Cancer cells are surrounded by extracellular matrix, fibroblasts, immune cells and blood vessels in the tumor microenvironment. Unlike normal tissue, the tumor microenvironment is a stressed ecosystem for cancer cells. This is mainly due to the natural tissue remodeling or due to treatments that exacerbate hypoxia, oxygen fluctuations and nutrient restriction. While this stressed environment can restrict some tumors, it helps other tumors grow and metastasize. Sounni’s team is investigating how cancer cells adapt to the stressed microenvironment and target metabolic vulnerabilities of cancer cells to combat drug resistance.

Metabolic adaptation to hypoxia and re-oxygenation

It is well recognized that malignant tumor tissues are composed heterogeneous cell populations, as determined by genomic mutation data, metabolic and morphological features of cells within a tumor. However, very little is known about (i)the distinctive composition of the subpopulations within a cancer tissue and (ii) how they rewire their metabolic needs in instable tumor micro-environment affected by hypoxia and re-oxygenation fluctuations during tumor development stages. These instabilities in O2and nutrient supply to tumor resulted in a stressed tumor microenvironment (TME) that can affect cell viability but also resistance to treatments such as anti-angiogenic and radio-therapies. Here, we are investigating the role of hypoxia and re-oxygenation induced by anti-angiogenic therapy and treatment cessation leading to tumor hyper oxygenation after a long period of hypoxia imposed by the complete blockade of angiogenesis. We have previously carried out large screening analyses on xenografts models after anti-angiogenic therapy and re-oxygenation. By combining transcriptomics, proteomics and metabolomics analysis, we evidenced a metabolic reprogramming in these tumors. A natural hypothesis is to test whether each tumor consists of different subpopulations or acquisition of new capabilities to cope with fluctuating O2and nutrients scare. While following distinct genetic mutations experimentally within a cancer tissue is very challenging, we are tackling these problems by exploring the metabolic dynamic of cancer and stromal cells by mimicking hypoxia and re-oxygenation at different time points during cancer progression. We found that lipid metabolism is the key metabolism pathway used by tumors to cope with hypoxia and metabolic stress imposed by TME. The metabolic cooperation and exchange between different cell types within a tissue are currently explored in experimental models of breast, colon and lung cancers. Increasing our thorough understanding about these concerns will not only offer new insights about the mechanisms of a cancer adaptation to treatments but also possibly lead to improved cancer treatment options.

Novel combination therapy for triple negative breast cancer

Triple negative breast cancer (TNBC) comprises heterogeneous tumors displaying an aggressive pattern of progression and metastases. Standard systemic treatment relies entirely on chemotherapy. Paradoxically, TNBC has higher response to chemotherapy (30-40%) and the highest relapse rates. The lack of well-defined TNBC sub-classification based on actionable targets hampers the use of available targeted therapies. There is an urgent unmeet need for improving TNBC patient treatment. Given the expression of epidermal growth factor receptor (EGFR) by TNBC, anti-EGFR targeted therapies have been conducted, but were ineffective in unselected patients who showed limited, transient or no response. Here, we have defined new molecular markers (MT4-MMP/EGFR/RB) that are expressed together in about 50% of TNBC and that can be targeted by erlotinib and palbociclib combination. In this context, we have explored EGFR-dependent TNBC proliferation and discovered a new molecular EGFR partner, the membrane-type 4 matrix metalloprotease (MT4-MMP), which potentiates receptor intracellular signaling. MT4-MMP interacts with EGFR and enhances its activation leading to retinoblastoma protein (RB) inactivation and breast cancer cell proliferation. Through immunohistochemistry analyses of human TNBC and PDX, we found that 50% of TNBC express MT4-MMP, EGFR and RB. Notably, these tumors are more sensitive to erlotinib (anti-EGFR) and palbociclib (CDK4/6 inhibitor) combination therapy, in vitro and in vivo on TNBC xenografts and PDX. We are exploring the efficacy of new treatment combination in PDX and testing different therapeutic strategies that could influence the TNBC immune response, thereby sensitizing tumors to treatments.

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