Identification of Potential Serum Protein Biomarkers and Pathways for Pancreatic Cancer Cachexia Using an Aptamer-Based Discovery Platform

Patients with pancreatic ductal adenocarcinoma (PDAC) suffer debilitating and deadly weight loss, known as cachexia. Development of therapies requires biomarkers to diagnose, and monitor cachexia; however, no such markers are in use. Via Somascan, we measured ~1300 plasma proteins in 30 patients with PDAC vs. 11 controls. We found 60 proteins specific to local PDAC, 46 to metastatic, and 67 to presence of >5% cancer weight loss (FC ≥ |1.5|, p ≤ 0.05). Six were common for cancer stage (Up: GDF15, TIMP1, IL1RL1; Down: CCL22, APP, CLEC1B). Four were common for local/cachexia (C1R, PRKCG, ELANE, SOST: all oppositely regulated) and four for metastatic/cachexia (SERPINA6, PDGFRA, PRSS2, PRSS1: all consistently changed), suggesting that stage and cachexia status might be molecularly separable. We found 71 proteins that correlated with cachexia severity via weight loss grade, weight loss, skeletal muscle index and radiodensity (r ≥ |0.50|, p ≤ 0.05), including some known cachexia mediators/markers (LEP, MSTN, ALB) as well as novel proteins (e.g., LYVE1, C7, F2). Pathway, correlation, and upstream regulator analyses identified known (e.g., IL6, proteosome, mitochondrial dysfunction) and novel (e.g., Wnt signaling, NK cells) mechanisms. Overall, this study affords a basis for validation and provides insights into the processes underpinning cancer cachexia.

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The systemic activin response to pancreatic cancer: Implications for effective cancer cachexia therapy

10.1101/343871 ◽

2018 ◽

Author(s):

Xiaoling Zhong ◽

Marianne Pons ◽

Christophe Poirier ◽

Yanlin Jiang ◽

Jianguo Liu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Weight Loss ◽

Pancreatic Ductal Adenocarcinoma ◽

Conditioned Medium ◽

Tumor Cells ◽

Stromal Cells ◽

Cancer Cachexia ◽

Dominant Negative ◽

Prolonged Survival ◽

Ductal Adenocarcinoma

AbstractPancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy with high rates of cachexia. Serum activin correlates with PDAC cachexia and mortality, while activin administration causes cachexia in mice. We studied activin in human tumors and in mice with orthotopic or genetic PDAC. Cachexia severity correlated with activin expression in tumor lines. Activins were expressed in both cancer and tumor stromal cells, but also in organs in murine PDAC cachexia. Tumor cells expressed activin-βA, or Inhba, while organs expressed both activin-βA and activin-βB, or Inhbb. PDAC elicits activin expression; PDAC conditioned medium induced activin and atrophy of myotubes. Treatment with the activin trap, ACVR2B/Fc, reduced cachexia and prolonged survival in mice with activin-low tumors, and reduced cachexia in activin-high tumors, without affecting activin expression in organs. Mice expressing dominant negative ACVR2B in muscle were protected for weight loss but not survival. Overall our results indicate that PDAC induces a systemic activin response, leading to cachexia, and that activin targets might include organs beyond muscle. Targeting of both tumor-derived and host-derived activins could improve cachexia therapy.

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A Proteomic Study on the Personalized Protein Corona of Liposomes. Relevance for Early Diagnosis of Pancreatic DUCTAL Adenocarcinoma and Biomarker Detection

Journal of Nanotheranostics ◽

10.3390/jnt2020006 ◽

2021 ◽

Vol 2 (2) ◽

pp. 82-93

Author(s):

Luca Digiacomo ◽

Francesca Giulimondi ◽

Daniela Pozzi ◽

Alessandro Coppola ◽

Vincenzo La Vaccara ◽

...

