Extracellular matrix (ECM) remodeling is a central driver of disease progression in idiopathic pulmonary fibrosis (IPF) and other ILDs. At the cellular level, these remodeling processes ultimately lead to the decline in lung function seen in patients.
For drug developers, this means that modifying ECM remodeling is a key therapeutic objective.
But to evaluate whether novel compounds are working, we need reliable tools that measure the biological processes driving the disease.
We have developed a panel of ECM remodeling biomarkers based on our ProteinFingerprint Technology™ and 30 years of biomarker expertise.
For years, Endotrophin has been discussed as a circulating signal linked to fibroinflammatory disease severity and adverse outcomes. But there has been a persistent gap between association and a clearly defined, targetable mechanism. Now, a new report addresses that gap by identifying CD44 as a receptor for Endotrophin and connecting Endotrophin–CD44 binding to STAT3 signaling in hepatocellular carcinoma (HCC).
This publication anchors that association mechanistically by showing that Endotrophin is produced in fibrotic liver by COL6A3‑rich hepatic stellate cells (HSCs) and is not merely a degradation product, but a bioactive hormone-like peptide that signals into neighboring cells.
In the study’s experimental system, Endotrophin binding to CD44 activated STAT3 signaling and was linked to phenotypes relevant to tumor progression, including epithelial–mesenchymal transition (EMT), proliferation, and sorafenib resistance.
Fibroblast-derived Endotrophin signals into CD44+ cells and sustains itself
The paper further describes that hepatic stellate cell–derived Endotrophin targets pericentral CD44+ tumor cells, induces COL6A3 expression, and sustains Endotrophin production via a STAT3-dependent feedback loop.
Schematic of Endotrophin binding to CD44 and downstream STAT3 signaling. Created in BioRender. Gongora, F. (2026) https://BioRender.com/juay2se
When the Endotrophin-CD44 axis is activated, Endotrophin/PRO-C6 can serve as target engagement or stratification tools. Created in BioRender. Laursen, C. (2026) https://BioRender.com/2kd3vyi
By defining CD44–STAT3 as the principal Endotrophin signaling route in HCC, the paper suggests a shared signaling logic by which Endotrophin‑rich fibrotic niches (kidney, heart, adipose tissue) can drive organ damage and risk of outcome through similar downstream pathways.
Interested in how Endotrophin relate to fibroblast activity?
Circulating Endotrophin likely reflects an activated Endotrophin-CD44–STAT3 loop in fibrotic organs. High circulating Endotrophin is not only a marker of fibroblast activity but a surrogate for an ongoing pathogenic signaling circuit. Inhibiting the Endotrophin–CD44–STAT3 axis (genetic Col6a3/Cd44 deletion, STAT3 inhibition, or CD44‑binding‑defective Endotrophin mutants) attenuates fibrosis, EMT, steatosis and chemoresistance, positioning this axis as a therapeutic target in metabolic dysfunction-associated HCC.
Endotrophin‑rich fibrotic niches can drive organ damage and risk of outcome
Endotrophin does not only stage and prognosticate fibrotic disease but can also identify patients in whom Endotrophin‑driven fibro-inflammatory signaling is active and may be actionable by Endotrophin‑neutralizing antibodies or STAT3‑targeted interventions.
Why measure outcomes and risk signals across chronic disease
Endotrophin in the blood reflects fibro-inflammatory remodeling associates with cardiac and kidney fibrosis, mortality, and progression of MASH, cirrhosis, and HCC, with levels rising across the spectrum of metabolic diseases.
Endotrophin is not just “another fibrosis marker,” but a circulating readout of active fibro-inflammatory biology. In a systematic review and individual participant data meta-analysis, higher circulating Endotrophin independently associated with increased mortality risk across a broad range of chronic diseases: a core clinical reason to measure Endotrophin and nordicPRO-C6™ in programs where baseline biology and outcome risk need to be quantified.
Mechanistically, Endotrophin upregulates and releases into circulation as a consequence of recurring pathophysiological mechanisms across diseases. The functional implication of circulating Endotrophin supports PRO-C6 as an operational biomarker in clinical programs, where a blood-based measurement aligned with fibroblast-driven remodeling biology can be used at scale and longitudinally.
How does CD44 connect to existing literature on Endotrophin?
