O'Brien, S. A. | Search bioRxiv

bioRxiv2025

In-depth proteomic profiling of the extracellular matrix of pancreatic ductal adenocarcinomas identifies signatures correlating with lymphocyte infiltration

The extracellular matrix (ECM) is a complex assembly of proteins surrounding cells. It is a critical component of the tumor microenvironment that plays an active role in tumor progression and modulation of tumor response to treatment. Pancreatic ductal adenocarcinoma (PDAC) is a cancer type characterized by one of the worst prognoses, as it is often diagnosed at an advanced stage. It is also characterized by a very dense ECM, which hinders efficient drug delivery. In addition, PDACs are considered "cold" tumors as they fail to elicit a strong immune response, challenging the use of immunotherapy for PDAC cancer patients. Yet, the interplay between the ECM and immune cells within the PDAC tumor microenvironment remains poorly understood. Here, we employed ECM-focused proteomics to profile the ECM compositions of PDAC mouse models characterized by different levels of CD8+ T-cell infiltration. We found that CD8lo, or "cold" tumors, and CD8hi, or "hot" tumors, exhibited different ECM compositions. Interrogation of publicly available single-cell RNA-sequencing datasets of human PDACs further revealed that the ECM proteins distinguishing hot and cold PDACs are secreted by multiple stromal cell populations, including cancer-associated fibroblasts, stellate cells, and macrophages. Last, we found that the expression of a subset of the genes encoding ECM proteins characteristic of the CD8lo phenotype correlated with CD8+ T-cell infiltration in human PDAC samples and patient survival. This study paves the way for the development of ECM-modulating interventions to enhance immune cell infiltration and responsiveness to immunotherapy. SignificanceWe report the identification of ECM protein signatures correlating with the level of CD8+ lymphocyte infiltration in murine models of pancreatic ductal adenocarcinomas and human samples. This work paves the way for the development of ECM-modulating therapeutic strategies to enhance lymphocyte infiltration and, hence, the efficacy of immunotherapies.

cancer biology↗

bioRxiv2025

Mobile species' responses to surrounding land use generate trade-offs among nature's contributions to people

Agricultural landscapes provide material, non-material and regulating contributions that affect human wellbeing. The responses of these natures contributions to people (NCP) to land-use patterns depend on supporting biota with different habitat requirements, generating trade-offs and synergies. Predictions of NCP trade-offs could inform land-use decisions, but these do not typically account for the effects of land-use patterns on the movement of NCP-providing species, nor for interactions among NCP providers. To explore spatial trade-offs and synergies in eight indicators of NCP, we used Bayesian models that allow for interactions among land uses and among NCP using data from 150 grassland sites across rural Germany. We found that spatial arrangements of forest and open habitat influenced many NCP: acoustic diversity, birdwatching potential, natural enemy abundance and pollination. In particular, the amount and proximity of land uses in the surrounding landscape, especially forest and open habitat, drove the supply of most NCP. However, NCP provided by smaller-bodied taxa (herbivory and pathogen infection) responded weakly to landscape factors. Multiple NCP provided by a given taxon responded differently to their surrounding landscape (e.g. bird-provided caterpillar predation and seed predation), leading to trade-offs among NCP over short distances ([≤]60 m). These were caused by different rates and directions of response to amount and location of land uses. Resulting spatial predictions revealed that grassland-dominated or mixed forest-grassland areas better maximize beneficial NCP and minimize detrimental NCP across landscapes than purely forest-dominated areas. This suggests promoting semi-natural vegetation in agricultural landscapes to provide greater-than-additive benefits to net NCP supply. Significance StatementLand use affects natures contributions to people (NCP), including those provided by mobile species, in complex ways. Variation in the responses of species to the amount and location of land uses results in NCP trade-offs across landscapes, but decision-makers lack the capacity to spatially predict these trade-offs. We predict how the supply of both beneficial and detrimental NCP and associated trade-offs vary across diverse rural landscapes and find that grassland-dominated or mixed forest-grassland areas deliver higher net NCP supply than forest-dominated areas in our study system. Our findings support policies for promoting semi-natural vegetation cover in agricultural landscapes, as these may provide non-additive benefits for NCP.

ecology↗