Keyword(s):

Pancreatic Cancer ◽

Early Diagnosis ◽

Pancreatic Ductal Adenocarcinoma ◽

Protein Corona ◽

Detection Sensitivity ◽

Ductal Adenocarcinoma ◽

Protein Biomarkers ◽

Ca 19.9 ◽

Proteomic Study

Due to late diagnosis, high incidence of metastasis, and poor survival rate, pancreatic cancer is one of the most leading cause of cancer-related death. Although manifold recent efforts have been done to achieve an early diagnosis of pancreatic cancer, CA-19.9 is currently the unique biomarker that is adopted for the detection, despite its limits in terms of sensitivity and specificity. To identify potential protein biomarkers for pancreatic ductal adenocarcinoma (PDAC), we used three model liposomes as nanoplatforms that accumulate proteins from human plasma and studied the composition of this biomolecular layer, which is known as protein corona. Indeed, plasma proteins adsorb on nanoparticle surface according to their abundance and affinity to the employed nanomaterial, thus even small differences between healthy and PDAC protein expression levels can be, in principle, detected. By mass spectrometry experiments, we quantified such differences and identified possible biomarkers for PDAC. Some of them are already known to exhibit different expressions in PDAC proteomes, whereas the role of other relevant proteins is still not clear. Therefore, we predict that the employment of nanomaterials and their protein corona may represent a useful tool to amplify the detection sensitivity of cancer biomarkers, which may be used for the early diagnosis of PDAC, with clinical implication for the subsequent therapy in the context of personalized medicine.

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Incidence and frequency of cancer cachexia during chemotherapy for advanced pancreatic ductal adenocarcinoma

Supportive Care in Cancer ◽

10.1007/s00520-020-05346-8 ◽

2020 ◽

Vol 28 (11) ◽

pp. 5271-5279 ◽

Cited By ~ 1

Author(s):

Shuichi Mitsunaga ◽

Eiji Kasamatsu ◽

Koji Machii

Keyword(s):

Overall Survival ◽

Weight Loss ◽

Pancreatic Ductal Adenocarcinoma ◽

Cancer Cachexia ◽

Ductal Adenocarcinoma ◽

Cancer Therapies ◽

First Line ◽

Timing Of Onset ◽

Line Chemotherapy

Abstract Purpose Cachexia influences the patient’s physical wellbeing and quality of life, and the patient’s ability to tolerate their cancer therapies, especially cytotoxic chemotherapy. The purpose of this study was to investigate the frequency and timing of onset of cancer cachexia during chemotherapy and its association with prognosis and toxicity in patients with pancreatic ductal adenocarcinoma (PDAC). Methods We performed a retrospective study in patients who underwent first-line chemotherapy after diagnosis of advanced PDAC between 6 June 2008 and 31 March 2017. Base cachexia (weight loss up to 6 months before starting first-line chemotherapy) and follow-up cachexia (after starting first-line chemotherapy) were defined as weight loss > 2% with a body mass index (BMI) < 20 kg/m2 or weight loss > 5%. Results A total of 150 patients were registered. The median age and BMI were 65 years and 21.7 kg/m2, respectively. Base cachexia occurred in 50% of patients. Follow-up cachexia occurred in 32% within 12 weeks of starting first-line chemotherapy, reaching 64% at 1 year. Overall survival was not significantly different between patients with and without follow-up cachexia, regardless of whether cancer cachexia occurred within 12, 24, or 48 weeks of starting first-line treatment. Appetite loss, fatigue, nausea, and diarrhea were more frequent in patients with follow-up cachexia than in those without follow-up cachexia. Conclusion Follow-up cachexia had an early onset, but was not a prognostic factor for overall survival in patients with PDAC. Some adverse events tended to be more frequent in patients with follow-up cachexia than in those without follow-up cachexia.