The new receptor paper changes how to interpret associations by providing a defined signaling handle. CD44 was identified as an Endotrophin receptor, and Endotrophin–CD44 engagement activated STAT3 signaling with disease-relevant phenotypes. When a circulating molecule is both outcome-associated and connected to a receptor axis, measuring Endotrophin and PRO-C6 becomes a practical component of biology-aware stratification and monitoring in fibro-inflammatory clinical programs. Nordic’s measurement approach centers on assays that quantify Endotrophin-related biology in circulation, including PRO-C6-based measurement supported through clinical evidence.
If your program involves fibro-inflammatory biology, position Endotrophin measurement as an evidence-aligned readout to support:
Baseline characterization of fibroblast-associated signaling burden,
Risk stratification informed by published outcome associations across chronic disease,
Mechanistic hypothesis testing in settings where CD44/STAT3 biology is part of the rationale.
A recent analysis published in JAMA highlights a major epidemiological shift: Colorectal cancer (CRC) is now the leading cause of cancer-related death among adults under 50 in the United States.
CRC has long been perceived as a disease of older populations. The rapid rise in early-onset cases challenges that assumption and reinforces the need to rethink both biology and treatment strategies.
Why standard therapies still fall short: the fibrotic stroma as a resistance mechanism
Therapeutically, the backbone remains surgery in localized disease, combination chemotherapy regimens such as FOLFOX and FOLFIRI, anti-VEGF or anti-EGFR targeted therapies in selected patients, and immunotherapy in MSI-high/dMMR tumors. While these approaches have extended survival, resistance and relapse remain frequent, particularly in advanced disease.
One key and often underestimated driver of progression and resistance is fibrosis. CRC tumors are embedded in a collagen-rich, fibrostenotic microenvironment shaped by cancer-associated fibroblasts (CAFs). This dense extracellular matrix (ECM) does not merely provide structure. It represents a desmoplastic barrier that limits drug penetration, reduces treatment efficacy, and supports tumor progression.
PRO-C6 correlates with TGF-β levels and overall survive in mCRC patients
From biology to measurement: collagen remodeling biomarkers
Collagens are central components of this barrier, and increased collagen deposition and remodeling consistently associate with poorer outcomes. One notable example is type VI collagen. Its gene expression is strongly associated with KRAS mutations and high TGF-β levels in CRC. New type VI collagen formation releases protein fragments to the bloodstream, which can be quantified in serum using our PRO-C6 biomarker and correlate to high TGF-β levels and poor OS.
In this context, measuring collagen formation and degradation becomes highly relevant. Quantifying ECM remodeling can provide insight into tumor aggressiveness, stromal activation, and potentially treatment response.
As early-onset CRC continues to rise, integrating stromal blood-based biomarkers into clinical strategy may refine risk stratification and open new opportunities for stroma-targeted interventions.
The future of CRC management will not rely solely on targeting tumor cells. It will require understanding and measuring the fibrotic environment that sustains them.
Nordic Bioscience´s neurology team has had 4 abstracts and oral presentation accepted at the AD/PD™ Alzheimer’s Disease and Parkinson’s Disease Conference in 2026.
The abstracts cover the following topics:
Modulation of blood-brain barrier integrity biomarkers in neurological disorders
Upregulation of serum calprotectin biomarkers in patients with Parkinson’s Disease
Elevation of type III and IV collagen fragments in the serum of treatment naïve multiple sclerosis patients
Biomarker profiling for the diagnosis of Parkinson’s disease
Alzheimer’s Disease, Multiple Sclerosis and Parkinson’s Disease are neurological disorders with devastating consequences for those affected and their families. These diseases are characterized by a lack of biomarkers specifically tracking disease progression and the effect of potential disease modifying therapies, leading to inadequate treatment possibilities and patient care.
In Alzheimer’s Disease (AD), recently developed fluid biomarkers, such as phospho-Tau isoforms (pTau217), have shown the ability to predict disease progression and treatment response in both plasma and CSF (measured in our CAP/CLIA-certified lab). This clearly illustrates how far the neuro field has come and highlights the importance of such biomarkers or continuous drug development in AD.
For Multiple Sclerosis (MS) and Parkinson’s Disease (PD), the work focuses on identifying a panel of biomarkers reflecting different aspects of these complex diseases, including neuroinflammation, blood-brain barrier integrity and active neurodegeneration.
From pTau217 to α-Synuclein: New Biomarkers Driving Neurodegeneration and Neuroinflammation Research
There are therapies and biomarkers available in MS, but we still lack refined biomarkers to monitor the ongoing efficacy of the drugs. Such biomarkers can be used to enrich patient populations with respect to responses, as well as supporting the development of new drugs. Biomarkers such as fragments of collagen type IV, which reflect turnover of the basement membrane of the blood-brain barrier, have shown promise.
