Home > Technical Resources > Case Studies > Lipid Removal for Phenotypic Cell Response in Cancer Research > Biotech Support Group and Leiden University Medical Center Report on a Gene Signature Ratio derived from Stroma Liquid Biopsy™ that Predicts Survival in Colon Cancer
Lipid Removal for Phenotypic Cell Response in Cancer Research

Biotech Support Group and Leiden University Medical Center Report on a Gene Signature Ratio derived from Stroma Liquid Biopsy™ that Predicts Survival in Colon Cancer

Methods to monitor the influence, potentially modulating the systemic response to cancer, offer new avenues for diagnosis, personalized medicine and therapeutic modalities.


The landscape of cancer-associated DNA mutations has supported the initial enthusiasm for liquid biopsies, a non-invasive way to characterize molecular changes taking place due to the presence of a tumor.
However, as mutational analysis predominates, the tumor microenvironment has largely remained unacknowledged in liquid biopsy research. As a result, there remains a significant unmet medical need for protein biomarkers derived from blood, which can detect cancer early and personalize treatment.

The Challenge

While most protein biomarker investigations focus on identifying very low abundance proteins shed from malignant cells, the discovery, characterization and measurement of ‘needle in the haystack’ type biomarkers remains an industry-wide proteomic challenge. Rather than focus on tissue derived proteins, we instead investigated the host systemic response as measured from blood, to the presence of cancer anywhere in the body

The Solution: Methods to Monitor the Systemic Response to Cancer

The Stroma Liquid Biopsy™ (SLB) proteomics patent pending panel comprises a set of 13 proteins from interconnected stromal pathways (i.e., coagulation, complement, acute phase inflammation) and is believed to capture a plasma proteomic blueprint indicative of a deranged systemic response in cancer. As such, it encompasses the importance of the tumor microenvironment (TME) compartment in liquid biopsy. Within similar context, the histologic tumor-stroma ratio (TSR), a stroma-derived biomarker developed by Leiden University Medical Center (LUMC), has been validated as an independent predictor of patient survival in various primary tumor types. The current work provides an explorative gene transcriptomic characterization of the SLB proteomics panel in colon carcinoma by integrating single-cell and bulk transcriptomics data from publicly available repositories.

The Outcome

Together BSG and LUMC published a journal article in Cancers. It is based upon on their joint goal to correlate BSG’s patent pending Stroma Liquid Biopsy™ panel of blood-borne biomarkers, to tissue derived tumor-stroma ratio (TSR[CR1] ) scoring methods developed by LUMC. The citation is:

The Stromal-Epithelial Gene Signature Ratio, is based on genes from the SLB panel, and classified by their expression as being derived from stromal-phenotypic or epithelial-phenotypic cells. In this way, it is demonstrated that histologic high stromal content is accompanied by increased gene expression of stroma-associated pathways in comparison to tumors with low stromal content. The gene signature ratio described in this study was found to be related to previous investigations of TSR and demonstrated a remarkably similar prognostic performance. These findings provide further molecular evidence for the prognostic power of the tumor stroma in clinical practice.

In addition to patient prognosis, high
gene signature ratio-risk scores were associated with an increased proportion of Microsatellite instability (MSI) in comparison to low ratio-risk scores. Given the increased proportion of MSI in the high ratio risk score group, the signature ratio might be predictive of immune checkpoint inhibitor (ICI) therapy response in colon cancer and should be the subject of future studies in ICI therapy-treated patient cohorts.

The current report provides a first theoretical framework for proteomic signatures to potentially serve as an indicator for tumor-stroma content when applied in liquid biopsy. Ultimately, the stromal conditioning protein blueprint, as captured by the SLB panel, may provide a more refined stratification of the tumor and patient prognosis, and offer new insights into therapeutic strategies that might beneficially modulate the tumor-microenvironment.

Finally, our selection of patent pending Stroma Liquid Biopsy™ biomarkers offer key analytical benefits as they are:

With few exceptions, of relative high abundance in serum and measurable by LC-MS

all highly differentiated – many severely, in the cancer population, and very stable in the normal/healthy population

pleotropic and determinately linked to innate immunity

in part, functional sub-forms, that can now be monitored by our patent pending methods, and which cannot be monitored by antigen presentation, aptamer or like binding motifs.

“It is very rewarding to see how, through the use of one of our enrichment products - AlbuVoid™, because of its unique selection properties, we observed something that others did not. Our experimental design was at first quite simple. Using proteomic data, we wanted to determine whether a systemic response was measurable in blood, to most if not all cancers, regardless of primary tumor, stage, or metastatic disease. This discovery research ultimately led to our patent pending panel of Stroma Liquid Biopsy™ biomarkers. From this, the genes from this panel have now been investigated through our collaboration with Leiden, providing a first theoretical framework for the panel’s suitability in liquid biopsy. We welcome commercial partnership opportunities so that we can advance the clinical utility for proteomic characterization of stromal conditioning in cancer. This can be an objective way to stratify patients towards the best treatment options, and personalize bedside decisions, which ultimately can prolong survival.” Swapan Roy, Ph.D., President and Founder of Biotech Support Group.

Lead authors Dr.Wilma Mesker (Associate Professor) and Cor Ravensbergen (Senior Medical Student) of the Leiden University Medical Center concur, and state further that, “the tumor-stroma microenvironment is an important prognostic parameter for patients with epithelial cancer types. However, tissue staining provides only qualitative information and does not offer any insight into specific cellular or protein mechanisms that impact survival. We do know that patients with a high amount of stromal cells in the primary tumor have a bad prognosis and respond worse to current chemo-, radio- and/or immunotherapy regimens. Now with the help of BSG’s Stroma Liquid Biopsy™ panel, our working hypothesis is showing real evidence for how stromal conditioning impacts survival. We will soon start our LC-MS analysis of the Stroma Liquid Biopsy™ protein panel on patient sera. From this analysis, we can envision future therapeutic strategies that can potentially modulate the tumor microenvironment, as the tumor-stroma ratio was found to be associated with pathologic response to neoadjuvant therapy. This supports the notion that the tumor microenvironment affects therapeutic response. So, we can begin to think about how modulation of stromal conditioning might improve immuno-oncology treatments, for example turning ‘cold’ tumors to ‘hot’. Consequently, we are very excited about the prospects for bridging the histologic tumor-stroma ratio with biomarkers for systemic response, as reported by the blood-based Stroma Liquid Biopsy™ panel.”

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[CR1]Decapitalized tumor-stroma ratio