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Background <p>Metastasis is the leading cause of cancer-related mortality. In ovarian cancer, dissemination within the peritoneal cavity is the primary driver of patient death, underscoring a critical need to define the molecular mechanisms that initiate metastatic seeding and remodel the peritoneal microenvironment. Stem-like tumor cell programs are increasingly recognized as central to metastatic competence, yet the regulators linking tumor stemness to microenvironmental reprogramming remain poorly defined. Doublecortin-like kinase 1 (DCLK1), a serine/threonine kinase associated with tumor stemness, has been implicated in cancer progression, but its role in ovarian cancer metastasis is not fully understood.</p> Methods <p>We employed genetic loss-of-function approaches to investigate the role of DCLK1 in ovarian cancer metastasis using in vivo intraperitoneal dissemination models. Metastatic burden and overall survival were assessed following DCLK1 depletion. DCLK1 expression was analyzed across patient-derived ascites cultures established from primary and recurrent ovarian cancer patients and correlated with markers of metastasis-initiating cells. Functional assays were used to assess tumor cell adhesion, mesothelial clearance, stemness features and mesothelial-to-mesenchymal transition. Targeted transcriptomic and secretome analyses identified DCLK1-regulated cytokine programs. Paracrine signaling to mesothelial cells was evaluated using pharmacologic inhibition of IL-6 receptor and downstream JAK–STAT signaling.</p> Results <p>Genetic loss of DCLK1 significantly reduced intraperitoneal metastatic burden and prolonged overall survival in vivo. DCLK1 expression correlated strongly with established markers of stem-like, metastasis-initiating tumor cells across the patient-derived ascites cultures. Mechanistically, DCLK1 promoted early metastatic colonization by enhancing tumor cell adhesion, mesothelial clearance, and mesothelial-to-mesenchymal transition. Transcriptomic and secretome profiling identified interleukin-6 (IL-6) as a key downstream effector of DCLK1, with DCLK1 depletion leading to a marked reduction in IL-6 expression and secretion. Tumor-derived IL-6 activated JAK–STAT signaling in mesothelial cells, promoting mesothelial migration and a permissive metastatic niche; these effects were reversed by pharmacologic blockade of IL-6 receptor signaling.</p> Conclusions <p>These findings position DCLK1 as a central molecular mediator linking tumor-intrinsic stemness to microenvironmental reprogramming that primes the peritoneal niche for metastatic progression. Targeting DCLK1 or downstream IL-6/JAK–STAT signaling may therefore offer a rational strategy to disrupt metastatic dissemination in ovarian cancer.</p>

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DCLK1 regulates stemness and IL-6/STAT3–dependent metastatic niche formation in chemoresistant ovarian cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月28日

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  • Samrita Dogra,
  • Sugantha Priya Elayapillai,
  • Cole Hladik,
  • Ameera Hasan,
  • Maitreyee Das,
  • Laura F. Mortan,
  • Dongfeng Qu,
  • Courtney W. Houchen,
  • Bethany N. Hannafon

摘要

Background

Metastasis is the leading cause of cancer-related mortality. In ovarian cancer, dissemination within the peritoneal cavity is the primary driver of patient death, underscoring a critical need to define the molecular mechanisms that initiate metastatic seeding and remodel the peritoneal microenvironment. Stem-like tumor cell programs are increasingly recognized as central to metastatic competence, yet the regulators linking tumor stemness to microenvironmental reprogramming remain poorly defined. Doublecortin-like kinase 1 (DCLK1), a serine/threonine kinase associated with tumor stemness, has been implicated in cancer progression, but its role in ovarian cancer metastasis is not fully understood.

Methods

We employed genetic loss-of-function approaches to investigate the role of DCLK1 in ovarian cancer metastasis using in vivo intraperitoneal dissemination models. Metastatic burden and overall survival were assessed following DCLK1 depletion. DCLK1 expression was analyzed across patient-derived ascites cultures established from primary and recurrent ovarian cancer patients and correlated with markers of metastasis-initiating cells. Functional assays were used to assess tumor cell adhesion, mesothelial clearance, stemness features and mesothelial-to-mesenchymal transition. Targeted transcriptomic and secretome analyses identified DCLK1-regulated cytokine programs. Paracrine signaling to mesothelial cells was evaluated using pharmacologic inhibition of IL-6 receptor and downstream JAK–STAT signaling.

Results

Genetic loss of DCLK1 significantly reduced intraperitoneal metastatic burden and prolonged overall survival in vivo. DCLK1 expression correlated strongly with established markers of stem-like, metastasis-initiating tumor cells across the patient-derived ascites cultures. Mechanistically, DCLK1 promoted early metastatic colonization by enhancing tumor cell adhesion, mesothelial clearance, and mesothelial-to-mesenchymal transition. Transcriptomic and secretome profiling identified interleukin-6 (IL-6) as a key downstream effector of DCLK1, with DCLK1 depletion leading to a marked reduction in IL-6 expression and secretion. Tumor-derived IL-6 activated JAK–STAT signaling in mesothelial cells, promoting mesothelial migration and a permissive metastatic niche; these effects were reversed by pharmacologic blockade of IL-6 receptor signaling.

Conclusions

These findings position DCLK1 as a central molecular mediator linking tumor-intrinsic stemness to microenvironmental reprogramming that primes the peritoneal niche for metastatic progression. Targeting DCLK1 or downstream IL-6/JAK–STAT signaling may therefore offer a rational strategy to disrupt metastatic dissemination in ovarian cancer.