Stem Cells and Cancer Lab
DNA mutations are layered onto existing transcriptional programs of the cell that acquires those alterations. The importance of the pre-existing cellular lineage programs is highlighted by the fact that certain DNA mutations are tumorigenic only in particular cellular contexts, a phenomenon called oncogenic competence. Thanks to the human pluripotent stem cell (hPSC)-based technologies, we can study how oncogenic competence changes at different maturation states along a specific cellular lineage.
In melanoma, we have shown that human progenitor cells are more “competent” to acquire a malignant state compared to mature melanocytes. However, competence can be acquired, and mature melanocytes give rise to melanoma upon expression of ATAD2, an epigenetic factor expressed in human progenitor cells and frequently amplified and overexpressed in melanoma patients.
Both lineage programs (cell fate) and maturation programs (cell state) regulate oncogenic competence. Those are not only cell-intrinsic processes, as they are also extensively regulated by the cell-extrinsic factors from the microenvironment. Thanks to the hPSC-derived organoid technologies and mouse models, we study how oncogenic competence is regulated at the cell-intrinsic level and depending on the microenvironment.
Why are only some cells ‘competent’ to form cancer? The Stem Cells and Cancer group studies melanoma and how oncogenic competence is acquired, maintained, and influenced by the microenvironment. The group takes an integrative approach using cutting-edge human pluripotent stem cell (hPSC)-based technologies, cellular engineering, organoid models, and mouse biology to study the mechanisms of oncogenic competence during melanoma initiation and progression.
Epigenetic regulation of embryonic development, tumor initiation and drug resistance
Cellular lineage plays a crucial role in determining the transcriptional response to oncogenic mutations. However, the mechanisms linking developmental lineage programs to oncogenic competence remain poorly understood. We have previously developed a human pluripotent stem cell (hPSC)-based cancer model and showed that the transforming ability of BRAFV600E depends upon the intrinsic transcriptional programs present in the cell of origin.
Molecular profiling revealed that the progenitor cells of melanocytes, both neural crest cells and melanoblasts, have a distinct expression of chromatin-modifying enzymes, and we showed that the chromatin factor ATAD2 is required for response to BRAFV600E and tumor initiation. Our lab is now dissecting the ATAD2-mediated mechanisms of malignant transformation and the role of other developmental epigenetic factors in tumor formation and progression.
Melanoma brain metastasis
Melanoma is the most aggressive skin cancer because of its high metastatic potential. Brain metastases are observed in 10-40% of melanoma patients, and this number increases up to more 90% in post mortem brains, suggesting that melanoma patients frequently develop brain metastases during the progression of the disease.
Increasing evidence suggests that the brain microenvironment plays an important role in the pathogenesis of brain metastasis. Our lab is investigating the role of the microenvironment on the metastatic growth and, in turn, the neurological impact of the tumor.
The tumor microenvironment of the primary melanoma is composed of keratinocytes, adipocytes, fibroblasts, immune cells, blood vessels and nerves. Nowadays, it is well known that each cellular compartment of the tumor microenvironment reacts to the cancer cells, and it either acquires a pro- or anti-tumorigenic state. Tumor-associated macrophages are known, for instance, to play an opposite role depending on the microenvironment. Peripheral nerves have also recently caught a lot of attention for their role in tumor growth. Cancer cells secrete molecular cues to guide peripheral nerve infiltration. In turn, nerves promote tumor growth and metastasis in various types of cancer, including melanoma. Finally, cancer cells also infiltrate nerves, a process called perineural invasion. Our lab is interested in understanding the role of the peripheral nervous system in melanoma.