Autophagy is required for mammary tumor recurrence by promoting dormant tumor cell survival following therapy.

IF 7.4 1区 医学 Q1 Medicine
Samantha Dwyer, Jason Ruth, Hans E Seidel, Amelie A Raz, Lewis A Chodosh
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引用次数: 0

Abstract

Background: Mortality from breast cancer is principally due to tumor recurrence. Recurrent breast cancers arise from the pool of residual tumor cells, termed minimal residual disease, that survive treatment and may exist in a dormant state for 20 years or more following treatment of the primary tumor. As recurrent breast cancer is typically incurable, understanding the mechanisms underlying dormant tumor cell survival is a critical priority in breast cancer research. The importance of this goal is further underscored by emerging evidence suggesting that targeting dormant residual tumor cells in early-stage breast cancer patients may be a means to prevent tumor recurrence and its associated mortality. In this regard, the role of autophagy in dormant tumor cell survival and recurrence remains unresolved, with conflicting reports of both pro-survival/recurrence-promoting and pro-death/recurrence-suppressing effects of autophagy inhibition in dormant tumor cells. Resolving this question has important clinical implications.

Methods: We used genetically engineered mouse models that faithfully recapitulate key features of human breast cancer progression, including minimal residual disease, tumor dormancy, and recurrence. We used genetic and pharmacological approaches to inhibit autophagy, including treatment with chloroquine, genetic knockdown of ATG5 or ATG7, or deletion of BECN and determined their effects on dormant tumor cell survival and recurrence.

Results: We demonstrate that the survival and recurrence of dormant mammary tumor cells following therapy is dependent upon autophagy. We find that autophagy is induced in vivo following HER2 downregulation and remains activated in dormant residual tumor cells. Using genetic and pharmacological approaches we show that inhibiting autophagy by chloroquine administration, ATG5 or ATG7 knockdown, or deletion of a single allele of the tumor suppressor Beclin 1 is sufficient to inhibit mammary tumor recurrence, and that autophagy inhibition results in the death of dormant mammary tumor cells in vivo.

Conclusions: Our findings demonstrate a pro-tumorigenic role for autophagy in tumor dormancy and recurrence following therapy, reveal that dormant tumor cells are uniquely reliant upon autophagy for their survival, and indicate that targeting dormant residual tumor cells by inhibiting autophagy impairs tumor recurrence. These studies identify a pharmacological target for a cellular state that is resistant to commonly used anti-neoplastic agents and suggest autophagy inhibition as an approach to reduce dormant minimal residual disease in order to prevent lethal tumor recurrence.

自噬是乳腺肿瘤复发的必要条件,它能促进休眠肿瘤细胞在治疗后存活。
背景:乳腺癌致死的主要原因是肿瘤复发。复发性乳腺癌产生于残留的肿瘤细胞池,被称为 "极小残留病",这些肿瘤细胞在治疗后存活下来,并可能在原发肿瘤治疗后的 20 年或更长时间内处于休眠状态。由于复发性乳腺癌通常无法治愈,因此了解休眠肿瘤细胞的生存机制是乳腺癌研究的重中之重。新出现的证据表明,针对早期乳腺癌患者的休眠残留肿瘤细胞可能是预防肿瘤复发及其相关死亡率的一种手段,这进一步强调了这一目标的重要性。在这方面,自噬在休眠肿瘤细胞存活和复发中的作用仍悬而未决,关于抑制自噬对休眠肿瘤细胞的存活/复发促进作用和死亡/复发抑制作用的报道相互矛盾。解决这一问题具有重要的临床意义:我们利用基因工程小鼠模型忠实地再现了人类乳腺癌进展的关键特征,包括最小残留病、肿瘤休眠和复发。我们使用基因和药物方法抑制自噬,包括氯喹治疗、基因敲除 ATG5 或 ATG7 或删除 BECN,并确定它们对休眠肿瘤细胞存活和复发的影响:结果:我们证明,休眠乳腺肿瘤细胞在治疗后的存活和复发取决于自噬。我们发现,HER2 下调后,自噬在体内被诱导,并在休眠残留肿瘤细胞中保持激活状态。我们利用遗传学和药理学方法表明,通过服用氯喹、敲除 ATG5 或 ATG7 或删除肿瘤抑制因子 Beclin 1 的单个等位基因来抑制自噬足以抑制乳腺肿瘤的复发,而且自噬抑制会导致体内休眠的乳腺肿瘤细胞死亡:我们的研究结果证明了自噬在肿瘤休眠和治疗后复发中的促肿瘤作用,揭示了休眠肿瘤细胞的生存对自噬的独特依赖性,并表明通过抑制自噬靶向休眠残余肿瘤细胞会影响肿瘤复发。这些研究为一种对常用抗肿瘤药物具有抗药性的细胞状态找到了药理靶点,并建议将抑制自噬作为减少休眠最小残留病的一种方法,以防止致命的肿瘤复发。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
12.00
自引率
0.00%
发文量
76
审稿时长
12 weeks
期刊介绍: Breast Cancer Research, an international, peer-reviewed online journal, publishes original research, reviews, editorials, and reports. It features open-access research articles of exceptional interest across all areas of biology and medicine relevant to breast cancer. This includes normal mammary gland biology, with a special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal covers preclinical, translational, and clinical studies with a biological basis, including Phase I and Phase II trials.
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