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Continued Weight Loss and Sarcopenia Predict Poor Outcomes in Locally Advanced Pancreatic Cancer Treated with Chemoradiation

Cancers ◽

10.3390/cancers11050709 ◽

2019 ◽

Vol 11 (5) ◽

pp. 709 ◽

Cited By ~ 10

Author(s):

Patrick Naumann ◽

Jonathan Eberlein ◽

Benjamin Farnia ◽

Thilo Hackert ◽

Jürgen Debus ◽

...

Keyword(s):

Skeletal Muscle ◽

Pancreatic Cancer ◽

Weight Loss ◽

Muscle Mass ◽

Muscle Wasting ◽

Statistical Tests ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Skeletal Muscle Index ◽

Poor Outcomes

Background: Surgical resection offers the best chance of survival in patients with pancreatic cancer, but those with locally advanced disease (LAPC) are usually not surgical candidates. This cohort often receives either neoadjuvant chemotherapy or chemoradiation (CRT), but unintended weight loss coupled with muscle wasting (sarcopenia) can often be observed. Here, we report on the predictive value of changes in weight and muscle mass in 147 consecutive patients with LAPC treated with neoadjuvant CRT. Methods: Clinicopathologic data were obtained via a retrospective chart review. The abdominal skeletal muscle area (SMA) at the third lumbar vertebral body was determined via computer tomographic (CT) scans as a surrogate for the muscle mass and skeletal muscle index (SMI) calculated. Uni- and multi-variable statistical tests were performed to assess for impact on survival. Results: Weight loss (14.5 vs. 20.3 months; p = 0.04) and loss of muscle mass (15.1 vs. 22.2 months; p = 0.007) were associated with poor outcomes. The highest survival was observed in patients who had neither cachectic weight loss nor sarcopenia (27 months), with improved survival seen in those who ultimately received a resection (23 vs. 10 months; p < 0.001). Cox regression revealed that either continued weight loss or continued muscle wasting (SMA reduction) was predictive of poor outcomes, whereas a sarcopenic SMI was not. Conclusions: Loss of weight and lean muscle in patients with LAPC is prognostic when persistent. Therefore, both should be assessed longitudinally and considered before surgery.

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Tumor-derived IL-6 and trans-signaling among tumor, fat, and muscle mediate pancreatic cancer cachexia

Journal of Experimental Medicine ◽

10.1084/jem.20190450 ◽

2021 ◽

Vol 218 (6) ◽

Author(s):

Joseph E. Rupert ◽

Ashok Narasimhan ◽

Daenique H.A. Jengelley ◽

Yanlin Jiang ◽

Jianguo Liu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Culture ◽

Weight Loss ◽

Pancreatic Adenocarcinoma ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Malignant Cells ◽

Feed Forward ◽

Orthotopic Xenografts

Most patients with pancreatic adenocarcinoma (PDAC) suffer cachexia; some do not. To model heterogeneity, we used patient-derived orthotopic xenografts. These phenocopied donor weight loss. Furthermore, muscle wasting correlated with mortality and murine IL-6, and human IL-6 associated with the greatest murine cachexia. In cell culture and mice, PDAC cells elicited adipocyte IL-6 expression and IL-6 plus IL-6 receptor (IL6R) in myocytes and blood. PDAC induced adipocyte lipolysis and muscle steatosis, dysmetabolism, and wasting. Depletion of IL-6 from malignant cells halved adipose wasting and abolished myosteatosis, dysmetabolism, and atrophy. In culture, adipocyte lipolysis required soluble (s)IL6R, while IL-6, sIL6R, or palmitate induced myotube atrophy. PDAC cells activated adipocytes to induce myotube wasting and activated myotubes to induce adipocyte lipolysis. Thus, PDAC cachexia results from tissue crosstalk via a feed-forward, IL-6 trans-signaling loop. Malignant cells signal via IL-6 to muscle and fat, muscle to fat via sIL6R, and fat to muscle via lipids and IL-6, all targetable mechanisms for treatment of cachexia.

