Intrinsic FGFR2 and Ectopic FGFR1 Signaling in the Prostate and Prostate Cancer

Advanced castrate-resistant prostate cancer (CRPC) is a poorly prognostic disease currently lacking effective cure. Understanding the molecular mechanism that underlies the initiation and progression of CRPC will provide new strategies for treating this deadly disease. One candidate target is the fibroblast growth factor (FGF) signaling axis. Loss of the intrinsic FGF7/FGF10-type 2 FGF receptor (FGFR2) pathway and gain of the ectopic type 1 FGF receptor (FGFR1) pathway are associated with the progression to malignancy in prostate cancer (PCa) and many other epithelial originating lesions. Although FGFR1 and FGFR2 share similar amino acid sequences and structural domains, the two transmembrane tyrosine kinases elicit distinctive, even sometime opposite signals in cells. Recent studies have revealed that the ectopic FGFR1 signaling pathway contributes to PCa progression via multiple mechanisms, including promoting tumor angiogenesis, reprogramming cancer cell metabolism, and potentiating inflammation in the tumor microenvironment. Thus, suppression of FGFR1 signaling can be an effective novel strategy to treat CRPC

Optogenetic Control of Voltage-Gated Calcium Channels

Voltage-gated Ca(2+) (CaV ) channels mediate Ca(2+) entry into excitable cells to regulate a myriad of cellular events following membrane depolarization. We report the engineering of RGK GTPases, a class of genetically encoded CaV channel modulators, to enable photo-tunable modulation of CaV channel activity in excitable mammalian cells. This optogenetic tool (designated optoRGK) tailored for CaV channels could find broad applications in interrogating a wide range of CaV -mediated physiological processes

Ectopic Fibroblast Growth Factor Signaling in Reprogramming Prostate Cancer Cell Metabolism and Immune Evasion

Prostate cancer (PCa) is the third leading cause of cancer death. The lack of an effective cure for advanced stages and an overall low response to immunotherapy give prominence to the critical need for developing novel therapies. PCa has an “immune cold” tumor microenvironment (TME), suggesting that immunotherapy can be enhanced by converting the immune “cold” TME to immune “hot” TME, which will be at the front lines to overcome immune evasion in PCa. Understanding the mechanism of PCa progression and TME remodeling will be essential to change the unfavorable TME and develop new therapeutic strategies. To meet the challenges of bio-molecular synthesis for fast growth, cancer cells reprogram their metabolism to derive energy to aerobic glycolysis, and such reprograming usually results from a composite consequence of genetic and environmental changes. This includes the depletion of glucose and the accumulation of tumor-derived lactate. Together with the secretion of immunosuppressive cytokines, these contribute to establishing an immune “cold” TME, suggesting that suppression of metabolic reprogramming in cancer cells can be an effective way to inhibit immune evasion. However, as aerobic glycolysis and oxidative phosphorylation (OXPHOS) are also needed for T cell activation and function, general metabolic inhibitors directly targeting metabolism can disrupt hemostasis in T cells as well, and thus will not be effective for changing the immune “cold” tumors. A new cancer cell specific suppression of aerobic glycolysis without inhibiting T cell metabolism is needed to improve the PCa immunotherapy. In this study, we report that deletion of ectopic FGFR1 signaling reduced aerobic glycolysis and promoted OXPHOS in PCa cells, suggesting a reversal of PCa metabolic reprogramming. Since normal T cells do not express FGFR1, it is expected that suppression of FGFR1 signaling can be a normal strategy to selectively target aerobic glycolysis in PCa cells to improve PCa immunotherapy. We found that conditioned medium from PCa cells suppressed T cell growth in vitro, potentially through tumor-derived cytokines and metabolites secreted. We observed blunting ectopic FGFR1 signaling either by inactivating FGFR1 gene or by treating with FGFR tyrosine kinase inhibitor increased CD3⁺CD8⁺ T cells in the TRAMP PCa model, indicating that inactivating ectopic FGFR1 signaling facilitates penetration of T cells to the tumor. Moreover, this T-cell mediated immune response can be boosted by treating with anti-immune checkpoint antibody, anti-PD-1 antibody. In addition, bioinformatics analysis of the public database of the single-cell RNA sequence of human PCa revealed that the tumor with FGFR1 expression in epithelial cells was associated with a high CD8α⁺ T cell population, suggesting that high FGFR1 expression in epithelial cells suppressed infiltration of CD8α⁺ T cells, which is consistent with our data derived from PCa cell and mouse models. Together, the data suggest that the combination of FGFR1 inhibitor and anti-checkpoint treatment can be an effective way to increase CD8⁺ T cell-mediated immune response in prostate tumors, and therefore, reveals a novel strategy for PCa treatment

