Our team is studying the mechanisms that regulate gut stem cell (SC) homeostasis in physiological and pathological conditions. Gut SCs physiology depends on a complex interplay between the various cell types that constitute the stem cell niche and that interact via complementary signalling pathways including Wnt, Notch and BMP. A set of recent evidences has unquestionably demonstrated that the alteration of this crosstalk contributes to the neoplastic transformation of the intestinal SC and promotes tumor initiation.
Within this context, we are actively studying the cellular and molecular processes of gut SC transformation with the aim to develop novel therapeutic strategies.
Context
Colorectal cancer (CRC) is one of the most common cancers in the world and the current therapeutic strategy includes surgical ablation and chemotherapy. However, the cancer reappears in 30-50% of cases. The peculiarity of the intestinal epithelium is its continuous renewal fuelled by multipotent stem cells (SC) located in the crypts, generating all differentiated cell types. Recent studies have highlighted that the crypt SC are the cells responsible for CRC. It is, in fact, proposed that their neoplastic transformation may be the cause of cancer stem cells (CSCs), known to support tumour growth, metastatic spread and responsible for drug resistance. In agreement with this hypothesis, a molecular signature of SCs is predictive of a high risk of recurrence in patients. Understand the mechanisms that control SC homeostasis and determine how their impairment contributes to the neoplastic transformation of these cells is needed to develop efficient diagnostic and therapeutic tools.
In this context, we are developing several complementary research axes. Indeed, our team showed the involvement of thyroid hormones through the TRa1 nuclear receptor in regulating the homeostasis of the intestinal epithelium precursor cells in physiological and pathological conditions. These results opened new perspectives in the study of this extrinsic signal in the physiopathology of the crypt SCs. In another research axis, we defined the activity of the CXCL12 chemokine and its receptors CXCR4 and CXCR7 in CRCs and metastatic dissemination.
The aim of our current research activities is to better understand the regulatory networks governing the homeostasis of CS and their contribution to neoplastic transformation. The project also takes into account functional interactions between the intrinsic factors of intestinal pathophysiology and external signals such as hormones and chemokines.