The leukemic matrisome interface as a source of markers and targets for acute myeloid leukemia

The leukemic matrisome interface as a source of markers and targets for acute myeloid leukemia - ELMI is a research consortium led by Prof. Taina Pihlajaniemi (University of Oulu), Prof. Jyrki Heino (Univ. of Turk) and Adj. Prof. Valerio Izzi (University of Oulu), with important collaborative contributions by Assistant Prof. Alexandra Naba (Univ. of Illinois at Chicago), Prof. Caroline Heckman, (Institute for Molecular Medicine Finland - FIMM), Prof. Simon Méndez-Ferrer (Cambridge School of Medicine), Adj. Prof. Katri Pylkäs (University of Oulu), and the personnel of Oulu University Hospital. It is funded by the Academy of Finland Molecular Regulatory Networks of Life (R'Life) program for the years 2020 - 2023.

Hijacking and shaping the microenvironment through extracellular matrix (ECM) proteins, extracellular enzymes, cytokines and growth factors is a hallmark of cancer. All these biological entities, collectively known as the “matrisome”, cooperate to cancer growth and spreading and they are also crucial for drug resistance and metastatization. In acute myeloid leukemia (AML), the deadliest form of blood cancer, the interaction of neoplastic cells with the bone marrow microenvironment is of paramount importance and participates to the creation of “leukemic niches” where leukemia stem cells (LSCs) reside out of reach of antineoplastic drugs. Osteoblasts are crucial stromal components of these niches and their dynamic communication with LSCs establishes regulatory networks that ultimately concur to create a specific matrisome interface within the leukemic niche. Our recent studies show a prominent and previously unrecognized role for AML cells in generating their own matrisome microenvironment and, furthermore, indicate its crucial clinical importance for therapeutic outcome and patient survival. Hence, here we aim at characterizing the composition and regulation of the matrisome interface, understanding how it changes during chemotherapy and its impact on clinical outcome and therapeutic possibilities. To this aim, we propose to start from a controlled AML-osteoblast coculture approach, performing and integrating transcriptomics and proteomics analyses in presence or absence of the antileukemic drug Ara-C, to obtain a first quantitative and qualitative understanding of the leukemic matrisome interface (LMI) and its regulatory mechanisms, which will be refined and validated further. At the patient level, the regulatory networks will be tested into 1) available omics data from open-access AML cohorts, 2) omics data from therapy responder/non-responder patients, collected before and after therapy, to further explore the mechanics of LMI regulation in the context of different genetic backgrounds and cancer drivers and, 3) primary patient samples (AML cells) to evaluate the druggability potential of our findings. In parallel, we will also investigate LMI dynamics in murine AML models and cell lines, testing findings and targets with high- and low-throughput approaches also for potential therapeutic intervention. We foresee the discovery of new markers and targets of AML, opening to new therapeutic possibilities in the fight against this form of cancer.