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Identification of circulating protein biomarkers for pancreatic cancer cachexia

10.1101/359661 ◽

2018 ◽

Author(s):

Safi Shahda ◽

Ashok Narasimhan ◽

Joshua Kays ◽

Susan M. Perkins ◽

Lijun Cheng ◽

...

Keyword(s):

Skeletal Muscle ◽

Weight Loss ◽

Cell Signaling ◽

B Cell ◽

Expression Analysis ◽

Killer Cell ◽

Model Systems ◽

Protein Biomarkers ◽

Skeletal Muscle Index ◽

Secreted Factors

AbstractBackgroundOver 80% of patients with pancreatic ductal adenocarcinoma (PDAC) suffer from cachexia, characterized by severe muscle and fat loss. Although various model systems have improved our understanding of cachexia, translating the findings to human cachexia has remained a challenge. In this study, our objectives were to i) identify circulating protein biomarkers using serum for human PDAC cachexia, (ii) identify the ontological functions of the identified biomarkers and (iii) identify new pathways associated with human PDAC cachexia by performing protein co-expression analysis.MethodsSerum from 30 patients with PDAC was collected. Body composition measurements of skeletal muscle index (SMI), skeletal muscle density (SMD), total adipose index (TAI) were obtained from computed tomography scans (CT). Cancer associated weight loss (CAWL), an ordinal classification of history of weight loss and body mass index (BMI) was obtained from medical record. Serum protein profiles and concentrations were generated using SOMAscan, a quantitative aptamer-based assay. Ontological analysis of the proteins correlated with clinical variables (r≥ 0.5 and p<0.05) was performed using DAVID Bioinformatics. Protein co-expression analysis was determined using pairwise Spearman’s correlation.ResultsOverall, 111 proteins of 1298 correlated with these clinical measures, 48 proteins for CAWL, 19 for SMI, 14 for SMD, and 30 for TAI. LYVE1, a homolog of CD44 implicated in tumor metastasis, was the top CAWL-associated protein (r= 0.67, p=0.0001). Other proteins such as INHBA, MSTN/GDF11, and PIK3R1 strongly correlated with CAWL. Proteins correlated with cachexia included those associated with proteolysis, acute inflammatory response, as well as B cell and T cell activation. Protein co-expression analysis identified networks such as activation of immune related pathways such as B-cell signaling, Th1 and Th2 pathways, natural killer cell signaling, IL6 signaling, and mitochondrial dysfunction.ConclusionTaken together, these data both identify immune system molecules and additional secreted factors and pathways not previously associated with PDAC and confirm the activation of previously identified pathways. Identifying altered secreted factors in serum of PDAC patients may assist in developing minimally invasive laboratory tests for clinical cachexia as well as identifying new mediators.

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Local and Systemic Cytokine Profiling for Pancreatic Ductal Adenocarcinoma to Study Cancer Cachexia in an Era of Precision Medicine

International Journal of Molecular Sciences ◽

10.3390/ijms19123836 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3836 ◽

Cited By ~ 6

Author(s):

Michael H. Gerber ◽

Patrick W. Underwood ◽

Sarah M. Judge ◽

Daniel Delitto ◽

Andrea E. Delitto ◽

...

Keyword(s):

