Radiotherapy-Activated Cancer-Associated Fibroblasts Promote Tumor Progression through Paracrine IGF1R Activation.

Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer, a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAFs are abundantly present, the effects of RT to CAF and its impact on cancer cells are unknown. We evaluated the damage responses of CAF to RT and investigated changes in colorectal cancer cell growth, transcriptome, metabolome, and kinome in response to paracrine signals emerging from irradiated CAF. RT to CAF induced DNA damage, p53 activation, cell-cycle arrest, and secretion of paracrine mediators, including insulin-like growth factor-1 (IGF1). Subsequently, RT-activated CAFs promoted survival of colorectal cancer cells, as well as a metabolic switch favoring glutamine consumption through IGF1 receptor (IGF1R) activation. RT followed by IGF1R neutralization in orthotopic colorectal cancer models reduced the number of mice with organ metastases. Activation of the downstream IGF1R mediator mTOR was significantly higher in matched (intrapatient) samples and in unmatched (interpatient) samples from rectal cancer patients after neoadjuvant chemoradiotherapy. Taken together, our data support the notion that paracrine IGF1/IGF1R signaling initiated by RT-activated CAF worsens colorectal cancer progression, establishing a preclinical rationale to target this activation loop to further improve clinical responses and patient survival.Significance: These findings reveal that paracrine IGF1/IGF1R signaling promotes colorectal cancer progression, establishing a preclinical rationale to target this activation loop. Cancer Res; 78(3); 659-70. ©2017 AACR.

Cancer-associated adipose tissue promotes breast cancer progression by paracrine oncostatin M and Jak/STAT3 signaling.

Increasing evidence supports the critical roles played by adipose tissue in breast cancer progression. Yet, the mediators and mechanisms are poorly understood. Here, we show that breast cancer-associated adipose tissue from freshly isolated tumors promotes F-actin remodeling, cellular scattering, invasiveness, and spheroid reorganization of cultured breast cancer cells. A combination of techniques, including transcriptomics, proteomics, and kinomics enabled us to identify paracrine secretion of oncostatin M (OSM) by cancer-associated adipose tissue. Specifically, OSM, expressed by CD45(+) leucocytes in the stromal vascular fraction, induced phosphorylation of STAT3 (pSTAT3-) Y705 and S727 in breast cancer cells and transcription of several STAT3-dependent genes, including S100 family members S100A7, S100A8, and S100A9. Autocrine activation of STAT3 in MCF-7 cells ectopically expressing OSM-induced cellular scattering and peritumoral neovascularization of orthotopic xenografts. Conversely, selective inhibition of OSM by neutralizing antibody and Jak family kinases by tofacitinib inhibited STAT3 signaling, peritumoral angiogenesis, and cellular scattering. Importantly, nuclear staining of pSTAT3-Y705 identified at the tumor invasion front in ductal breast carcinomas correlates with increased lymphovascular invasion. Our work reveals the potential of novel therapeutic strategies targeting the OSM and STAT3 axis in patients with breast cancer harboring nuclear pSTAT3-Y705.

Activation of adenylyl cyclases, regulation of insulin status, and cell survival by G(alpha)olf in pancreatic beta-cells.

Because we recently identified the G(alpha)olf subunit in rat pancreatic beta-cells, we investigated the downstream effectors and the biological functions of this G protein in HEK-293T cells and the insulin-secreting mouse betaTC-3 cell line. With the use of transient transfection of HEK-293T cells with constitutively activated G(alpha)olf (G(alpha)olfQ214L, i.e., AG(alpha)olf), together with expression vectors encoding the adenylyl cyclase (AC) isoforms (AC-I to -VIII and soluble AC), compared with cotransfections using AG(alphas) (G(alphas)R201C), we observed that AG(alpha)olf preferentially activates AC-I and -VIII, which are also expressed in beta-cells. Stable overexpression of wild-type or AG(alpha)olf in betaTC-3 cells resulted in partial attenuation of insulin secretion and biosynthesis, suggesting that chronic activation of the G(alpha)olf-signaling pathway is associated with beta-cell desensitization. In agreement, transfected betaTC-3 cells present a decreased insulin content with respect to parental cells, whereas the proinsulin convertases PC-1 and PC-2 were unaffected. Furthermore, betaTC-3-AG(alpha)olf cells are resistant to serum starvation-induced apoptosis. Our findings suggest that G(alpha)olf is involved in insulin status, cell survival, and regeneration of the insulin-secreting beta-cells during development and diabetes.