Abstract A024: Tissue biomarkers in the tumor microenvironment predicting the development of cachexia in pancreatic cancer patients
Authors: Kee Hyun Jung , Lee Jinhee , Bae Ju Young , Jung Hia , Kim Jeehoon , Leem Galam , Lee Hee Seung , Park Jeong Youp , Bang Seungmin , Park Seung Woo , Chung Moon Jae 
Published: November 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) poses significant challenges due to its aggressive nature and the limited efficacy of existing treatments. The complex interactions within the tumor microenvironment (TME) and tumor cell itself remain poorly understood, particularly in relation to cancer cachexia, which is characterized by weight loss, muscle wasting, systemic inflammation, and metabolic disturbances, and has a profound impact on PDAC outcomes. This study investigated the role of the TME in the development of cachexia in PDAC patients, focusing on the potential of cachexia-related proteins as tissue biomarkers in the TME. In this retrospective study, tissue samples from 13 PDAC patients obtained via Endoscopic Ultrasound-Guided Fine Needle Aspiration at the time of diagnosis were analyzed using immunofluorescence staining, supplemented by epidemiological data. The initial classification of cachexia based on epidemiological data, including patients body mass index and three-month weight changes, was further refined through body composition trend analysis during 180 days after the diagnosis with consecutive computed tomography images. These detailed classification criteria allowed for a more realistic classification of cachexia compared to the conventional classification of cachexia based on weight change, resulting in 5 patients being classified as cachexia and 8 as non-cachexia. We selected NAMPT (nicotinamide phosphoribosyl transferase) as a candidate tissue biomarker, a rate-limiting enzyme crucial in the NAD+ salvage pathway, due to its significant role in cellular metabolism, and the regulation of energy depletion and consumption in muscle cells. We hypothesized that NAMPT is closely linked to the mechanisms of cachexia because NAD+ is essential for muscle regeneration. Additionally, PTHLH (Parathyroid Hormone-Like Hormone), selected as another candidate marker, plays a critical role by being secreted from tumor cells, promoting cancer cell growth and metastasis. The overexpression of PTHLH can lead to malignant hypercalcemia, which may trigger severe systemic inflammatory responses in cancer patients, contributing to the development of cachexia. We utilized the coordinated expression of these two proteins as potential tissue biomarkers predicting cachexia at the time of diagnosis of PDAC. In our study, PTHLH expression was significantly elevated in the cachexia group, while NAMPT expression was higher in the non- cachexia group. Although both markers are known to be overexpressed in most metastatic pancreatic cancers, their correlations vary depending on the presence of cachexia. These findings suggest that even in metastatic pancreatic cancer, these markers can serve as precise biomarker signatures that determine the possibility of developing cachexia. To further validate our findings, we are currently testing a larger validation set (cachectic PDAC patients=100, non-cachectic PDAC patients=100) to determine whether the expression of these two markers can be utilized as biomarkers for the early detection of cachexia.
Citation Format: Hyun Jung Kee, Jinhee Lee, Ju Young Bae, Hia Jung, Jeehoon Kim, Galam Leem, Hee Seung Lee, Jeong Youp Park, Seungmin Bang, Seung Woo Park, Moon Jae Chung. Tissue biomarkers in the tumor microenvironment predicting the development of cachexia in pancreatic cancer patients [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A024.