Gene Expression ◽

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Cancer Cachexia ◽

Soluble Proteins ◽

Triceps Surae ◽

Human Pancreatic Cancer ◽

Ductal Adenocarcinoma ◽

Related Gene ◽

Pdx Models

Cancer cachexia is a debilitating condition seen frequently in patients with pancreatic ductal adenocarcinoma (PDAC). The underlying mechanisms driving cancer cachexia are not fully understood but are related, at least in part, to the immune response to the tumor both locally and systemically. We hypothesize that there are unique differences in cytokine levels in the tumor microenvironment and systemic circulation between PDAC tumors and that these varying profiles affect the degree of cancer cachexia observed. Patient demographics, operative factors, oncologic factors, and perioperative data were collected for the two patients in the patient derived xenograft (PDX) model. Human pancreatic cancer PDX were created by implanting fresh surgical pancreatic cancer tissues directly into immunodeficient mice. At PDX end point, mouse tumor, spleen and muscle tissues were collected and weighed, muscle atrophy related gene expression measured, and tumor and splenic soluble proteins were analyzed. PDX models were created from surgically resected patients who presented with different degrees of cachexia. Tumor free body weight and triceps surae weight differed significantly between the PDX models and control (P < 0.05). Both PDX groups had increased atrophy related gene expression in muscle compared to control (FoxO1, Socs3, STAT3, Acvr2b, Atrogin-1, MuRF1; P < 0.05). Significant differences were noted in splenic soluble protein concentrations in 14 of 15 detected proteins in tumor bearing mice when compared to controls. Eight splenic soluble proteins were significantly different between PDX groups (P < 0.05). Tumor soluble proteins were significantly different between the two PDX groups in 15 of 24 detected proteins (P < 0.05). PDX models preserve the cachectic heterogeneity found in patients and are associated with unique cytokine profiles in both the spleen and tumor between different PDX. These data support the use of PDX as a strategy to study soluble cachexia protein markers and also further efforts to elucidate which cytokines are most related to cachexia in order to provide potential targets for immunotherapy.

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Early Detection and Biomarkers in Pancreatic Cancer

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2007.0086 ◽

2007 ◽

Vol 5 (10) ◽

pp. 1034-1041 ◽

Cited By ~ 36

Author(s):

David E. Misek ◽

Tasneem H. Patwa ◽

David M. Lubman ◽

Diane M. Simeone

Keyword(s):

Pancreatic Cancer ◽

Early Detection ◽

Cancer Control ◽

The United States ◽

Ductal Adenocarcinoma ◽

Protein Biomarkers ◽

Recent Developments ◽

New Biomarkers ◽

Low Sensitivity ◽

Sensitivity Specificity

Major advances in cancer control will be greatly aided by early detection for diagnosing and treating cancer in its preinvasive state before metastasis. Unfortunately, for pancreatic ductal adenocarcinoma (PDAC), which is the fourth leading cause of cancer-related death in the United States, effective early detection and screening are currently not available and tumors are typically diagnosed at a late stage, frequently after metastasis. Partly because of low sensitivity/specificity, existing biomarkers such as CA19-9 are not adequate as early detection markers of pancreatic cancer. Thus, a great need exists for new biomarkers for pancreatic cancer. This article focuses on recent developments in the identification of new serum protein biomarkers that are useful in the early detection of PDAC.

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Plasma ceramides as a sexually dimorphic biomarker of pancreatic cancer-induced cachexia

10.1101/2020.06.01.20111492 ◽

2020 ◽

Author(s):

Jeffery M. Chakedis ◽

Mary E. Dillhoff ◽

Carl R. Schmidt ◽

Priyani V. Rajasekera ◽

David C. Evans ◽

...

Keyword(s):

