Scholarlink

<p>Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest human malignancies, with limited therapeutic options and a lack of druggable vulnerabilities beyond a narrow set of oncogenic drivers. To identify cancer dependencies that are both essential in vivo and drug-tractable, we performed an unbiased genome-wide CRISPR loss-of-function screen under in vivo tumor-selective pressure. This approach revealed the mitochondrial co-chaperone HSPE1 (Hsp10) as a previously unrecognized, tumor-promoting dependency in PDAC. Genetic depletion of HSPE1 markedly impaired tumor growth, survival, and tumor-initiating capacity across multiple PDAC models in vitro and in vivo, including patient-derived xenografts. Mechanistically, HSPE1 functioned as a central survival node by engaging two parallel and targetable mitochondrial pathways. First, HSPE1 cooperated with its canonical partner HSPD1 to regulate cell-cycle progression, and apoptosis. Second, HSPE1 was functionally associated with mitochondrial dynamics, correlating with altered regulation of the OPA1/OMA1 axis, revealing an HSPD1-independent mechanism linking mitochondrial stress adaptation to cancer cell fitness. This dual signaling architecture exposes a previously unappreciated mitochondrial vulnerability selectively exploited by PDAC cells. Importantly, both HSPE1-regulated pathways were amenable to therapeutic targeting in vivo. Pharmacological inhibition of the HSPD1/HSPE1 complex or the OPA1/OMA1 pathway significantly suppressed tumor growth, while combined targeting produced robust synergistic antitumor activity in both cell line–derived and patient-derived PDAC models. Moreover, this combination strategy provides a modest yet consistent incremental benefit to standard-of-care chemotherapies, underscoring its translational relevance. Together, these findings establish HSPE1 as a bona fide cancer dependency uncovered through in vivo functional genomics, uncover a dual mitochondrial vulnerability, and provide a rational framework for combination therapy design. More broadly, this work highlights the power of in vivo CRISPR screening to directly inform therapeutic strategies and identifies mitochondrial stress adaptation as a promising and generalizable target in cancer.</p> Graphical Abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Identification of HSPE1 as a new actionable cancer vulnerability leads to an innovative and effective combination therapy for pancreatic ductal adenocarcinoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月5日

查看全文
  • Julien Boudreault,
  • Shima Rahimirad,
  • Ni Wang,
  • Gang Yan,
  • Leslie Chaltel Lima,
  • Sophie Poulet,
  • Meiou Dai,
  • Suhad Ali,
  • Jean-Jacques Lebrun

摘要

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest human malignancies, with limited therapeutic options and a lack of druggable vulnerabilities beyond a narrow set of oncogenic drivers. To identify cancer dependencies that are both essential in vivo and drug-tractable, we performed an unbiased genome-wide CRISPR loss-of-function screen under in vivo tumor-selective pressure. This approach revealed the mitochondrial co-chaperone HSPE1 (Hsp10) as a previously unrecognized, tumor-promoting dependency in PDAC. Genetic depletion of HSPE1 markedly impaired tumor growth, survival, and tumor-initiating capacity across multiple PDAC models in vitro and in vivo, including patient-derived xenografts. Mechanistically, HSPE1 functioned as a central survival node by engaging two parallel and targetable mitochondrial pathways. First, HSPE1 cooperated with its canonical partner HSPD1 to regulate cell-cycle progression, and apoptosis. Second, HSPE1 was functionally associated with mitochondrial dynamics, correlating with altered regulation of the OPA1/OMA1 axis, revealing an HSPD1-independent mechanism linking mitochondrial stress adaptation to cancer cell fitness. This dual signaling architecture exposes a previously unappreciated mitochondrial vulnerability selectively exploited by PDAC cells. Importantly, both HSPE1-regulated pathways were amenable to therapeutic targeting in vivo. Pharmacological inhibition of the HSPD1/HSPE1 complex or the OPA1/OMA1 pathway significantly suppressed tumor growth, while combined targeting produced robust synergistic antitumor activity in both cell line–derived and patient-derived PDAC models. Moreover, this combination strategy provides a modest yet consistent incremental benefit to standard-of-care chemotherapies, underscoring its translational relevance. Together, these findings establish HSPE1 as a bona fide cancer dependency uncovered through in vivo functional genomics, uncover a dual mitochondrial vulnerability, and provide a rational framework for combination therapy design. More broadly, this work highlights the power of in vivo CRISPR screening to directly inform therapeutic strategies and identifies mitochondrial stress adaptation as a promising and generalizable target in cancer.

Graphical Abstract