Despite recent advance in early diagnosis and adjuvant therapy, treatment of triple negative breast cancer (TNBC) remains a significant challenge because of the high incidence of metastasis and relapse after treatment. Signaling from extracellular matrix (ECM), an essential component of the tumor microenvironment, is required for TNBC progression and metastasis. However, it is not known how cancer cell-deposited ECM proteins and ECM signaling in cancer cells are regulated and promote TNBC metastasis/relapse. We recently identified Hsp47 as a hub of the ECM transcription network. Hsp47 is a molecular chaperon that regulates secretion and deposition of ECM proteins. Increased Hsp47 expression has been detected in TNBC and is associated with cancer metastasis. Silencing Hsp47 restrains the aggressive phenotype of TNBC cells in 3D culture and inhibits tumor growth and lung colonization in the xenograft model, indicating that increased Hsp47 expression is crucial for the TNBC progression. EMT promotes cancer progression by enhancing cancer cell dissemination and endowing cancer cells with ?stemness? properties that favor successful colonization in distant organs and contribute to chemoresistance. Platelet adhesion and activation are required for cancer cell colonization at the distal sites. We found that silencing Hsp47 in metastatic breast cancer cells significantly reduced platelet adhesion. These results suggest that Hsp47 promotes TNBC metastasis/relapse by inducing EMT and platelet recruitment.
In Aim 1, we will investigate the molecular mechanism by which Hsp47 regulates EMT and stemness properties.
In Aim 2, we will determine the cellular mechanism by which Hsp47 promotes colonization of breast cancer cells at the secondary organs.
In Aim 3, we will define the roles of Hsp47 in promoting cancer metastasis and chemoresistance in TNBC. This investigation will change the current concept of ECM microenvironment in cancer metastasis by revealing new roles of cancer cell-derived collagen in inducing cancer cell-platelet interaction and metastasis. Characterization of Hsp47 as a hub of collagen/DDR2 signaling will identify a novel pathway to inhibit TNBC progression and chemoresistance.
Defining roles of Hsp47 and collagen signaling in regulating platelet recruitment and cell plasticity will fill critical gaps in our knowledge of the tumor microenvironment and cancer metastasis. The study of Hsp47 in regulating DDR2 will identify a novel pathway regulating oncogene DDR2 and may characterize a potential strategy to sensitize TNBC to chemotherapy.
|Xiong, Gaofeng; Stewart, Rachel L; Chen, Jie et al. (2018) Collagen prolyl 4-hydroxylase 1 is essential for HIF-1? stabilization and TNBC chemoresistance. Nat Commun 9:4456|
|Qi, Yifei; Xu, Ren (2018) Roles of PLODs in Collagen Synthesis and Cancer Progression. Front Cell Dev Biol 6:66|
|Zhang, Hui; Fredericks, Tricia; Xiong, Gaofeng et al. (2018) Membrane associated collagen XIII promotes cancer metastasis and enhances anoikis resistance. Breast Cancer Res 20:116|
|Wang, Shike; Li, Zhenyu; Xu, Ren (2018) Human Cancer and Platelet Interaction, a Potential Therapeutic Target. Int J Mol Sci 19:|
|Xu, Ren (2017) Mammary epithelial polarity and macrophage infiltration. Macrophage (Houst) 4:|