At the same time, in PD, there is a lack of biomarkers reflecting the underlying neuronal pathology especially in plasma/serum. Consequently, there is a competition on being the first to robustly detect the key protein α-synuclein—a biomarker that can capture the underlying pathology. Here, we introduced a novel assay detecting fragments of α-synuclein, which are generated during the loss of neurons. After further investigation, this biomarker could potentially become an important tool for drug development in PD.
Overall, fluid biomarkers for neurodegenerative diseases have come a long way in the last decade and are clearly critical to the success of drug development trials.
We have highlighted some our publications that we and our collaborators worked on in the first quarter of 2024—in no particular order. We invite you to browse and read according to your interests!
Oncology
Fibroblast activation protein (FAP) is almost exclusively expressed in pathological conditions including multiple types of fibrosis and cancers, making it an optimal target for treatment.
Treatment strategies utilizing the unique proteolytic activity of FAP are emerging, thus emphasizing the importance of biomarkers to directly assess FAP activity.
CWe developed a non-invasive quantification tool for FAP-activity, specifically generated through FAP-mediated cleavage (C3F) for selection and monitoring of patients in FAP-related clinical trials.
Novel treatments for Alzheimer’s Disease are intensely sought; however, there is a dire lack of good biomarkers identifying the population with active disease progression, i.e. those in need of treatment.
We measured our Tau-A and Tau-C assays in a clinical cohort of patients with well-characterized Alzheimer’s Disease, and we observed that Tau-A was related to the CSF-levels of Aβ1-42, while Tau-C levels were indicative of fast progression, and as such identified a population of great interest.
We explored the involvement of the extracellular matrix (ECM) in various cardiomyopathies and its impact on myocardial stiffness and fibrosis. We also discussed the potential of ECM fragments for early diagnosis, prognosis, and risk stratification.
Cardiomyopathies constitute a diverse group of disorders characterized by fibrosis, ultimately leading to heart failure. Utilizing ECM biomarkers could enhance diagnosis and guide personalized therapies targeting fibrosis.
We investigated whether a degradation fragment of collagen type III (C3M) correlated with markers of inflammation and endothelial dysfunction and whether C3M was a risk marker for progression of chronic kidney disease (CKD)in persons with type 2 diabetes and microalbuminuria.
Higher serum C3M is a risk marker for CKD progression and correlates with markers of inflammation in persons with type 2 diabetes. Moreover, a doubling of serum C3M was associated with CKD progression (with mortality as competing risk) after adjustment for conventional risk factors.
In our first rheumatology publication, we investigated M6495, a new drug targeting ADAMTS-5, in healthy volunteers and osteoarthritis patients.
M6495 was safe and well-tolerated at doses up to 300mg. It significantly reduced a key biomarker of cartilage breakdown, suggesting potential to slow disease progression.
In the second study explored a new biomarker for response to Tocilizumab, a treatment for rheumatoid arthritis. Measuring type VI collagen degradation (C6M) identified patients who benefited more from the drug.
This approach has potential to personalize treatment and improve outcomes for RA patients.
In our third rheumatology publication, highlighted the need for better ways to classify osteoarthritis (OA). Current treatments only manage symptoms, and a deeper understanding of the disease is crucial.
We propose using a panel of biochemical markers to define different OA subtypes (endotypes).
We are changing people’s lives and making an impact!
“I hope this year will be as productive as last year! Congratulations to Team Nordic,” said Morten Karsdal, CEO of Nordic Bioscience, as we close out 2021 and head into 2022. “Thank you for your commitment and support to our mission: to change people’s lives through precision medicine and serological quantification of the extracellular matrix (ECM), enabled by high-precision instrumentation,” Morten Karsdal emphasized.
Nordic Bioscience has published a total of 59 publications in 2021, exclusively in peer-reviewed journals, with an average impact factor of 6.62, which shows the impact Nordic Bioscience scientists are leaving in the field. This means that quantity and quality go hand in hand, as an impact factor above 5 is a very good distinction. Even more, many of these 59 publications have an impact factor above 10 or even 20.
Nordic Bioscience’s research group is highly regarded in its field and a leader in extracellular matrix (ECM) science and quantification, proving that the company’s efforts are having an impact.