Emerging Role of ERBB2 in Targeted Therapy for Metastatic Colorectal Cancer: Signaling Pathways to Therapeutic Strategies

Despite recent improvements in the comprehensive therapy of malignancy, metastatic colorectal cancer (mCRC) continues to have a poor prognosis. Notably, 5% of mCRC cases harbor Erb-B2 receptor tyrosine kinase 2 (ERBB2) alterations. ERBB2, commonly referred to as human epidermal growth factor receptor 2, is a member of the human epidermal growth factor receptor family of protein tyrosine kinases. In addition to being a recognized therapeutic target in the treatment of gastric and breast malignancies, it is considered crucial in the management of CRC. In this review, we describe the molecular biology of ERBB2 from the perspective of biomarkers for mCRC-targeted therapy, including receptor structures, signaling pathways, gene alterations, and their detection methods. We also discuss the relationship between ERBB2 aberrations and the underlying mechanisms of resistance to anti-EGFR therapy and immunotherapy tolerance in these patients with a focus on novel targeted therapeutics and ongoing clinical trials. This may aid the development of a new standard of care in patients with ERBB2-positive mCRC

Optogenetic engineering of STING signaling allows remote immunomodulation to enhance cancer immunotherapy

Abstract The cGAS-STING signaling pathway has emerged as a promising target for immunotherapy development. Here, we introduce a light-sensitive optogenetic device for control of the cGAS/STING signaling to conditionally modulate innate immunity, called ‘light-inducible SMOC-like repeats’ (LiSmore). We demonstrate that photo-activated LiSmore boosts dendritic cell (DC) maturation and antigen presentation with high spatiotemporal precision. This non-invasive approach photo-sensitizes cytotoxic T lymphocytes to engage tumor antigens, leading to a sustained antitumor immune response. When combined with an immune checkpoint blocker (ICB), LiSmore improves antitumor efficacy in an immunosuppressive lung cancer model that is otherwise unresponsive to conventional ICB treatment. Additionally, LiSmore exhibits an abscopal effect by effectively suppressing tumor growth in a distal site in a bilateral mouse model of melanoma. Collectively, our findings establish the potential of targeted optogenetic activation of the STING signaling pathway for remote immunomodulation in mice

Protein-Directed Synthesis of Bifunctional Adsorbent-Catalytic Hemin-Graphene Nanosheets for Highly Efficient Removal of Dye Pollutants via Synergistic Adsorption and Degradation

Herein, for the first time, we report a “green”, one-pot reduction/decoration method for the synthesis of bifunctional adsorbent-catalytic hemin-graphene nanosheets by using a common available protein (bovine serum albumin, BSA) as both a reductant and a stabilizer. Our prepared nanosheets are highly stable and possess intrinsic peroxidase-like catalytic activity due to the decoration of BSA and hemin. Furthermore, benefiting from the combined advantages of graphene and BSA, these nanosheets are able to efficiently adsorb dye pollutants from aqueous solution. More importantly, due to their adsorption and catalytic ability, these adsorbent-catalytic nanosheets can be applied to highly efficient dye removal via synergistic adsorption and degradation. Specifically, our catalysts can easily bring organic dyes to their surface by adsorption, and then activate H₂O₂ to generate hydroxyl radicals, leading to the degradation of the dyes. Such catalytic mechanism of our as-prepared nanosheets was analogous to that of natural enzymes, in which the extremely high catalytic efficiency is largely dependent upon their ability to bring substrates in close proximity to the active sites of enzymes. Our finding may open new potential applications of hemin-graphene hybrid nanosheets in environmental chemistry, biotechnology, and medicine