisms for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA168464-07
Application #
9483257
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Ault, Grace S
Project Start
2012-07-09
Project End
2022-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
Samanta, Sanjoy; Guru, Santosh; Elaimy, Ameer L et al. (2018) IMP3 Stabilization of WNT5B mRNA Facilitates TAZ Activation in Breast Cancer. Cell Rep 23:2559-2567
Goel, Hira Lal; Pursell, Bryan; Shultz, Leonard D et al. (2016) P-Rex1 Promotes Resistance to VEGF/VEGFR-Targeted Therapy in Prostate Cancer. Cell Rep 14:2193-2208
Yoshii, Tatsuyuki; Geng, Yingying; Peyton, Shelly et al. (2016) Biochemical and biomechanical drivers of cancer cell metastasis, drug response and nanomedicine. Drug Discov Today 21:1489-1494
Samanta, S; Sun, H; Goel, H L et al. (2016) IMP3 promotes stem-like properties in triple-negative breast cancer by regulating SLUG. Oncogene 35:1111-21
Chang, Cheng; Goel, Hira Lal; Gao, Huijie et al. (2015) A laminin 511 matrix is regulated by TAZ and functions as the ligand for the ?6B?1 integrin to sustain breast cancer stem cells. Genes Dev 29:1-6
Parker, Matthew W; Linkugel, Andrew D; Goel, Hira Lal et al. (2015) Structural basis for VEGF-C binding to neuropilin-2 and sequestration by a soluble splice form. Structure 23:677-87
Barney, L E; Dandley, E C; Jansen, L E et al. (2015) A cell-ECM screening method to predict breast cancer metastasis. Integr Biol (Camb) 7:198-212
Li, Jiarong; Sun, Huayan; Feltri, M Laura et al. (2015) Integrin ?4 regulation of PTHrP underlies its contribution to mammary gland development. Dev Biol 407:313-20
Goel, Hira Lal; Gritsko, Tatiana; Pursell, Bryan et al. (2014) Regulated splicing of the ?6 integrin cytoplasmic domain determines the fate of breast cancer stem cells. Cell Rep 7:747-61
Samanta, Sanjoy; Pursell, Bryan; Mercurio, Arthur M (2013) IMP3 protein promotes chemoresistance in breast cancer cells by regulating breast cancer resistance protein (ABCG2) expression. J Biol Chem 288:12569-73

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