RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness.
RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness.
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DOI：
10.1016/j.devcel.2021.04.022
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发表时间：
2021-06-21
影响因子：
11.8
通讯作者：
Gonzalez-Suarez E
中科院分区：
文献类型：
--
作者：
Benítez S;Cordero A;Santamaría PG;Redondo-Pedraza J;Rocha AS;Collado-Solé A;Jimenez M;Sanz-Moreno A;Yoldi G;Santos JC;De Benedictis I;Gómez-Aleza C;Da Silva-Álvarez S;Troulé K;Gómez-López G;Alcazar N;Palmero I;Collado M;Serrano M;Gonzalez-Suarez E
Rank信号增强小鼠和人乳腺上皮细胞（MEC）的干性，并介导乳腺肿瘤的发生。由癌基因或致癌物暴露引发的乳腺肿瘤显示高水平的Rank和Rank通路抑制剂已成为乳腺癌预防和治疗的新策略。在这里，我们表明，在乳腺上皮细胞中的异位Rank表达出乎意料地延迟了肿瘤的发作，并降低了癌基因驱动的Neu和PyMT模型中的肿瘤发病率。从机制上讲，我们发现Rank的异位表达或暴露于Rankl诱导衰老，即使在不存在其他致癌突变的情况下。等级通过p16/p19导致DNA损伤和衰老。此外，RANK诱导的衰老对于Rank驱动的干性是必不可少的，尽管最初转化为延迟的肿瘤生长，但最终促进肿瘤进展和转移。我们揭示了Rank在乳腺上皮中的双重作用：Rank诱导衰老和干细胞，延迟肿瘤的发生，但增加肿瘤的侵袭性。在癌基因驱动的模型中，Rank表达延迟乳腺肿瘤的发病Rank信号的激活通过p16/p19诱导衰老Rank诱导的管腔细胞衰老增加基底和管腔干细胞Rank诱导的衰老细胞促进乳腺肿瘤生长Rank通路抑制剂已成为乳腺癌预防和治疗的治疗选择。Benitez等人显示Rank信号传导的激活诱导衰老，这矛盾地延迟肿瘤发作和发病率，但促进肿瘤侵袭性。用senolytics治疗可以消除Rank诱导的衰老细胞，减少干细胞和乳腺癌的生长。
Rank signaling enhances stemness in mouse and human mammary epithelial cells (MECs) and mediates mammary tumor initiation. Mammary tumors initiated by oncogenes or carcinogen exposure display high levels of Rank and Rank pathway inhibitors have emerged as a new strategy for breast cancer prevention and treatment. Here, we show that ectopic Rank expression in the mammary epithelia unexpectedly delays tumor onset and reduces tumor incidence in the oncogene-driven Neu and PyMT models. Mechanistically, we have found that ectopic expression of Rank or exposure to Rankl induces senescence, even in the absence of other oncogenic mutations. Rank leads to DNA damage and senescence through p16/p19. Moreover, RANK-induced senescence is essential for Rank-driven stemness, and although initially translates into delayed tumor growth, eventually promotes tumor progression and metastasis. We uncover a dual role for Rank in the mammary epithelia: Rank induces senescence and stemness, delaying tumor initiation but increasing tumor aggressiveness. Rank expression delays mammary tumor onset in oncogene-driven models Activation of Rank signaling induces senescence through p16/p19 Rank-induced senescence in luminal cells increases basal and luminal stemness Rank-induced senescent cells promote mammary tumor growth Rank pathway inhibitors have emerged as therapeutic options for breast cancer prevention and treatment. Benitez et al. show that activation of Rank signaling induces senescence, which paradoxically delays tumor onset and incidence but promotes tumor aggressiveness. Treatment with senolytics eliminates Rank-induced senescent cells, reducing stemness and breast cancer growth.
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影响因子：
78.5
作者：
Collado, Manuel;Serrano, Manuel
通讯作者：
Serrano, Manuel
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
12.3
作者：
Herschkowitz JI;Simin K;Weigman VJ;Mikaelian I;Usary J;Hu Z;Rasmussen KE;Jones LP;Assefnia S;Chandrasekharan S;Backlund MG;Yin Y;Khramtsov AI;Bastein R;Quackenbush J;Glazer RI;Brown PH;Green JE;Kopelovich L;Furth PA;Palazzo JP;Olopade OI;Bernard PS;Churchill GA;Van Dyke T;Perou CM
通讯作者：
Perou CM
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
5.3
作者：
Gonzalez-Suarez, Eva;Branstetter, Daniel;Dougall, William C.
通讯作者：
Dougall, William C.