Research projects - Molecular Oncology Lab
Currently ongoing projects:
Targeting cellular senescence in physiological, pathological and iatrogenic conditions
Development of senolytic therapies for chemotherapy-treated prostate cancer
Senescent cells are arrested cells that can be the source of inflammation and play a causal role in ageing. They accumulate along with age progression and preventing this accumulation delays age-related diseases. Even if the mechanism is still not adequately understood, accumulation can result from increasing the production of those cells or decreasing the removal of senescent cells with age, or both. Several reports have demonstrated that the removal of senescent cells can delay or sometimes restore the correct functionality of different systems. Alimonti team has developed many screening methodologies to identify compounds targeting cellular senescence in cancer and ageing. The team has already identified a set of compounds with activity on senescence that could impact on different age-related diseases. These compounds will be cross-validated using different approaches before assessing their efficacy in vivo in various mouse models. Finally, data derived from these experimental models will be integrated using different "omics" to identify common and specific pathways of cellular senescence that may be targeted in future studies.
We aim to precisely spot senescent cell's weak points to tailor a precise therapy aimed at removing senescent cells into the body or delaying the onset of senescence. This can ameliorate multiple aspects of social life and will allow us to slow down ageing.
Development of senolytic therapies for chemotherapy-treated prostate cancer
Cellular senescence, defined as a stable cell cycle arrest occurring in primary and tumor cells for the effect of loss of tumor suppressor genes (TSGs) or anti-cancer therapies, is considered a significant player in prostate cancer initiation, progression, and treatment resistance. While the enhancement of cellular senescence in tumor cells initially arrests cell growth, the persistence of senescent tumor cells can lead to tumor progression and treatment resistance. These antagonistic effects of senescence in cancer have been attributed to the senescence-associated secretory phenotype (SASP). The SASP of senescent tumor cells works as a source of chronic inflammation that can drive the proliferation and migration of non-senescent tumor cells and promote metastasis in specific contexts.
Recent findings from Alimonti team demonstrate that therapy-induced senescence (TIS) in prostate tumors driven by the combined loss of PTEN and TIMP1 promotes metastases formation through the SASP. In contrast, eliminating senescent tumor cells (senolytic therapy) prevented metastases in mice treated with TIS (Guccini et al. 2021, Cancer Cell). This project raises the need to finally develop an algorithm (Senescence index tool, SIT) that can precisely spot senescent cancer cells to characterize them, revealing an unexpected heterogeneity. Moreover, the SIT also allow the team to spot senescence vulnerability, identifying MCL-1 as a critical vulnerability of senescent cells (Troiani et al. 2022, Nat Comm.).
Targeting tumour-infiltrating immune cells for prostate cancer therapy
Cancer and immune system subsets have an indissoluble link. Especially prostate cancer has a clear connection with tumour-infiltrating myeloid cells, as Alimonti team has demonstrated over the years. Indeed this immune subpopulation can antagonize chemotherapy-induced senescence (Di Mitri et al., Nature 2014) and drive the onset of castration resistance in prostate cancers (Calcinotto et al., Nature 2018). We recently extended our interests to identifying novel immune checkpoints in prostate cancer and the characterization of non-myeloid immune cell subsets populating the tumour microenvironment, especially in response to pro-senescence compounds. These findings will be pivotal for designing new treatment modalities to fight prostate cancer.Alimonti team has an active branch of research in this regard, studying the role of many immune populations and their contribution to cancer progression.
Targeting the host microbiota to reverse therapeutic resistance in lethal prostate cancer
This lab core unit aims to understand the mechanism controlling host-microbiome interactions in prostate cancer. The intestine is inhabited by trillions of commensal bacteria that cohabit and produce a high load of bacterial products essential for our lives. Perturbation that modifies this homeostatic equilibrium (medications, diet, inflammation, genetics, etc.) can alter microbial organization. We recently discovered that androgen deprivation therapy, a standard of care in prostate cancer, selects for a peculiar "unfavourable" microbiota capable of synthesizing androgens, minimizing the effect of the therapy (Pernigoni, Science 2021). The microbiota can be considered a novel mechanism of resistance in prostate cancer. This core unit is now investigating other crucial aspects of microbiota in prostate cancer, finding treatments that can shift its composition towards a "favourable" one.
SenoTarg (project conducted in collaboration with EPFL, EOC and Cardiocentro Ticino)
SenoITarg is an interdisciplinary project aimed at elucidating the role of senescent cells in different biological contexts of critical clinical relevance, including aging, cancer, acute and chronic tissue injury following pathological or iatrogenic insults.
The study will lead to the identification of novel elements of cellular senescence and potentially discover innovative pharmacological therapies to modulate this biological process.
Through an efficient network between four different Swiss laboratories it will be possible to develop new hypotheses, prognostic biomarkers and rational drug selection for future studies.
