Abstract
Procollagen 11A1 (COL11A1) is a central component of the extracellular matrix in many carcinomas, which is considered to be mainly produced by cancer associated fibroblasts (CAFs). As COL11A1 expression correlates with adverse prognosis and is implicated in chemoresistance, it is a promising putative target. For the first time, we used RNA in-situ hybridization to systematically identify the cells that produce COL11A1 in the ten most prevalent carcinoma types, lymphomas (n = 275) and corresponding normal tissue (n = 55; panCancer cohort). Moreover, as most salivary gland carcinomas (SGC) display distinct stromal architectures, we also analysed 110 SGC. The corresponding protein formation of COL11A1 was determined by MALDI-TOF–MS-Imaging. We report that colon, breast and salivary duct carcinomas are highly infiltrated by COL11A1 positive CAFs (CAFsCOL11A1) and might thus be promising candidates for antidesmoplastic or COL11A1-targeted therapies. The amount of CAFsCOL11A1 correlated significantly with tumour grade, tumour stage and nodal spread in the panCancer cohort. Significant associations between CAFsCOL11A1 and vascular invasion, perineural spread and nodal spread were observed in the SGC cohort. Also, we discovered that tumour cells of intercalated duct derived SGC and CAFs produce COL11A1 in a mutually exclusive manner. Our findings represent a novel mode of extracellular matrix production in carcinomas and could be highly relevant in the future. Our findings elucidate the mode of COL11A1 expression in very different carcinoma types and may aid to categorise tumours in the setting of possible future COL11A1-related therapies.
Highlights
As the efficacy of mutation-specific therapies is limited by resistance mechanisms, more recently, the interest of cancer research has expanded towards the non-neoplastic tumour microenvironment (TME)
We measured the infiltration by CAFsCOL11A1 using a semiquantitative score (Score 0—4) that reflected the percentage of stromal surface stained by the COL11A1 RNA-ISH
We assessed the percentage of tumour cells with COL11A1 staining (TCCOL11A1). CAFsCOL11A1 were almost exclusively observed in tumour tissues with an overall positivity rate of 34.5% compared to 1.6% in normal tissue
Summary
As the efficacy of mutation-specific therapies is limited by resistance mechanisms, more recently, the interest of cancer research has expanded towards the non-neoplastic tumour microenvironment (TME). COL11A1 is expressed in cartilaginous tissues and mesenchymal stem cells while it is nearly undetectable in other normal tissues including resident fibroblasts and most benign sclerotic conditions [9, 17,18,19,20]. This relative specificity is an advantage over other fibroblast markers such as aSMA, PDFGRß or FAP and could make COL11A1 a more reliable indicator for a CAF phenotype [20, 21].
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