ONCOGENOMICS

Principal Investigator

Staff

Research topic

Pharmacogenomics and immunotherapy to combat cancer progression and resistance to treatment.

Background

Invasive-metastatic progression of cancer involves concomitant acquisition by neoplastic cells of two key biological properties: the ability to migrate, invade and colonize distant organs, and the resistance to pharmacological treatments. Acquisition of these properties is driven by a combination of many molecular aberrations, which makes each tumour potentially distinct from all others. To tackle this complexity, the Laboratory generates and analyses molecular and pharmacological data on large series of tumour samples and patient-derived experimental cancer models. Integrative analysis of these data has two main aims: (i) to improve patient classification into subgroups with different prognosis and treatment response (“molecular subtyping”); (ii) to identify patient-specific alterations that provide an effective therapeutic target. Along this line, the laboratory also exploits molecular information to guide immune killer cells specifically against cancer cells, by engineering them with chimaeric antigen receptors (CARs), an approach known as “adoptive immunotherapy”.

Research achievements

The Laboratory of Oncogenomics has been mostly focusing on colorectal cancer (CRC) and on the generation and analysis of multi-layer molecular and pharmacological data on large sets of CRC samples, patient-derived xenografts (PDXs) and cell lines. Such analysis was then followed by functional validation of identified candidates and mechanisms of neoplastic progression.

Main achievements: (i) characterisation of the role of stromal cells (fibroblasts, endothelial cells, leukocytes) in modulating CRC aggressiveness and resistance to treatment (Nature Genetics, 2015); (ii) Integrative pharmacogenomic profiling of a large collection of CRC cell lines (n=151), and identification of a mechanism of resistance to WNT pathway inhibition (EMBO Molecular Medicine, 2017); (iii) Integrative pharmacogenomic profiling of a large collection of CRC PDXs (n=515) and identification of new transcriptional subtypes of CRC with unprecedented predictive and prognostic performances (Nature Communications 2017); (iv) Extensive genomic profiling of PDXs and of the tumours of origin to confirm reliability of patient-derived models to study CRC (Nature Genetics 2021); (v) Application of machine learning algorithms to improve cancer classification (Genome Medicine 2023); (vi) Preclinical validation of combinatorial CAR-based adoptive immunotherapy against HER2-amplified CRC (Molecular Therapy 2024).

Sharing the genomic expertise of the Lab with other groups inside and outside the Institute also led to publication of several collaborative works.

Conclusions and Perspectives

The Laboratory will continue exploiting integrative genomics for better molecular stratification and for highlighting actionable therapeutic targets in CRC and other neoplastic diseases, with a specific focus on targeted therapies and adoptive immunotherapy.

Publications

At this link, you can find all the scientific publications of the Principal Investigator.