Biology subjects

Furuta, S.

Publications and source records attributed to Furuta, S..

3 recordsLinked to original sources

bioRxiv2024

Immunogenic shift of arginine metabolism triggers systemic metabolic and immunological reprogramming to prevent HER2+ breast cancer

Arginine metabolism in tumors is often shunted into the pathway producing pro-tumor and immune suppressive polyamines (PAs), while downmodulating the alternative nitric oxide (NO) synthesis pathway. Aiming to correct arginine metabolism in tumors, arginine deprivation therapy and inhibitors of PA synthesis have been developed. Despite some therapeutic advantages, these approaches have often yielded severe side effects, making it necessary to explore an alternative strategy. We previously reported that supplementing SEP, the endogenous precursor of BH4 (the essential NO synthase cofactor), could correct arginine metabolism in tumor cells and tumor-associated macrophages (TAMs) and induce their metabolic and phenotypic reprogramming. We saw that oral SEP treatment effectively suppressed the growth of HER2-positive mammary tumors in animals. SEP also has no reported dose-dependent toxicity in clinical trials for metabolic disorders. In the present study, we report that a long-term use of SEP in animals susceptible to HER2-positive mammary tumors effectively prevented tumor occurrence. These SEP-treated animals had undergone reprogramming of the systemic metabolism and immunity, elevating total T cell counts in the circulation and bone marrow. Given that bone marrow-resident T cells are mostly memory T cells, it is plausible that chronic SEP treatment promoted memory T cell formation, leading to a potent tumor prevention. These findings suggest the possible roles of the SEP/BH4/NO axis in promoting memory T cell formation and its potential therapeutic utility for preventing HER2-positive breast cancer.

cancer biology↗

bioRxiv2023

Reduced S-nitrosylation of TGFβ1 elevates its binding affinity towards the receptor and promotes fibrogenic signaling in the breast

Transforming Growth Factor {beta} (TGF{beta}) is a pleiotropic cytokine closely linked to tumors. TGF{beta} is often elevated in precancerous breast lesions in association with epithelial-to-mesenchymal transition (EMT), indicating its contribution to precancerous progression. We previously reported that basal nitric oxide (NO) levels declined along with breast cancer progression. We then pharmacologically inhibited NO production in healthy mammary glands of wild-type mice and found that this induced precancerous progression accompanied by desmoplasia and upregulation of TGF{beta} activity. In the present study, we tested our hypothesis that NO directly S-nitrosylates (forms an NO-adduct at a cysteine residue) TGF{beta} to inhibit the activity, whereas the reduction of NO denitrosylates TGF{beta} and de-represses the activity. We introduced mutations to three C-terminal cysteines of TGF{beta}1 which were predicted to be S-nitrosylated. We found that these mutations indeed impaired S-nitrosylation of TGF{beta}1 and shifted the binding affinity towards the receptor from the latent complex. Furthermore, in silico structural analyses predicted that these S-nitrosylation-defective mutations strengthen the dimerization of mature protein, whereas S-nitrosylation-mimetic mutations weaken the dimerization. Such differences in dimerization dynamics of TGF{beta}1 by denitrosylation/S-nitrosylation likely account for the shift of the binding affinities towards the receptor vs. latent complex. Our findings, for the first time, unravel a novel mode of TGF{beta} regulation based on S-nitrosylation or denitrosylation of the protein. Significance statementTransforming Growth Factor {beta} (TGF{beta}) is a widely studied cytokine associated with tumors. Because of its pleiotropic functions and dichotomous roles in tumorigenesis, the development of therapeutics targeted to TGF{beta} for cancer treatment has been challenging. In the present study, we report that TGF{beta} is indeed S-nitrosylated at specific sites for repressing its functions, whereas it is denitrosylated to derepress its activity. Such covalent modification-based regulation of TGF{beta} activity could potentially be utilized to design a new type of inhibitor or activator of the protein.

cancer biology↗

bioRxiv2023

Reprogramming of breast tumor-associated macrophages with modulation of arginine metabolism

HER2+ breast tumors have abundant immune-suppressive cells, including M2-type tumor associated macrophages (TAMs). While TAMs consist of the immune-stimulatory M1-type and immune-suppressive M2-type, M1/M2-TAM ratio is reduced in immune-suppressive tumors, contributing to their immunotherapy refractoriness. M1 vs. M2-TAM formation depends on differential arginine metabolism, where M1-TAMs convert arginine to nitric oxide (NO) and M2- TAMs convert arginine to polyamines (PAs). We hypothesize that such distinct arginine metabolism in M1- vs M2-TAMs is attributed to different availability of BH4 (NO synthase cofactor) and that its replenishment would reprogram M2-TAMs to M1-TAMs. Recently, we reported that sepiapterin (SEP), the endogenous BH4 precursor, elevates the expression of M1- TAM markers within HER2+ tumors. Here, we show that SEP restores BH4 levels in M2-TAMs, which then redirects arginine metabolism to NO synthesis and converts M2-TAMs to M1-TAMs. The reprogrammed TAMs exhibit full-fledged capabilities of antigen presentation and induction of effector T cells to trigger immunogenic cell death of HER2+ cancer cells. This study substantiates the utility of SEP in metabolic shift of HER2+ breast tumor microenvironment as a novel immunotherapeutic strategy.

cancer biology↗