“When we visited customers in December during our normal pharma tour,” says Morten Karsdal, “I often heard how impressed our customers were with the interaction of our senior scientists and directors and the seamless coordination of the lab. “It is clear that we are all making a difference by trying to do things a little bit better every day,” the CEO added.
These successes are the culmination of a year-long team effort. The publications are based on data, and all data start with an idea for a biomarker. Assay development, assay production, assay validation, assay measurements, biobank samples, legal contracts, quality control, data reporting, and so on: all these pieces of the puzzle are required to produce publications that demonstrate value to patients and science.
Finally, the 3rd edition of Nordic Bioscience’s collagen book will be published in 2022, after the 2nd edition was downloaded 9000 times.
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Nordic Bioscience digest of the Best of 2022 publication series
In 2022, our scientific teams have once again worked incredibly hard to advance our technologies to better benefit patients in need. With more than 60 publications, we have published an average of more than 5 articles per month this year.
We have put together the best of 2022 for you from our various focal points—in no particular order. We invite you to browse and read according to your interests!
Respiratory
Novel treatments for idiopathic pulmonary fibrosis (IPF) are needed to combat this devastating disease.
To investigate the antifibrotic effect of novel compounds and increase the chances of success in clinical trials, blood-based biomarkers may already be introduced at early stages of development.
Conventional serum calprotectin biomarkers are often not as clinically useful as the fecal versions because the short half-life of calprotectin in blood reduces the window in which the current serum calprotectin ELISA assay can detect calprotectin dimer protein.
CPa9-HNE ELISA has emerged as a novel serum calprotectin biomarker with significant clinical potential as a biomarker for patients with IBD to monitor disease activity and neutrophil activity.
Monitoring changes in the extracellular matrix during liver fibrosis is of great interest. Biomarkers to assess fibrogenesis already exist, but biomarkers of fibrosis resolution have not been validated.
These biomarkers would be equally valuable for understanding disease progression or the mechanism of a particular intervention, and for understanding the potential induction of hepatic fibrosis resolution.
Identification of biomarkers associated with psoriatic arthritis (PsA) disease and their potential as predictors of response to treatment are unmet needs in PsA.
The aim of the study was to investigate the association of serum levels of tissue turnover biomarkers with PsA disease phenotypes and response to Guselkumab treatment.
All agree that osteoarthritis (OA) is a heterogeneous disease – drugs in development fail because there is no approved way to segregate patients to give them targeted treatment.
Endotyping is necessary to understand the pathogenesis that drives the disease in individual patients. In the APPROACH consortium, we have measured biochemical markers that reflect the pathogenesis of different tissue compartments affected by the disease.
A persistent problem remains unresolved in heart failure with preserved ejection fraction – targeted treatment for highly heterogeneous patients.
This heterogeneity can be the cause of the lack of response to treatment in clinical trials, making it difficult for trials to succeed. The field needs better actionable biomarkers capable of finding the patients most in need of treatment – and that starts with PRO-C6.
Pancreatic cancer is an extremely lethal and fibrotic cancer disease. Novel tools such as biomarkers and preclinical models that can improve understanding of tumor fibrosis biology, drug development, and disease progression are urgently needed.
In this publication, we established a pseudo-3D in vitro pancreatic CAF model in combination with clinical collagen biomarkers (PRO-C3 and PRO-C6) as a translational screening tool for antifibrotic drugs.
Nordic Bioscience digest of the Best of 2023 publication series
2023 – a year of a series of scientific successes for Nordic! Our scientific teams have worked incredibly hard to advance our technologies to better benefit patients in need. With close to 60 publications, we averaged at least 5 articles per month – just like last year. We have put together the best of 2023 for you from our various focal points—in no particular order. We invite you to browse and read according to your interests!
New biomarkers are crucial for identifying fast-progressing idiopathic pulmonary fibrosis (IPF) patients. We evaluated the serological value of two vimentin neo-epitopes, VIM and VICM, in IPF.
While both originate from the same fragment, VIM measures vimentin degradation, and VICM reflects macrophage activity through citrullination. Notably, unlike VIM, VICM demonstrated significant prognostic value, effectively distinguishing fast-progressing from non-progressing IPF patients at diagnosis.
This paper highlights the potential of biomarkers to expedite drug development, emphasizing their role as early indicators for improved clinical response, enhanced patient safety, and personalized medicine.
We explore lessons learned by the EU IMI2-funded LITMUS consortium in their interactions with regulatory agencies, underscoring the significance of sharing such knowledge with the scientific community to increase the likelihood of qualifying relevant biomarkers and facilitating common understanding and support in decision-making frameworks.
