Plasma Membrane Channel TRPM4 Mediates Immunogenic Therapy–Induced Necrosis

Author:

Ghosh Santanu1ORCID,Yang Rachel1ORCID,Duraki Darjan1ORCID,Zhu Junyao1ORCID,Kim Ji Eun1ORCID,Jabeen Musarrat1ORCID,Mao Chengjian1ORCID,Dai Xinyi1ORCID,Livezey Mara R.1ORCID,Boudreau Matthew W.12ORCID,Park Ben H.3ORCID,Nelson Erik R.1245ORCID,Hergenrother Paul J.124ORCID,Shapiro David J.14ORCID

Affiliation:

1. 1Departments of Biochemistry, Molecular and Integrative Physiology and Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois.

2. 2Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois.

3. 3Vanderbilt University College of Medicine, Nashville, Tennessee.

4. 4Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois.

5. 5Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois.

Abstract

Abstract Several emerging therapies kill cancer cells primarily by inducing necrosis. As necrosis activates immune cells, potentially, uncovering the molecular drivers of anticancer therapy–induced necrosis could reveal approaches for enhancing immunotherapy efficacy. To identify necrosis-associated genes, we performed a genome-wide CRISPR-Cas9 screen with negative selection against necrosis-inducing preclinical agents BHPI and conducted follow-on experiments with ErSO. The screen identified transient receptor potential melastatin member 4 (TRPM4), a calcium-activated, ATP-inhibited, sodium-selective plasma membrane channel. Cancer cells selected for resistance to BHPI and ErSO exhibited robust TRPM4 downregulation, and TRPM4 reexpression restored sensitivity to ErSO. Notably, TRPM4 knockout (TKO) abolished ErSO-induced regression of breast tumors in mice. Supporting a broad role for TRPM4 in necrosis, knockout of TRPM4 reversed cell death induced by four additional diverse necrosis-inducing cancer therapies. ErSO induced anticipatory unfolded protein response (a-UPR) hyperactivation, long-term necrotic cell death, and release of damage-associated molecular patterns that activated macrophages and increased monocyte migration, all of which was abolished by TKO. Furthermore, loss of TRPM4 suppressed the ErSO-induced increase in cell volume and depletion of ATP. These data suggest that ErSO triggers initial activation of the a-UPR but that it is TRPM4-mediated sodium influx and cell swelling, resulting in osmotic stress, which sustains and propagates lethal a-UPR hyperactivation. Thus, TRPM4 plays a pivotal role in sustaining lethal a-UPR hyperactivation that mediates the anticancer activity of diverse necrosis-inducing therapies. Significance: A genome-wide CRISPR screen reveals a pivotal role for TRPM4 in cell death and immune activation following treatment with diverse necrosis-inducing anticancer therapies, which could facilitate development of necrosis-based cancer immunotherapies.

Funder

Division of Diabetes, Endocrinology, and Metabolic Diseases

National Cancer Institute

U.S. Department of Defense

Susan G. Komen

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

Reference70 articles.

1. Intracellular ATP levels determine cell death fate by apoptosis or necrosis;Eguchi;Cancer Res,1997

2. Phagocytosis of necrotic debris at sites of injury and inflammation;Westman;Front Immunol,2020

3. Cytoplasmic vacuolization in cell death and survival;Shubin;Oncotarget,2016

4. Crosstalk between apoptosis, necrosis and autophagy;Nikoletopoulou;Biochim Biophys Acta,2013

5. Strong and sustained activation of the anticipatory unfolded protein response induces necrotic cell death;Livezey;Cell Death Differ,2018

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3