Fatty Acid Signaling Impacts Prostate Cancer Lineage Plasticity in an Autocrine and Paracrine Manner.
Fatty Acid Signaling Impacts Prostate Cancer Lineage Plasticity in an Autocrine and Paracrine Manner.
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脂肪酸信号以自分泌和旁分泌方式影响前列腺癌谱系可塑性。
作者：
高脂肪饮食与前列腺癌患者的进展有关。前列腺癌相关成纤维细胞在促进肿瘤进展和对雄激素受体信号传导抑制剂（如恩杂鲁胺）的治疗耐药性方面发挥重要作用。我们研究了饱和脂肪酸对前列腺癌重编程的影响机制。我们的工作表明，肿瘤微环境定义了饱和脂肪酸诱导的前列腺癌进展的生物学。这项研究还提供了相关数据，通过抑制已识别的信号通路，可能改善高脂肪摄入患者的预后。前列腺癌（PCa）每年影响估计250，000名男性，每年导致34，000人死亡。高脂饮食和肥胖与PCa进展和死亡率相关。这项研究的前提是新的观察PCa上皮细胞和癌症相关的成纤维细胞（CAF）之间的串扰棕榈酸酯介导的谱系可塑性。我们发现胆固醇通过增加PCa细胞中纤毛Gli活性激活经典Hedgehog（Hh）信号传导，而棕榈酸酯独立于Gli激活Hh。在与CAF共培养的PCa细胞中，外源性棕榈酸激活了已知的谱系可塑性介质SOX 2。当与PCa细胞共培养并用棕榈酸酯处理时，基质衍生的Wnt5a在CAF中上调。CAF中的Wnt 5a敲低抑制了来自共培养物的PCa细胞中Hh和SOX 2的表达。这些发现支持了我们提出的高脂饮食促进肿瘤微环境中Hh信号介导的转化的机制。SOX2和Wnt5a的表达受到CD36中和抗体的限制。用PCa上皮细胞和CAF肿瘤异种移植的小鼠喂食高脂肪饮食，与喂食等热量啮齿动物饮食的小鼠相比，导致SOX 2表达和谱系可塑性重编程升高。与Enzalutamide单独给药相比，Enzalutamide对CD36的抑制可通过TUNEL法增加细胞凋亡，但限制增殖和SOX 2表达。这项研究揭示了高脂肪饮食影响前列腺癌进展的机制。我们发现饱和脂肪通过Wnt5a和Hh信号与CAF相互作用诱导PCa谱系可塑性重编程。
A high-fat diet is implicated in prostate cancer progression in patients. Prostate-cancer-associated fibroblasts play an important role in promoting tumor progression and therapeutic resistance to androgen-receptor-signaling inhibitors, such as enzalutamide. We investigated the mechanism of saturated fatty acids’ impact on prostate cancer reprogramming. Our work demonstrates that the tumor microenvironment defines the biology of prostate cancer progression induced by saturated fatty acids. This study also provides relevant data to potentially improve prognosis for patients with high fat intake through the inhibition of the identified signaling pathways. Prostate cancer (PCa) affects an estimated 250,000 men every year and causes 34,000 deaths annually. A high-fat diet and obesity are associated with PCa progression and mortality. This study’s premise was the novel observation of crosstalk between PCa epithelia and cancer-associated fibroblasts (CAF) in response to palmitate-mediated lineage plasticity. We found that cholesterol activated canonical Hedgehog (Hh) signaling by increasing cilium Gli activity in PCa cells, while palmitate activated Hh independent of Gli. Exogenous palmitate activated SOX2, a known mediator of lineage plasticity, in PCa cells cocultured with CAF. Stroma-derived Wnt5a was upregulated in CAF while cocultured with PCa cells and treated with palmitate. Wnt5a knockdown in CAF inhibited Hh and SOX2 expression in PCa cells from cocultures. These findings supported our proposed mechanism of a high-fat diet promoting Hh signaling-mediated transformation within the tumor microenvironment. SOX2 and Wnt5a expression were limited by the CD36 neutralizing antibody. Mice xenografted with PCa epithelia and CAF tumors were fed a high-fat diet, leading to elevated SOX2 expression and lineage plasticity reprogramming compared to mice fed an isocaloric rodent diet. CD36 inhibition with enzalutamide elevated apoptosis by TUNEL, but limited proliferation and SOX2 expression compared to enzalutamide alone. This study revealed a mechanism for a high-fat diet to affect prostate cancer progression. We found that saturated fat induced lineage plasticity reprogramming of PCa by interaction with CAF through Wnt5a and Hh signaling.
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影响因子：
5.9
作者：
Di Sebastiano KM;Mourtzakis M
通讯作者：
Mourtzakis M
DOI：
10.1111/dom.14486
发表时间：
2021-11
期刊：
Diabetes, obesity & metabolism
影响因子：
--
作者：
Clark AL;Yan Z;Chen SX;Shi V;Kulkarni DH;Diwan A;Remedi MS
通讯作者：
Remedi MS
影响因子：
8
作者：
Kato M;Placencio-Hickok VR;Madhav A;Haldar S;Tripathi M;Billet S;Mishra R;Smith B;Rohena-Rivera K;Agarwal P;Duong F;Angara B;Hickok D;Liu Z;Bhowmick NA
通讯作者：
Bhowmick NA
影响因子：
5.2
作者：
Bianchi-Frias, Daniella;Basom, Ryan;Nelson, Peter S.
通讯作者：
Nelson, Peter S.
影响因子：
4.9
作者：
Gupta, Sachin;Takebe, Naoko;Lorusso, Patricia
通讯作者：
Lorusso, Patricia