This publication introduces a novel approach for nonalcoholic fatty liver disease (NAFLD) by identifying a “high-risk, high-fibrogenesis” patient endotype using collagen formation biomarkers.
Characterized by elevated fibroblast activity, this endotype responds well to a very low-calorie diet, showing a significant reduction in collagen fibrogenesis with weight loss. Quantifying fibrogenesis biomarkers allows predicting treatment response at baseline.
Skin tissue remodeling is vital for maintaining homeostasis but can be disrupted in conditions like atopic dermatitis, psoriasis, and hidradenitis suppurativa. Type VI collagen is crucial for ECM assembly in human dermal fibroblasts.
Specific fragments of type VI collagen can serve as blood biomarkers for dermatological conditions. Quantifying the levels of type VI collagen inpatients with dermatological disorders could prove to be a valuable tool for both patient identification and drug development.
The pathogenesis of axial spondyloarthritis (axSpA) involves tumor necrosis factor (TNF)-α-induced joint inflammation. However, choosing optimal treatments for axSpA in a timely and non-invasive manner remains a challenge in clinical practice.
Blood-based biomarkers present a cost-effective and accessible solution. Exploring ECM biomarkers as potential pharmaco-dynamic markers may aid in predicting and monitoring TNF-α inhibitor treatment responses in axSpA patients. This research also sheds light on the development of new effective therapeutic strategies.
Recent evidence suggests Empagliflozin may have anti-fibrotic effects, notably reducing type I and III collagen (PINP and PRO-C3). Lower levels of type VI collagen (PRO-C6) are associated with milder heart failure outcomes but increased risks of hospitalization, mortality, and renal complications.
Accurate assessment of extracellular matrix remodeling is crucial for precise heart failure patient endotype identification. Other studies reveal a 12.4% and 9.2% increase in cardiovascular or all-cause mortality risk per 1 ng/ml rise in PRO-C6.
Our study explores tumor collagen quantity and quality, emphasizing cancer-associated fibroblasts (CAFs) and their role in tumor fibrosis. We connect serological collagen biomarkers to specific CAF subtypes within the tumor microenvironment, building on our FDA-supported letter of support for the initial serological biomarker for tumor fibrosis.
The unique collagen profiles linked to CAF subtypes present potential avenues for discovering new cancer biomarkers and therapeutic targets.
TGFβ signaling: a game changer in personalized cancer treatments?
Treatment outcomes are deeply influenced by the tumor microenvironment (TME) where TGFβ (Transforming Growth Factor Beta) has emerged as a critical factor that can dictate the success—or failure—of therapeutic strategies.
As shown below (Figure 1.) in an example from renal cell carcinoma (RCC), high TGFβ activity contributes to poor responses to tyrosine kinase inhibitors (TKIs) as compared immune checkpoint inhibitors. TGFβ activity was measured by the TGFβ-LAP biomarker in pre-treatment serum.
Conventional TGFβ assays are affected by platelets releasing TGFβ during clotting (drastically affecting the measurements in serum). In contrast, the TGFβ-LAP biomarker quantifies a cleaved latent activating protein (LAP) fragment which is independent of platelet TGFβ release providing a novel tool to indirectly measure TGFβ in serum.
Figure 1.TGFβ (Transforming Growth Factor Beta) has emerged as a critical factor that can indicate success rate
Why does this happen?
TKIs, such as Sunitinib, are primarily targeting angiogenesis and signaling pathways critical for tumor growth. However, elevated TGFβ promotes an immunosuppressive and fibrotic TME, counteracting these therapies by enhancing tumor resilience and protecting vasculature from the intended effects of TKIs. On the other hand, anti-PD-1/anti-CTLA-4 immuno-oncology (IO) therapies such as Nivolumab and Ipilimumab, which aim to re-activate T-cell responses, may be relatively more effective even in a TGFβ-rich environment.
Personalizing treatment (TKI vs. IO) with biomarker-driven approaches
Understanding TGFβ activity could be a game-changer in personalizing cancer treatments. Biomarkers that measure TGFβ levels or its downstream effects might help clinicians choose between TKIs or immunotherapy – or even better, design combination regimens. This underscores the importance of a biomarker-driven approach to cancer treatments. As we continue to unravel these mechanisms, the goal remains clear: to turn the TME from a shield into a target.
Our approach is designed to be implemented into clinical trials and research programs on TKI vs. IO, and to help explore the intersection of TGFβ biology and therapeutic resistance.
