There is an unmet need to identify and validate tumor-specific therapeutic targets to enable more effective treatments for cancer. Heterogeneity in patient clinical characteristics as well as biological and genetic features of tumors present major challenges for the optimization of therapeutic interventions, including the development of novel and more effective precision medicine. The expression of keratin 17 (K17) is a hallmark of the most aggressive forms of cancer across a wide range of anatomical sites and histological types. K17 correlates with shorter patient survival, predicts resistance to specific chemotherapeutic agents, and harbors functional domains that suggest it could be therapeutically targeted. Here, we explore the role of K17 in the hallmarks of cancer and summarize evidence to date for K17-mediated mechanisms involved in each hallmark, elucidating functional roles that warrant further investigation to guide the development of novel therapeutic strategies.

The basal-like molecular subtype of pancreatic ductal adenocarcinoma (PDAC) is highly lethal and therapy resistant. A better understanding of the underlying molecular mechanisms driving this aggressive tumor subtype is necessary for the development of effective therapies. Notably, upregulation of keratin 17 (K17) in cancer is associated with poor patient outcome and the basal-like PDAC subtype. In this study, we identified a critical dependency of basal-like PDACs on de novo pyrimidine biosynthesis, driven by intramitochondrial K17. Mechanistically, K17 translocated into the mitochondrial intermembrane space via a mitochondrial localization signal recognized by the translocase of outer mitochondrial membrane 20. In the mitochondria, K17 bound to and stabilized dihydroorotate dehydrogenase, the rate-limiting enzyme of de novo pyrimidine biosynthesis, by preventing its ubiquitination-mediated degradation. Blocking the entry of K17 into the mitochondria sensitized cancer cells to gemcitabine, a pyrimidine analogue and standard chemotherapeutic agent. In animal studies, pharmacologic inhibition of dihydroorotate dehydrogenase combined with gemcitabine treatment decreased tumor growth and doubled survival in mice bearing K17+ but not K17− PDAC. These findings define a mitochondrial role for K17 in driving pyrimidine biosynthesis and uncover a metabolic vulnerability in K17+ basal-like PDACs that can be therapeutically targeted. Significance: Targeting the mitochondrial role of keratin 17 in pyrimidine biosynthesis represents a promising strategy to sensitize basal-like pancreatic cancer to gemcitabine and improve outcomes in this lethal subtype.

In cytologic analysis of lung nodules, specimens classified as atypia cannot be definitively diagnosed as benign or malignant. Atypia patients are typically subject to additional procedures to obtain repeat samples, thus delaying diagnosis. We evaluate morphologic categories predictive of lung cancer in atypia patients. This retrospective study stratified patients evaluated for primary lung nodules based on cytologic diagnoses. Atypia patients were further stratified based on the most severe verbiage used to describe the atypical cytology. Logistic regressions and receiver operator characteristic curves were performed. Of 129 patients with cytologic atypia, 62.8% later had cytologically or histologically confirmed lung cancer and 37.2% had benign respiratory processes. Atypia severity significantly predicted final diagnosis even while controlling for pack years and modified Herder score (p = 0.012). Pack years, atypia severity, and modified Herder score predicted final diagnosis independently and while adjusting for covariates (all p < 0.001). This model generated a significantly improved area under the curve compared to pack years, atypia severity, and modified Herder score (all p < 0.001) alone. Patients with severe atypia may benefit from repeat sampling for cytologic confirmation within one month due to high likelihood of malignancy, while those with milder atypia may be followed clinically.

Supplementary Table from Dissecting the Oncogenic Roles of Keratin 17 in the Hallmarks of Cancer

Supplementary Figure 1: K17 upregulates nucleotide-related pathways. A. Unbiased TCGA data analysis using primary PDAC tumor samples. K17 mRNA levels correlate with normalized enrichment scores (NES); Spearman correlation and P-values are shown. NES values were compared between previously established high and low K17 groupings using the Wilcoxon rank-sum test. The top 17 pathways with the highest enrichment scores and P-values are shown. B-C. Human PANC-1 PDAC cells are transduced to stably express either empty vector (EV) or human K17 (K17) as a stable expression (SE) model. By Immunofluorescence, K17 is shown in green, and the nucleus is indicated by DAPI stain in blue. Scale bar = 100 μm. D. Metabolomic analyses in PANC-1 K17 SE cell line model. Data are shown in heatmaps with n = 5 per group. Two-way ANOVA followed by Šídák's test. Statistical significance between groups is indicated. E-G. Metabolomic analyses in K17 LOF (E) and SE (F-G) cell line models. Relative levels of glycolysis, TCA cycle, and PPP were shown with n = 5 per group. Two-way ANOVA followed by Šídák's test. *P<0.05, **P<0.01, ***P<0.001.