This tissue section of human pancreatic cancer uses immunofluorescence to identify different types of proteins, which are represented by specific, selected colors. The teal-colored cells express K17 in the sample.
Image Credit: Kenneth Shroyer.
Scientific Frontline: Extended "At a Glance" Summary: Keratin 17 (K17) in Pancreatic Cancer
The Core Concept: Keratin 17 (K17) is a protein that has been identified as a primary driver of chemotherapy resistance in highly aggressive forms of cancer, most notably pancreatic ductal adenocarcinoma (PDAC).
Key Distinction/Mechanism: While K17 typically functions as a structural protein during embryonic development, it is re-expressed in cancer cells where it behaves entirely differently. It enters the mitochondria to stabilize dihydroorotate dehydrogenase (DHODH), an enzyme essential for synthesizing pyrimidines (DNA building blocks). This metabolic alteration drastically decreases the tumor's sensitivity to chemotherapy agents like gemcitabine.
Major Frameworks/Components:
- Keratin 17 (K17) Overexpression: The re-emergence of an embryologic protein that influences cell growth, invasion, and survival in adult tumor tissues.
- Mitochondrial Relocation: The atypical mechanism by which K17 enters the mitochondria to alter internal cellular metabolism.
- DHODH Stabilization: The core enzymatic interaction that accelerates pyrimidine biosynthesis.
- Gemcitabine Chemoresistance: The end result of the K17 pathway, which fortifies cancer cells against standard chemical interventions.
Branch of Science: Oncology, Molecular Biology, Biochemistry, and Cellular Pathology.
Future Application: These findings expose a specific metabolic vulnerability within K17 basal-like PDACs, laying the groundwork for the development of novel, targeted therapeutics designed to disrupt the K17-DHODH interaction and restore tumor sensitivity to chemotherapy.
Why It Matters: K17 expression in pancreatic and other cancers is directly correlated with shorter patient survival times. Understanding and therapeutically neutralizing this cellular pathway could dramatically improve treatment outcomes for patients facing the most lethal and aggressive cancer subtypes.
A national team of cancer researchers, led by Kenneth Shroyer and Natalia Marchenko at Stony Brook Medicine and Luisa Escobar-Hoyos of Yale School of Medicine, investigated the role of Keratin 17 (K17) in the most common form of pancreatic cancer.
They discovered that the protein is a key driver for chemoresistance to gemcitabine, an agent that is often used to treat a wide range of cancers, including advanced tumors of the pancreas, lung, and breast. Their findings highlight K17 as a potential target for the development of novel treatments to address the most aggressive forms of cancer.
Their paper, published in Cancer Research, a premier journal of the American Association for Cancer Research, explains how they uncovered the mechanisms through which K17 drives chemoresistance.
In recent years, the Shroyer–Marchenko–Escobar-Hoyos team and many other cancer researchers have determined that the expression of K17 in pancreatic and other types of cancer is associated with shorter patient survival. Beyond serving as a structural protein during embryological development, K17 is re-expressed in many types of cancer and impacts multiple hallmarks of cancer, including cell growth, invasion, and chemoresistance.
This study used cancer cell lines and tissue from human and mouse pancreatic ductal adenocarcinomas (PDACs), particularly from the most aggressive “basal” molecular subtype of the disease.
“A better understanding of the underlying molecular mechanisms driving this aggressive pancreatic cancer subtype is necessary for the development of effective therapies,” explained Shroyer, chair of the Department of Pathology in the Renaissance School of Medicine (RSOM) at Stony Brook University and a co-senior author. “We showed that K17 enters the mitochondria of the cells to stabilize dihydroorotate dehydrogenase (DHODH), a key enzyme used to build pyrimidines, one of the key building blocks of DNA. This decreases the sensitivity of cancer cells to gemcitabine, providing insight into why K17 expression correlates with shorter patient survival.”
According to Shroyer and his co-authors, the findings define a mitochondrial role for K17 in pyrimidine biosynthesis and uncover a metabolic vulnerability of K17 basal-like PDAC that they hope can be therapeutically targeted.
Funding: The research was supported in part by grants from the National Institutes of Health’s National Cancer Institute (NCI), the American Cancer Society, and the Pancreatic Cancer Action Network.
Published in journal: Cancer Research
Title: Mitochondrial-Localized Keratin 17 Promotes Chemoresistance in Basal-like Pancreatic Cancer
Authors: Chun-Hao Pan, Yinghuan Lyu, Monisankar Ghosh, Md Afjalus Siraj, Robert Tseng, Nina V. Chaika, John D. Haley, Bahman Khalvatifahlylani, David A. Tuveson, Hardik D. Patel, Muaz Faruque, Girish H. Rajacharya, Katie L. Donnelly, Cindy V. Leiton, Carlos Mauricio Mejia Arbelaez, Haoting Chen, Sumedha Chowdhury, Shayan Sarkar, Lyanne Delgado Coka, Lucia Roa-Peña, Michael Horowitz, Natalia Marchenko, Pankaj K. Singh, Kenneth R. Shroyer, and Luisa F. Escobar-Hoyos
Source/Credit: Stony Brook University
Edited by: Scientific Frontline
Reference Number: ongy052126_01
