Tumor Microenvironment

Principal Investigator

Staff

Research topic

Semaphorins and Plexins: new targets to “normalize” the tumor microenvironment ecosystems and to halt tumor progression and metastasis formation.

Background

The tumor microenvironment (TME) is essential to dynamically regulate cancer progression and, due to its influence to the therapeutic outcome, multiple therapies directed to diverse TME components have been developed in these last years. For instance, immunotherapy that targets different immune cells, by unleashing their anti-tumor properties, has shown encouraging results in different tumor types. It is also well described that tumor vessel “normalization” represents a remarkably advantageous anti-cancer strategy, reducing tumor hypoxia and being able to favor chemotherapy delivery. Recently it has been shown that combination of compounds that normalize tumor vessels and reprogram cancer-associated fibroblasts (CAFs) with immunotherapeutic drugs enhances their anti-cancer effects. On these bases is critical to identify new normalizing molecules and therapeutic strategies to target simultaneously different TME cell types to efficiently overcome the resistance to the therapies. In these years, several studies have showed that class3 semaphorins (Sema3s) – that act via receptor complexes binding neuropilins 1 and 2 (Nrp1/2) and transducing the signal by plexins (Plxns) – represent new targets to regulate the TME and cancer growth.

Research achievements

We have uncovered Sema3A as a new vessel normalizing and anti-metastatic agent in mouse models of spontaneous pancreatic neuroendocrine tumors (RIP-Tag2) of cervical carcinomas (HPV16/E2), and of pancreatic adenocarcinoma (PDAC). Interestingly the re-expression of Sema3A counteracted the resistance to the anti-angiogenic therapies by “normalizing” the tumor vasculature, inhibiting hypoxia and several hypoxia-induced pro-metastatic signaling pathways in pancreatic and cervical cancer models. In collaboration with the Laboratories of Cell Adhesion Dynamics of our Institute, we generated mutant Sema3A protein (Mut-Sema3A) that, binding with high affinity with PlexinA4, efficiently impaired PDAC progression and enhanced the anti-tumor efficacy of chemotherapy. We have previously shown that Sema4A exerted a pro-angiogenic effect enhancing the expression of VEGF-A in macrophages. Our current findings indicated that inhibition of Sema4A-expressing myeloid cells, blocked tumor progression and distal metastases, promoted vessel normalization and reprogrammed the immune cells in PDAC models. Moreover, we showed that genetic and pharmacological PlexnB1 depletion in the TME, by acting on T-cells, hampered tumor growth, metastatic spreading in triple-negative breast cancer (TNBC) models and enhanced the efficacy of anti-PD1 immunotherapy in triple-negative breast cancer (TNBC) models. Together, these observations demonstrated that Semas and Plexins represent suitable targets for new therapies that act on TME able to block more efficiently tumor progression.

Conclusions and perspectives

Our findings provide evidence that Sema3A/PlexA4 and Sema4A/PlexnB1 signaling axes regulates the function of several TME cell subtypes (e.g., vessels, CAFs and immune cells) and that represents new targets to impair tumor growth and metastasis spreading in different tumor types. Based on these findings the main focus of the laboratory are the following: i) investigation of the molecular mechanisms by which Sema3A and Sema4A modulate the TME cell populations in PDAC and TNBC, by using Single cells RNAseq, Spatial Transcriptomics and Proteomics analysis; ii) identification of the role of different Sema3s and Plexins in modulating the cross-talk among tumor vessels, immune cells, CAFs and nerves both in mouse and human PDAC and TNBC; (iii) evaluation of new therapeutic “immune” combinatorial strategies by targeting Sema3A/PlexinA4 and Sema4A/PlexinB1 signaling axes to enhance the anti-tumor effects of immune check point inhibitors in several mouse models of PDAC and breast cancers; iv) identification of Semas and Plexins as novel targets and predictive biomarkers for immunotherapy in PDAC and TNBC patients.  

Publications

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