Project description:The tyrosine kinase receptors HER2 and HER3 play an important role in breast cancer. The HER2/HER3 heterodimer is a critical oncogenic unit associated with reduced relapse-free and decreased overall survival. We provide gene expression profile of the mammary epithelial cells MCF10A expressing HER2, HER3 or HER2/HER3 and grown in three-dimensional cultures for 15 days in the presence of heregulin, a known HER3-ligand that stabilizes and activates the HER2/HER3 heterodimer. The mammary epithelial cells MCF10A were transduced with retroviral vectors expressing HER2, HER3 or both. Cells from each group were grown for 15 days in three-dimensional cultures. At the end of the experiment, RNA was extracted for gene expression analysis.
Project description:The tyrosine kinase receptors HER2 and HER3 play an important role in breast cancer. The HER2/HER3 heterodimer is a critical oncogenic unit associated with reduced relapse-free and decreased overall survival. We provide gene expression profile of the mammary epithelial cells MCF10A expressing HER2, HER3 or HER2/HER3 and grown in three-dimensional cultures for 15 days in the presence of heregulin, a known HER3-ligand that stabilizes and activates the HER2/HER3 heterodimer.
Project description:The first bona fide PTP proto-oncogene was the Src-homology 2 domain-containing phosphatase SHP2 (encoded by PTPN11), an ubiquitously expressed PTP that transduces mitogenic, pro-survival, cell fate and/or pro-migratory signals from numerous growth factor-, cytokine- and extracellular matrix receptors. In malignancies, SHP2 is hyperactivated either downstream of oncoproteins or by mutations.We provide analysis of the mammary epithelial cells MCF10A overexpressing human HER2 and HER3 and grown in 3D cultures for 15 days in the presence or absence of SHP2. The human mammary epithelial cells MCF10A were transduced with a doxycycline-inducible lentiviral vector expressing a CTRL miR or SHP2 miR1 or SHP2 miR2. Cells from each group were grown in 3D cultures, and the knockdown of SHP2 was induced for 15 days. RNA was extracted for gene expression analysis.
Project description:The first bona fide PTP proto-oncogene was the Src-homology 2 domain-containing phosphatase SHP2 (encoded by PTPN11), an ubiquitously expressed PTP that transduces mitogenic, pro-survival, cell fate and/or pro-migratory signals from numerous growth factor-, cytokine- and extracellular matrix receptors. In malignancies, SHP2 is hyperactivated either downstream of oncoproteins or by mutations.We provide analysis of the mammary epithelial cells MCF10A overexpressing human HER2 and HER3 and grown in 3D cultures for 15 days in the presence or absence of SHP2.
Project description:Cancer-associated fibroblasts (CAF) are part of the tumor microenvironment that enable cancer cells to establish metastases, but the mechanisms of these interactions are not fully known. Herein, we identify a novel paracrine mechanism in which CAF-secreted asporin (ASPN) activates ErbB signaling and subsequent migration of adjacent metastatic prostate cancer cells. Our data support that ASPN binds directly to HER3 to induce HER2/HER3 heterodimerization and activation of the PI3-kinase and MAP-kinase pathways. Genetic and therapeutic inhibition of HER2/HER3 ablated ASPN-induced signaling and migration. Small molecule and antibody-drug conjugates targeting HER2/HER3 demonstrated efficacy in vitro, with near complete resolution of tumors in vivo. Clinically, over 50% of human prostate cancer metastases show expression of HER2/HER3, along with ASPN expressing CAF. Collectively, these findings support ASPN functions as a HER3 ligand to induce cellular migration which can be targeted with anti-HER2/HER3 therapies, highlighting the potential clinical benefit for patients with metastatic prostate cancer.
Project description:Cancer-associated fibroblasts (CAF) are part of the tumor microenvironment that enable cancer cells to establish metastases, but the mechanisms of these interactions are not fully known. Herein, we identify a novel paracrine mechanism in which CAF-secreted asporin (ASPN) activates ErbB signaling and subsequent migration of adjacent metastatic prostate cancer cells. Our data support that ASPN binds directly to HER3 to induce HER2/HER3 heterodimerization and activation of the PI3-kinase and MAP-kinase pathways. Genetic and therapeutic inhibition of HER2/HER3 ablated ASPN-induced signaling and migration. Small molecule and antibody-drug conjugates targeting HER2/HER3 demonstrated efficacy in vitro, with near complete resolution of tumors in vivo. Clinically, over 50% of human prostate cancer metastases show expression of HER2/HER3, along with ASPN expressing CAF. Collectively, these findings support ASPN functions as a HER3 ligand to induce cellular migration which can be targeted with anti-HER2/HER3 therapies, highlighting the potential clinical benefit for patients with metastatic prostate cancer.