Weight Loss ◽

Cancer Patients ◽

National Cancer Institute ◽

Cancer Cachexia ◽

Clinical Decision Making ◽

Kidney Diseases ◽

Adverse Outcomes ◽

Ductal Adenocarcinoma ◽

Cancer Society ◽

Increased Risk

AbstractBackgroundCancer patients who lose weight have low treatment tolerance and poor outcomes compared to cancer patients without weight loss, termed cachexia. Despite the clear increased risk for patients, diagnosing cachexia still primarily relies on self-reported weight loss. A reliable biomarker to identify patients with cancer cachexia would be a valuable tool to improve clinical decision making and identification of patients at risk of adverse outcomes.MethodsTargeted metabolomics, including panels of amino acids, tricarboxylic acids, fatty acids, acylcarnitines, and sphingolipids, were conducted on plasma samples from patients with confirmed pancreatic ductal adenocarcinoma (PDAC) with and without cachexia and control patients without cancer. Receiver Operating Characteristic (ROC) analysis was undertaken to establish if any metabolite could effectively serve as a biomarker of cachexia.ResultsTargeted profiling revealed that cachectic patients had decreased circulating levels of three sphingolipids compared to either non-cachectic PDAC patients or patients without cancer. The ratio of C18-ceramide to C24-ceramide (C18:C24) outperformed a number of other previously proposed biomarkers of cachexia (area under ROC = 0.810). It was notable that some biomarkers, including C18:C24, were only elevated in cachectic males.ConclusionOur findings identify C18:C24 as a potentially new biomarker of PDAC-induced cachexia that also highlight a previously unappreciated sexual dimorphism in cancer cachexia.Trial registrationNone.FundingSupport was provided through a pilot grant from U24DK100469 from the National Institute of Diabetes and Digestive and Kidney Diseases (The Mayo Clinic), National Cancer Institute P30CA016058 (The Ohio State University), National Cancer Institute R01CA180057 (DCG), American Cancer Society PF-15-156-01-CSM (EET), and a Weiss Postdoctoral Fellowship (EET).

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Cancer cachexia, sarcopenia and hand-GRIP strength (HGS) in the prediction of outcome in patients with metastatic non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs): A prospective, observational study.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.9099 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 9099-9099

Author(s):

Sofia Agelaki ◽

Konstantinos Rounis ◽

Chara Papadaki ◽

Alexia A Monastirioti ◽

Lampros Vamvakas ◽

...

Keyword(s):

Weight Loss ◽

Cancer Cachexia ◽

Negative Impact ◽

Checkpoint Inhibitors ◽

Lumbar Vertebra ◽

Response Rates ◽

Skeletal Muscle Index ◽

Neutrophil Lymphocyte Ratio ◽

Lower Response ◽

Disease Stabilization

9099 Background: Cancer cachexia syndrome, affecting up to 80% of patients (pts) with NSCLC, is characterized by systemic inflammation, negative protein and energy balance and poor patient outcome. HGS has been independently correlated with outcome in pts with advanced cancer. We investigated the potential association between cachexia, sarcopenia and HGS with outcome in pts with advanced NSCLC treated with ICIs. Methods: Fifty-five pts with NSCLC treated with ICIs were included in the analysis. Patient and disease characteristics and data on outcome measures were prospectively collected. Cancer cachexia was defined as weight loss > 5% in the last 6 months, BMI < 20% (or baseline skeletal muscle index at the level of the 3rd lumbar vertebra consistent with sarcopenia) and any degree of weight loss > 2%. Baseline HGS was measured using the JAMAR analogue dynamometer. Results: Median age was 69 years, 50% of pts had non-squamous histology, 69% had PS 0-1, 61% had cancer cachexia and mean HGS was 27 kgs. Partial response, stable disease and progressive disease was recorded in 16%, 33% and 51% of pts, respectively. Median PFS was 4 months and median OS was 7.8 months. There was no association of cachexia or HGS with tumor burden, number of metastatic sites, LDH or neutrophil/lymphocyte ratio. Cachexia had a negative impact on HGS (p = 0,001). Pts with cachexia had lower response rates (4% vs 37%, p = 0.002), disease stabilization rates (32% vs 81%, p = 0.003) and shorter PFS (3.7 vs 8.2 months, p = 0.008) compared to non-cachectic pts. In multivariate analysis, cachexia independently predicted for shorter PFS (HR = 2.7, CI: 1.15 – 6.46, p = 0.023). Data on sarcopenia are being analyzed and will be presented at the meeting. Conclusions: Cancer cachexia is associated with lower response rates and disease stabilization rates and independently predicts for shorter PFS in pts with NSCLC treated with ICIs. To our knowledge this is the first report demonstrating a between the host’s immune and metabolic responses. The study of cancer cachexia may offer a new platform for the development of novel biomarkers of resistance to ICIs.

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