Low serum mesothelin in pancreatic cancer patients results from retention of shed mesothelin in the tumor microenvironment

Our plain-English summary of Low serum mesothelin in pancreatic cancer patients results from retention of shed mesothelin in the tumor microenvironment, by X. Zhang, Y. Yu, C.J. Peer, et al (Translational Oncology, 2022).

The study

• Authors: X. Zhang, Y. Yu, C.J. Peer, R. Landsman, N. Skorupan, L. Cao, C. Alewine
• Journal: Translational Oncology
• Published: 2022;21:101440
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelin (MSLN) is overexpressed by many cancers, including pancreatic ductal adenocarcinoma (PDAC) and has consequently become a target for anti-cancer therapeutics. Mature, membrane bound MSLN is cleaved by proteases, releasing a shed form that transits to the circulation. Many patients with mesothelioma and ovarian cancer have abnormally high serum MSLN concentration. However, serum MSLN concentration in PDAC patients rarely exceeds levels of healthy controls. Here, serum MSLN concentration in advanced PDAC patients was examined pre- and post-treatment. Serum MSLN did not correlate with tumor MSLN expression, nor with changes in tumor burden as assessed by PDAC serum tumor marker CA19-9. Subsequently, tumor-bearing mouse models were used to investigate the fate of shed MSLN in PDAC versus a control cervical cancer model. Efficiency of MSLN secretion into the serum was cell-line dependent. Tumors from some PDAC lines had poor MSLN secretion efficiency although these lines had similar or higher MSLN shedding rate, total and surface MSLN expression. Measurements of compartment-specific MSLN concentration taken at equilibrium suggested that tumors with poor MSLN secretion efficiency trapped shed MSLN in the tumor microenvironment (TME), a finding confirmed by dynamic experiments using a doxycycline-inducible MSLN expression system. Tumors with the poorest MSLN secretion efficiency had higher collagen density and increased abundance of MSLN binding partner MUC16. The tumor with the worst secretion efficiency could rebind shed MSLN to the cancer cell surface. Altogether, these data suggest that PDAC can trap shed MSLN within the TME. This finding has potential significance for design of MSLN-targeted therapeutics.

Copyright © 2022. Published by Elsevier Inc.

In plain English

This laboratory and clinical study examined why serum mesothelin (MSLN) rarely exceeds healthy-control levels in pancreatic ductal adenocarcinoma (PDAC) despite tumour MSLN expression. In patients with previously treated advanced PDAC, mean serum MSLN was 0.856 nM (range 0.291 to 1.54 nM) and mean MPF 0.511 ng/mL (range 0.150 to 1.61 ng/mL), which the authors reported as within ranges previously reported for healthy donors. Archival tumour samples were available for 18 of 38 patients with pancreatobiliary cancer; all 18 had detectable MSLN, but expression did not correlate with serum MSLN, and no correlation with change in CA 19-9 appeared in 13 evaluable samples. In tumour-bearing nude mice, fitted slopes of serum MSLN against tumour weight (ng/mL per g, 95% CI) were KB 181 [128 to 233], AsPC1 97.0 [76.1 to 118], T3M4 65.3 [45.5 to 85.1] and KLM1 6.75 [3.80 to 9.71]. In doxycycline-inducible tumours the serum to intratumoral fluid MSLN ratio was 0.203 for KLM1+; native KLM1 tumours had the densest collagen and highest MUC16, and cultured KLM1 knockout cells rebound shed MSLN. The authors concluded advanced PDAC traps shed MSLN within the tumour microenvironment.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Combined analysis of serum and archival tumour samples from patients on a clinical protocol plus mouse xenograft and cell-culture experiments
• Who was studied: Patients with previously treated advanced PDAC sampled at the NIH Clinical Center (August 2016 to June 2019), with archival tumour samples available in 18 of 38 patients with pancreatobiliary cancer; plus female athymic nude mice bearing subcutaneous human tumour cell line xenografts
• Exposure: Not an exposure study: mesothelin expression and shedding by human PDAC cell lines (KLM1, T3M4, AsPC1), control cervical cancer line KB, mesothelioma lines Meso16/Meso29, and doxycycline-inducible MSLN constructs
• Main results:
  • Mean patient serum MSLN was 0.856 nM (range 0.291 to 1.54 nM) and mean MPF 0.511 ng/mL (range 0.150 to 1.61 ng/mL); the authors described these as within the range previously reported for healthy donors
  • Tumour MSLN expression in archival tissue did not correlate with serum MSLN concentration
  • Change in serum MSLN with treatment did not correlate with change in CA 19-9 in the 13 evaluable patient samples
  • In tumour-bearing mice, fitted slopes of serum MSLN concentration against tumour weight (with 95% confidence intervals) differed by cell line, lowest for the PDAC line KLM1
  • In the engineered doxycycline-inducible tumours, the serum to intratumoral fluid MSLN ratio for KLM1+ was 0.203
  • For the T3M4+ and KB+ inducible tumours, serum and intratumoral fluid MSLN concentrations were approximately equal
  • Collagen density in the tumour models was highest in KLM1 and lowest in KB
  • MUC16 expression was highest in KLM1, then T3M4, with almost none in KB
  • Cultured KLM1 knock-out cells exposed to MSLN-containing conditioned medium showed increased surface MSLN, consistent with rebinding
  • Injecting matrix-disrupting enzymes into KLM1 tumours produced little to no change in serum MSLN
• The authors' conclusion: The authors concluded that advanced PDAC traps shed mesothelin within the tumour microenvironment, which may matter for mesothelin-targeted therapeutics
• Limitations the authors state:
  • All tumours were grown subcutaneously rather than in the pancreas
  • The mouse model lacked a fully intact immune system
  • The authors could not test whether secretion efficiency changes in much larger tumours
  • The role of MUC16 could not be tested directly in MUC16-deficient cells
  • The authors noted their ITF extraction may have been less efficient in T3M4 tumours

Topics

Medical terms in this study, explained in our Lexicon: Mesothelin, Tumor Microenvironment, Adenocarcinoma, Mesothelioma, Ovarian Cancer, Tumor Burden, Tumor Marker, Collagen.

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• Mesothelin expression remodeled the immune-matrix tumor microenvironment predicting the risk of death in patients with malignant pleural mesothelioma — A.N. Qualiotto, C.M. Baldavira, et al. (2023)
• Serum soluble mesothelin concentrations in malignant pleural mesothelioma: relationship to tumor volume, clinical stage and changes in tumor burden — J. Creaney, R.J. Francis, et al. (2011)
• Sensitive and specific new enzyme-linked immunosorbent assay for N-ERC/mesothelin increases its potential as a useful serum tumor marker for mesothelioma — K. Shiomi, Y. Hagiwara, et al. (2008)
• The relationship between tumor MSLN methylation and serum mesothelin (SMRP) in mesothelioma — H.H. Nelson, L.M. Almquist, et al. (2011)

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