Project description:Cancer-associated fibroblasts (CAF) are part of the tumor microenvironment that enable cancer cells to establish metastases, but the mechanisms of these interactions are not fully known. Herein, we identify a novel paracrine mechanism in which CAF-secreted asporin (ASPN) activates ErbB signaling and subsequent migration of adjacent metastatic prostate cancer cells. Our data support that ASPN binds directly to HER3 to induce HER2/HER3 heterodimerization and activation of the PI3-kinase and MAP-kinase pathways. Genetic and therapeutic inhibition of HER2/HER3 ablated ASPN-induced signaling and migration. Small molecule and antibody-drug conjugates targeting HER2/HER3 demonstrated efficacy in vitro, with near complete resolution of tumors in vivo. Clinically, over 50% of human prostate cancer metastases show expression of HER2/HER3, along with ASPN expressing CAF. Collectively, these findings support ASPN functions as a HER3 ligand to induce cellular migration which can be targeted with anti-HER2/HER3 therapies, highlighting the potential clinical benefit for patients with metastatic prostate cancer.
Project description:Cancer-associated fibroblasts (CAF) are part of the tumor microenvironment that enable cancer cells to establish metastases, but the mechanisms of these interactions are not fully known. Herein, we identify a novel paracrine mechanism in which CAF-secreted asporin (ASPN) activates ErbB signaling and subsequent migration of adjacent metastatic prostate cancer cells. Our data support that ASPN binds directly to HER3 to induce HER2/HER3 heterodimerization and activation of the PI3-kinase and MAP-kinase pathways. Genetic and therapeutic inhibition of HER2/HER3 ablated ASPN-induced signaling and migration. Small molecule and antibody-drug conjugates targeting HER2/HER3 demonstrated efficacy in vitro, with near complete resolution of tumors in vivo. Clinically, over 50% of human prostate cancer metastases show expression of HER2/HER3, along with ASPN expressing CAF. Collectively, these findings support ASPN functions as a HER3 ligand to induce cellular migration which can be targeted with anti-HER2/HER3 therapies, highlighting the potential clinical benefit for patients with metastatic prostate cancer.
Project description:Cancer-associated fibroblasts (CAF) are part of the tumor microenvironment that enable cancer cells to establish metastases, but the mechanisms of these interactions are not fully known. Herein, we identify a novel paracrine mechanism in which CAF-secreted asporin (ASPN) activates ErbB signaling and subsequent migration of adjacent metastatic prostate cancer cells. Our data support that ASPN binds directly to HER3 to induce HER2/HER3 heterodimerization and activation of the PI3-kinase and MAP-kinase pathways. Genetic and therapeutic inhibition of HER2/HER3 ablated ASPN-induced signaling and migration. Small molecule and antibody-drug conjugates targeting HER2/HER3 demonstrated efficacy in vitro, with near complete resolution of tumors in vivo. Clinically, over 50% of human prostate cancer metastases show expression of HER2/HER3, along with ASPN expressing CAF. Collectively, these findings support ASPN functions as a HER3 ligand to induce cellular migration which can be targeted with anti-HER2/HER3 therapies, highlighting the potential clinical benefit for patients with metastatic prostate cancer.
Project description:Cancer-associated fibroblasts (CAF) are part of the tumor microenvironment that enable cancer cells to establish metastases, but the mechanisms of these interactions are not fully known. Herein, we identify a novel paracrine mechanism in which CAF-secreted asporin (ASPN) activates ErbB signaling and subsequent migration of adjacent metastatic prostate cancer cells. Our data support that ASPN binds directly to HER3 to induce HER2/HER3 heterodimerization and activation of the PI3-kinase and MAP-kinase pathways. Genetic and therapeutic inhibition of HER2/HER3 ablated ASPN-induced signaling and migration. Small molecule and antibody-drug conjugates targeting HER2/HER3 demonstrated efficacy in vitro, with near complete resolution of tumors in vivo. Clinically, over 50% of human prostate cancer metastases show expression of HER2/HER3, along with ASPN expressing CAF. Collectively, these findings support ASPN functions as a HER3 ligand to induce cellular migration which can be targeted with anti-HER2/HER3 therapies, highlighting the potential clinical benefit for patients with metastatic prostate cancer.